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Lamezia 3 luglio 2013
u I REM behavioural
disorders
u Biancamaria Guarnieriu Centro di Medicina del Sonno
u Riconosciuto AIMS
u Casa di Cura accreditata ldquoVilla Serenardquo Cittagrave S
Angelo Pescara
I vari disturbi
comportamentali in sonno
REM
u Disturbo del comportamento in sonno
REM ( RBD)
u Disturbo da incubi
u Paralisi ipnagogiche
u helliphelliphelliphelliphelliphellip
uldquoRBD is one of the more
intriguing clinical curiosities
in medicine and certainly in
sleep medicine and
neurologyrdquo
RBD come contributo del sonno
nellrsquoesplorazione del funzionamento
cerebrale
u Verso la possibile rilevazione di precoci markers di neurodegenerazione
Descrizioni fondamentali
Schenk C Manhowald M
ldquo REM sleep beahvior disorder clinical
developmental and neuroscience
perspective 16 years after its formal
identification in SLEEPrdquo Sleep 2002
Schenk C
rdquo Paradox lost-Midnight in the battleground
of sleep and dreamsviolent moving
nightmares REM sleep behavior
disorderrdquo Extreme nights LLC 2005
REM SLEEP BEHAVIOR DISORDER (RBD)
u Parasonnia formalmente identificata nel 1986 da Schenck e
Mahowald
u Comportamenti motori vigorosi e spesso violenti di solito
associati a sogni spiacevoli e vividi (ldquo dream enacting behaviorsrdquo)
u PSG perdita intermittente o completa dellrsquoatonia muscolare del
milo-ioideo e o un incremento dellrsquoattivitagrave muscolare fasica ( milo
ioideo e muscoli degli arti) durante sonno R senza evidente
attivazione vegetativa
u Lrsquoincubo tipico dellrsquoRBD essere attaccati da animali o persone
sconosciute e anche combattere per autodifesa o tentativo di fuggire
International Classification of Sleep Disorders
AASM 2005- criteri diagnostici di RBD definito
u A-Presence of RSWA on PSG
u B- At least one of the following
sleep-related injurious potentially injurious or
disruptive behaviors by history (ie dream enactment
behavior) andor
abnormal REM sleep behavior documented during
polysomnographic monitoring
u Absence of EEG epileptiform activity during REM sleep
unless RBD can be clearly distinguished from any
concurrent REM sleep related seizure disorder
u The sleep disorder is not better explained by another sleep
disorder medical or neurological disorder mental
disorder medication use or substance use disorder
RBD clinicamente probabile
u In assenza di polisonnografia o in chi
non riesce a collaborare o in chi ha
pochissimo o assente sonno REM in
PSG per la diagnosi
u Anamnesi di eventi motorio-
comportamentali tipici
u Risposte congrue a specifici
questionari possibilmente validati
Mayo RBD questionnaire for PD
and cognitive
declined patients
2011
validato su 176
soggetti (normal
MCI AD LBD
PD PDD
98
Sensibilitagrave
74
Specificitagrave
per
RBD
A clinically probable RBD was diagnosed in
patients presenting during sleep about 1 h after
falling asleep rude movements andor
vocalizations as if they were enacting terrifying
nightmares sometimes provoking harm to self or
to their bed partner these episodes do not
necessarily cause the complete awakening of the
subject
Guarnieri B et al 2012
REM senza atonia ( RSWA)
u RSWA is a requisite diagnostic
feature of RBD but may also be
seen in patients without clinical
symptoms or signs of dream
enactment as an incidental finding in
neurologically normal individuals
especially in patients receiving
antidepressant therapy
u RSWA non vuol dire RBD
RBDdecorso clinico
cronico
RBD
alcohol (sospensione)
meprobamate (sospensione)
TCA I-MAO SSRI
cioccolata (intoxication)
RBD inserito nel deliriumhelliphellip
idiopatico
sintomatico(neurological diseases
mostly α-synucleinopathies)
acuto
RBD e malattie neurodegenerative
α-synucleiopathies(Boeve et al 2001)
Sporadically reported in
tauopathies
(overlap LBD)
bull Parkinsonrsquos disease (PD) ++
bull Lewy Body Dementia (LBD) +++
bull Multiple System Atrophy (MSA) +++
bull Progressive Supranuclear Palsy (PSP)
bull Cortico-Basal degeneration (CBD)
bull Alzheimerrsquos disease
RBD = Positive predicting value for α-synucleinopathies gt 90
Mayo
Clinic
Neurol Sci 2012 Apr33(2)371-3
REM sleep behavior disorder in a patient
with frontotemporal dementia
Lo Coco D Cupidi C Mattaliano A Baiamonte V Realmuto S
Cannizzaro E
RBD idiopatico
u Non associato ad altre diagnosi neurologiche
u Prevalenza stimata con interviste
telefoniche ( soggetti 15-100 anni) 05 (Ohayon 1997)
u Con PSG in pz con etagrave avanzata spesso declino cognitivo che
si rivolgono a Centro del sonno 002 bias di selezione
u Prevalenza maschile (MF 91) in PD 72
In LBD72 In MSA 64
u Etagrave drsquoesordio maggiore di 50 anni
u Evoluzione verso malattie
neurodegenerative nel 65 dei casi
38 of 29 iRBD pts developed parkinsonism andor
dementia after 12 yrs from onset (and 65 after 21 yrs
from RBD onset) (Schenk 1996 and 2005)
45 developed PD MSA DLB MCI after a mean of 115
years from the RBD onset (Iranzo at al 2006)
Esiste realmente lrsquoRBD idiopatico
RBD idiopatico al follow up
Iranzo 2013 The Lancet Neurology
u idiopathic RBD represents the
prodromal phase of a Lewy body
disorder and with sufficient
follow-up most cases would
eventually be diagnosed with a
clinical defined Lewy body
disorder such as Parkinsons
disease (PD) or dementia with
Lewy bodies (DLB)
u Patients from an IRBD cohort recruited
between 1991 and 2003 and previously
assessed in 2005 were followed up
during an additional period of 7 years
u Of the 44 participants from the original
cohort 36 (82) by the 2012 assessment
16 patients were diagnosed with PD
u 14 with DLB
u 1 with multiple system atrophy
u 5 with mild cognitive impairment
Iranzo 2013
Follow-up of idiopathic RBD patients
Predicting value of PLMS
u In the study of Schenck et al 1996 the only variable that
differentiated iRBD that eventually developed PD (38)
from those remaining idiopathic was the PLMS index at
the time of RBD diagnosis (852 vs 359)
u In a serie of 100 patients with RBD diagnosed at the Sleep
Disorders Center of San Raffaele H the PLMS index was
significantly higher in the symptomatic RBD compared to
the idiopathic ones (86 vs 58 with a PLMS indexgt10) (Zucconi et al 2003)
Risk 5-year 177 10-year 406 12-year 524
( 14PD i 1MSA 11 dementia- 7LBD 4 AD )
Cohort of
93 IRBD (
PSG) pts
Neurology 2009
u Ann Neurol 2012 Jan71(1)49-56 doi
101002ana22655
u Probable rapid eye movement sleep behavior
disorder increases risk for mild cognitive
impairment and Parkinson disease a
population-based studyu Boot BP Boeve BF et al
u Cognitively normal subjects aged 70 to 89
years in a population-based study of aging who screened
positive for probable RBD using the Mayo Sleep
Questionnaire were followed at 15-month intervals
u INTERPRETATION
u In this population-based cohort study RBD confers a
22-fold increased risk of developing MCIPD over 4
years
Neurology 2007
3 YEARS
Follow-up
Mov Dis 2012 (early view)
u Lancet Neurol 2013 May12(5)417-9
u REM sleep behaviour disorder a markerof synucleinopathy
u Mahowald MW Schenck CH
u Lancet Neurol 2013 May 12 (5) 469-82
u Idiopathic RBD in the development of PD
u Boeve BF
u Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder anobservational cohort study
Inclusion of RBD improves the diagnostic
classification of dementia with Lewy
bodiesTJ Ferman PhD BF Boeve MD et al
u cohort of 234 autopsy-confirmed dementia
patients followed longitudinally
u a history of definite or probable RBD was
present in 76 of 98 autopsy-confirmed DLB
indicating it is a frequent feature of DLB
u A history of RBD improves clinical diagnostic
accuracy and increases the odds of autopsy-
confirmed DLB by 6-fold9u Neurology 201177875ndash88
RBD ndashdemenza a corpi di Lewy
u the presence of RBD may reflect a distinct subtype of DLB suggestive of a bottom-up disease progression
u while DLB without RBD has additional features suggestive of a top-down progression
u Does RBD define clinicopathologic subtypes of DLB with distinct patterns of disease progression and treatment response It could help the development of biomarkers that may assist in differential diagnosis early detection and prognosis of DLBhelliphelliphelliphelliphellip
RBD e allucinazioni
u Iniziali report hanno esaltato
lrsquoassociazione tra rbd e allucinazioni
visive (Pacchetti Sinforiani Onofrij)
u Alcuni le hanno considerate intrusioni
di sonno REMhelliphellip
u Studi piugrave recenti non hanno trovato
chiare associazioni (Postuma hellip)
uLa latenza di conversione da
RBD idiopatico a RBD in
malattia neurodegenerativa
cambia negli anni
u Maggior attenzione e capacitagrave
diagnostica
u Studi non solo retrospettivi
u Studi non piugrave limitati solo o
prevalentemente ai centri del sonno
Idiopathic RBD
Multiple subtle abnormalities
Slowing of waking EEG (Fantini 2003)
Neuropsicological deficits (Ferini-Strambi et al 2003 Vendette M 2000
Fantini et al 2011)
Subtle parkinsonism (motor and gait speed) (Postuma 2006)h
Autonomic impairment (Ferini-Strambi 1996 Lanfranchi 2007 Postuma
2010
Olfactory deficit (Fantini 2006 Postuma 2006)
Color vision impairment (Postuma 2006)
Neuroimaging
abilitagrave visuospaziali logiche non verbali attenzione funzioni esecutive
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
I vari disturbi
comportamentali in sonno
REM
u Disturbo del comportamento in sonno
REM ( RBD)
u Disturbo da incubi
u Paralisi ipnagogiche
u helliphelliphelliphelliphelliphellip
uldquoRBD is one of the more
intriguing clinical curiosities
in medicine and certainly in
sleep medicine and
neurologyrdquo
RBD come contributo del sonno
nellrsquoesplorazione del funzionamento
cerebrale
u Verso la possibile rilevazione di precoci markers di neurodegenerazione
Descrizioni fondamentali
Schenk C Manhowald M
ldquo REM sleep beahvior disorder clinical
developmental and neuroscience
perspective 16 years after its formal
identification in SLEEPrdquo Sleep 2002
Schenk C
rdquo Paradox lost-Midnight in the battleground
of sleep and dreamsviolent moving
nightmares REM sleep behavior
disorderrdquo Extreme nights LLC 2005
REM SLEEP BEHAVIOR DISORDER (RBD)
u Parasonnia formalmente identificata nel 1986 da Schenck e
Mahowald
u Comportamenti motori vigorosi e spesso violenti di solito
associati a sogni spiacevoli e vividi (ldquo dream enacting behaviorsrdquo)
u PSG perdita intermittente o completa dellrsquoatonia muscolare del
milo-ioideo e o un incremento dellrsquoattivitagrave muscolare fasica ( milo
ioideo e muscoli degli arti) durante sonno R senza evidente
attivazione vegetativa
u Lrsquoincubo tipico dellrsquoRBD essere attaccati da animali o persone
sconosciute e anche combattere per autodifesa o tentativo di fuggire
International Classification of Sleep Disorders
AASM 2005- criteri diagnostici di RBD definito
u A-Presence of RSWA on PSG
u B- At least one of the following
sleep-related injurious potentially injurious or
disruptive behaviors by history (ie dream enactment
behavior) andor
abnormal REM sleep behavior documented during
polysomnographic monitoring
u Absence of EEG epileptiform activity during REM sleep
unless RBD can be clearly distinguished from any
concurrent REM sleep related seizure disorder
u The sleep disorder is not better explained by another sleep
disorder medical or neurological disorder mental
disorder medication use or substance use disorder
RBD clinicamente probabile
u In assenza di polisonnografia o in chi
non riesce a collaborare o in chi ha
pochissimo o assente sonno REM in
PSG per la diagnosi
u Anamnesi di eventi motorio-
comportamentali tipici
u Risposte congrue a specifici
questionari possibilmente validati
Mayo RBD questionnaire for PD
and cognitive
declined patients
2011
validato su 176
soggetti (normal
MCI AD LBD
PD PDD
98
Sensibilitagrave
74
Specificitagrave
per
RBD
A clinically probable RBD was diagnosed in
patients presenting during sleep about 1 h after
falling asleep rude movements andor
vocalizations as if they were enacting terrifying
nightmares sometimes provoking harm to self or
to their bed partner these episodes do not
necessarily cause the complete awakening of the
subject
Guarnieri B et al 2012
REM senza atonia ( RSWA)
u RSWA is a requisite diagnostic
feature of RBD but may also be
seen in patients without clinical
symptoms or signs of dream
enactment as an incidental finding in
neurologically normal individuals
especially in patients receiving
antidepressant therapy
u RSWA non vuol dire RBD
RBDdecorso clinico
cronico
RBD
alcohol (sospensione)
meprobamate (sospensione)
TCA I-MAO SSRI
cioccolata (intoxication)
RBD inserito nel deliriumhelliphellip
idiopatico
sintomatico(neurological diseases
mostly α-synucleinopathies)
acuto
RBD e malattie neurodegenerative
α-synucleiopathies(Boeve et al 2001)
Sporadically reported in
tauopathies
(overlap LBD)
bull Parkinsonrsquos disease (PD) ++
bull Lewy Body Dementia (LBD) +++
bull Multiple System Atrophy (MSA) +++
bull Progressive Supranuclear Palsy (PSP)
bull Cortico-Basal degeneration (CBD)
bull Alzheimerrsquos disease
RBD = Positive predicting value for α-synucleinopathies gt 90
Mayo
Clinic
Neurol Sci 2012 Apr33(2)371-3
REM sleep behavior disorder in a patient
with frontotemporal dementia
Lo Coco D Cupidi C Mattaliano A Baiamonte V Realmuto S
Cannizzaro E
RBD idiopatico
u Non associato ad altre diagnosi neurologiche
u Prevalenza stimata con interviste
telefoniche ( soggetti 15-100 anni) 05 (Ohayon 1997)
u Con PSG in pz con etagrave avanzata spesso declino cognitivo che
si rivolgono a Centro del sonno 002 bias di selezione
u Prevalenza maschile (MF 91) in PD 72
In LBD72 In MSA 64
u Etagrave drsquoesordio maggiore di 50 anni
u Evoluzione verso malattie
neurodegenerative nel 65 dei casi
38 of 29 iRBD pts developed parkinsonism andor
dementia after 12 yrs from onset (and 65 after 21 yrs
from RBD onset) (Schenk 1996 and 2005)
45 developed PD MSA DLB MCI after a mean of 115
years from the RBD onset (Iranzo at al 2006)
Esiste realmente lrsquoRBD idiopatico
RBD idiopatico al follow up
Iranzo 2013 The Lancet Neurology
u idiopathic RBD represents the
prodromal phase of a Lewy body
disorder and with sufficient
follow-up most cases would
eventually be diagnosed with a
clinical defined Lewy body
disorder such as Parkinsons
disease (PD) or dementia with
Lewy bodies (DLB)
u Patients from an IRBD cohort recruited
between 1991 and 2003 and previously
assessed in 2005 were followed up
during an additional period of 7 years
u Of the 44 participants from the original
cohort 36 (82) by the 2012 assessment
16 patients were diagnosed with PD
u 14 with DLB
u 1 with multiple system atrophy
u 5 with mild cognitive impairment
Iranzo 2013
Follow-up of idiopathic RBD patients
Predicting value of PLMS
u In the study of Schenck et al 1996 the only variable that
differentiated iRBD that eventually developed PD (38)
from those remaining idiopathic was the PLMS index at
the time of RBD diagnosis (852 vs 359)
u In a serie of 100 patients with RBD diagnosed at the Sleep
Disorders Center of San Raffaele H the PLMS index was
significantly higher in the symptomatic RBD compared to
the idiopathic ones (86 vs 58 with a PLMS indexgt10) (Zucconi et al 2003)
Risk 5-year 177 10-year 406 12-year 524
( 14PD i 1MSA 11 dementia- 7LBD 4 AD )
Cohort of
93 IRBD (
PSG) pts
Neurology 2009
u Ann Neurol 2012 Jan71(1)49-56 doi
101002ana22655
u Probable rapid eye movement sleep behavior
disorder increases risk for mild cognitive
impairment and Parkinson disease a
population-based studyu Boot BP Boeve BF et al
u Cognitively normal subjects aged 70 to 89
years in a population-based study of aging who screened
positive for probable RBD using the Mayo Sleep
Questionnaire were followed at 15-month intervals
u INTERPRETATION
u In this population-based cohort study RBD confers a
22-fold increased risk of developing MCIPD over 4
years
Neurology 2007
3 YEARS
Follow-up
Mov Dis 2012 (early view)
u Lancet Neurol 2013 May12(5)417-9
u REM sleep behaviour disorder a markerof synucleinopathy
u Mahowald MW Schenck CH
u Lancet Neurol 2013 May 12 (5) 469-82
u Idiopathic RBD in the development of PD
u Boeve BF
u Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder anobservational cohort study
Inclusion of RBD improves the diagnostic
classification of dementia with Lewy
bodiesTJ Ferman PhD BF Boeve MD et al
u cohort of 234 autopsy-confirmed dementia
patients followed longitudinally
u a history of definite or probable RBD was
present in 76 of 98 autopsy-confirmed DLB
indicating it is a frequent feature of DLB
u A history of RBD improves clinical diagnostic
accuracy and increases the odds of autopsy-
confirmed DLB by 6-fold9u Neurology 201177875ndash88
RBD ndashdemenza a corpi di Lewy
u the presence of RBD may reflect a distinct subtype of DLB suggestive of a bottom-up disease progression
u while DLB without RBD has additional features suggestive of a top-down progression
u Does RBD define clinicopathologic subtypes of DLB with distinct patterns of disease progression and treatment response It could help the development of biomarkers that may assist in differential diagnosis early detection and prognosis of DLBhelliphelliphelliphelliphellip
RBD e allucinazioni
u Iniziali report hanno esaltato
lrsquoassociazione tra rbd e allucinazioni
visive (Pacchetti Sinforiani Onofrij)
u Alcuni le hanno considerate intrusioni
di sonno REMhelliphellip
u Studi piugrave recenti non hanno trovato
chiare associazioni (Postuma hellip)
uLa latenza di conversione da
RBD idiopatico a RBD in
malattia neurodegenerativa
cambia negli anni
u Maggior attenzione e capacitagrave
diagnostica
u Studi non solo retrospettivi
u Studi non piugrave limitati solo o
prevalentemente ai centri del sonno
Idiopathic RBD
Multiple subtle abnormalities
Slowing of waking EEG (Fantini 2003)
Neuropsicological deficits (Ferini-Strambi et al 2003 Vendette M 2000
Fantini et al 2011)
Subtle parkinsonism (motor and gait speed) (Postuma 2006)h
Autonomic impairment (Ferini-Strambi 1996 Lanfranchi 2007 Postuma
2010
Olfactory deficit (Fantini 2006 Postuma 2006)
Color vision impairment (Postuma 2006)
Neuroimaging
abilitagrave visuospaziali logiche non verbali attenzione funzioni esecutive
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
uldquoRBD is one of the more
intriguing clinical curiosities
in medicine and certainly in
sleep medicine and
neurologyrdquo
RBD come contributo del sonno
nellrsquoesplorazione del funzionamento
cerebrale
u Verso la possibile rilevazione di precoci markers di neurodegenerazione
Descrizioni fondamentali
Schenk C Manhowald M
ldquo REM sleep beahvior disorder clinical
developmental and neuroscience
perspective 16 years after its formal
identification in SLEEPrdquo Sleep 2002
Schenk C
rdquo Paradox lost-Midnight in the battleground
of sleep and dreamsviolent moving
nightmares REM sleep behavior
disorderrdquo Extreme nights LLC 2005
REM SLEEP BEHAVIOR DISORDER (RBD)
u Parasonnia formalmente identificata nel 1986 da Schenck e
Mahowald
u Comportamenti motori vigorosi e spesso violenti di solito
associati a sogni spiacevoli e vividi (ldquo dream enacting behaviorsrdquo)
u PSG perdita intermittente o completa dellrsquoatonia muscolare del
milo-ioideo e o un incremento dellrsquoattivitagrave muscolare fasica ( milo
ioideo e muscoli degli arti) durante sonno R senza evidente
attivazione vegetativa
u Lrsquoincubo tipico dellrsquoRBD essere attaccati da animali o persone
sconosciute e anche combattere per autodifesa o tentativo di fuggire
International Classification of Sleep Disorders
AASM 2005- criteri diagnostici di RBD definito
u A-Presence of RSWA on PSG
u B- At least one of the following
sleep-related injurious potentially injurious or
disruptive behaviors by history (ie dream enactment
behavior) andor
abnormal REM sleep behavior documented during
polysomnographic monitoring
u Absence of EEG epileptiform activity during REM sleep
unless RBD can be clearly distinguished from any
concurrent REM sleep related seizure disorder
u The sleep disorder is not better explained by another sleep
disorder medical or neurological disorder mental
disorder medication use or substance use disorder
RBD clinicamente probabile
u In assenza di polisonnografia o in chi
non riesce a collaborare o in chi ha
pochissimo o assente sonno REM in
PSG per la diagnosi
u Anamnesi di eventi motorio-
comportamentali tipici
u Risposte congrue a specifici
questionari possibilmente validati
Mayo RBD questionnaire for PD
and cognitive
declined patients
2011
validato su 176
soggetti (normal
MCI AD LBD
PD PDD
98
Sensibilitagrave
74
Specificitagrave
per
RBD
A clinically probable RBD was diagnosed in
patients presenting during sleep about 1 h after
falling asleep rude movements andor
vocalizations as if they were enacting terrifying
nightmares sometimes provoking harm to self or
to their bed partner these episodes do not
necessarily cause the complete awakening of the
subject
Guarnieri B et al 2012
REM senza atonia ( RSWA)
u RSWA is a requisite diagnostic
feature of RBD but may also be
seen in patients without clinical
symptoms or signs of dream
enactment as an incidental finding in
neurologically normal individuals
especially in patients receiving
antidepressant therapy
u RSWA non vuol dire RBD
RBDdecorso clinico
cronico
RBD
alcohol (sospensione)
meprobamate (sospensione)
TCA I-MAO SSRI
cioccolata (intoxication)
RBD inserito nel deliriumhelliphellip
idiopatico
sintomatico(neurological diseases
mostly α-synucleinopathies)
acuto
RBD e malattie neurodegenerative
α-synucleiopathies(Boeve et al 2001)
Sporadically reported in
tauopathies
(overlap LBD)
bull Parkinsonrsquos disease (PD) ++
bull Lewy Body Dementia (LBD) +++
bull Multiple System Atrophy (MSA) +++
bull Progressive Supranuclear Palsy (PSP)
bull Cortico-Basal degeneration (CBD)
bull Alzheimerrsquos disease
RBD = Positive predicting value for α-synucleinopathies gt 90
Mayo
Clinic
Neurol Sci 2012 Apr33(2)371-3
REM sleep behavior disorder in a patient
with frontotemporal dementia
Lo Coco D Cupidi C Mattaliano A Baiamonte V Realmuto S
Cannizzaro E
RBD idiopatico
u Non associato ad altre diagnosi neurologiche
u Prevalenza stimata con interviste
telefoniche ( soggetti 15-100 anni) 05 (Ohayon 1997)
u Con PSG in pz con etagrave avanzata spesso declino cognitivo che
si rivolgono a Centro del sonno 002 bias di selezione
u Prevalenza maschile (MF 91) in PD 72
In LBD72 In MSA 64
u Etagrave drsquoesordio maggiore di 50 anni
u Evoluzione verso malattie
neurodegenerative nel 65 dei casi
38 of 29 iRBD pts developed parkinsonism andor
dementia after 12 yrs from onset (and 65 after 21 yrs
from RBD onset) (Schenk 1996 and 2005)
45 developed PD MSA DLB MCI after a mean of 115
years from the RBD onset (Iranzo at al 2006)
Esiste realmente lrsquoRBD idiopatico
RBD idiopatico al follow up
Iranzo 2013 The Lancet Neurology
u idiopathic RBD represents the
prodromal phase of a Lewy body
disorder and with sufficient
follow-up most cases would
eventually be diagnosed with a
clinical defined Lewy body
disorder such as Parkinsons
disease (PD) or dementia with
Lewy bodies (DLB)
u Patients from an IRBD cohort recruited
between 1991 and 2003 and previously
assessed in 2005 were followed up
during an additional period of 7 years
u Of the 44 participants from the original
cohort 36 (82) by the 2012 assessment
16 patients were diagnosed with PD
u 14 with DLB
u 1 with multiple system atrophy
u 5 with mild cognitive impairment
Iranzo 2013
Follow-up of idiopathic RBD patients
Predicting value of PLMS
u In the study of Schenck et al 1996 the only variable that
differentiated iRBD that eventually developed PD (38)
from those remaining idiopathic was the PLMS index at
the time of RBD diagnosis (852 vs 359)
u In a serie of 100 patients with RBD diagnosed at the Sleep
Disorders Center of San Raffaele H the PLMS index was
significantly higher in the symptomatic RBD compared to
the idiopathic ones (86 vs 58 with a PLMS indexgt10) (Zucconi et al 2003)
Risk 5-year 177 10-year 406 12-year 524
( 14PD i 1MSA 11 dementia- 7LBD 4 AD )
Cohort of
93 IRBD (
PSG) pts
Neurology 2009
u Ann Neurol 2012 Jan71(1)49-56 doi
101002ana22655
u Probable rapid eye movement sleep behavior
disorder increases risk for mild cognitive
impairment and Parkinson disease a
population-based studyu Boot BP Boeve BF et al
u Cognitively normal subjects aged 70 to 89
years in a population-based study of aging who screened
positive for probable RBD using the Mayo Sleep
Questionnaire were followed at 15-month intervals
u INTERPRETATION
u In this population-based cohort study RBD confers a
22-fold increased risk of developing MCIPD over 4
years
Neurology 2007
3 YEARS
Follow-up
Mov Dis 2012 (early view)
u Lancet Neurol 2013 May12(5)417-9
u REM sleep behaviour disorder a markerof synucleinopathy
u Mahowald MW Schenck CH
u Lancet Neurol 2013 May 12 (5) 469-82
u Idiopathic RBD in the development of PD
u Boeve BF
u Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder anobservational cohort study
Inclusion of RBD improves the diagnostic
classification of dementia with Lewy
bodiesTJ Ferman PhD BF Boeve MD et al
u cohort of 234 autopsy-confirmed dementia
patients followed longitudinally
u a history of definite or probable RBD was
present in 76 of 98 autopsy-confirmed DLB
indicating it is a frequent feature of DLB
u A history of RBD improves clinical diagnostic
accuracy and increases the odds of autopsy-
confirmed DLB by 6-fold9u Neurology 201177875ndash88
RBD ndashdemenza a corpi di Lewy
u the presence of RBD may reflect a distinct subtype of DLB suggestive of a bottom-up disease progression
u while DLB without RBD has additional features suggestive of a top-down progression
u Does RBD define clinicopathologic subtypes of DLB with distinct patterns of disease progression and treatment response It could help the development of biomarkers that may assist in differential diagnosis early detection and prognosis of DLBhelliphelliphelliphelliphellip
RBD e allucinazioni
u Iniziali report hanno esaltato
lrsquoassociazione tra rbd e allucinazioni
visive (Pacchetti Sinforiani Onofrij)
u Alcuni le hanno considerate intrusioni
di sonno REMhelliphellip
u Studi piugrave recenti non hanno trovato
chiare associazioni (Postuma hellip)
uLa latenza di conversione da
RBD idiopatico a RBD in
malattia neurodegenerativa
cambia negli anni
u Maggior attenzione e capacitagrave
diagnostica
u Studi non solo retrospettivi
u Studi non piugrave limitati solo o
prevalentemente ai centri del sonno
Idiopathic RBD
Multiple subtle abnormalities
Slowing of waking EEG (Fantini 2003)
Neuropsicological deficits (Ferini-Strambi et al 2003 Vendette M 2000
Fantini et al 2011)
Subtle parkinsonism (motor and gait speed) (Postuma 2006)h
Autonomic impairment (Ferini-Strambi 1996 Lanfranchi 2007 Postuma
2010
Olfactory deficit (Fantini 2006 Postuma 2006)
Color vision impairment (Postuma 2006)
Neuroimaging
abilitagrave visuospaziali logiche non verbali attenzione funzioni esecutive
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
RBD come contributo del sonno
nellrsquoesplorazione del funzionamento
cerebrale
u Verso la possibile rilevazione di precoci markers di neurodegenerazione
Descrizioni fondamentali
Schenk C Manhowald M
ldquo REM sleep beahvior disorder clinical
developmental and neuroscience
perspective 16 years after its formal
identification in SLEEPrdquo Sleep 2002
Schenk C
rdquo Paradox lost-Midnight in the battleground
of sleep and dreamsviolent moving
nightmares REM sleep behavior
disorderrdquo Extreme nights LLC 2005
REM SLEEP BEHAVIOR DISORDER (RBD)
u Parasonnia formalmente identificata nel 1986 da Schenck e
Mahowald
u Comportamenti motori vigorosi e spesso violenti di solito
associati a sogni spiacevoli e vividi (ldquo dream enacting behaviorsrdquo)
u PSG perdita intermittente o completa dellrsquoatonia muscolare del
milo-ioideo e o un incremento dellrsquoattivitagrave muscolare fasica ( milo
ioideo e muscoli degli arti) durante sonno R senza evidente
attivazione vegetativa
u Lrsquoincubo tipico dellrsquoRBD essere attaccati da animali o persone
sconosciute e anche combattere per autodifesa o tentativo di fuggire
International Classification of Sleep Disorders
AASM 2005- criteri diagnostici di RBD definito
u A-Presence of RSWA on PSG
u B- At least one of the following
sleep-related injurious potentially injurious or
disruptive behaviors by history (ie dream enactment
behavior) andor
abnormal REM sleep behavior documented during
polysomnographic monitoring
u Absence of EEG epileptiform activity during REM sleep
unless RBD can be clearly distinguished from any
concurrent REM sleep related seizure disorder
u The sleep disorder is not better explained by another sleep
disorder medical or neurological disorder mental
disorder medication use or substance use disorder
RBD clinicamente probabile
u In assenza di polisonnografia o in chi
non riesce a collaborare o in chi ha
pochissimo o assente sonno REM in
PSG per la diagnosi
u Anamnesi di eventi motorio-
comportamentali tipici
u Risposte congrue a specifici
questionari possibilmente validati
Mayo RBD questionnaire for PD
and cognitive
declined patients
2011
validato su 176
soggetti (normal
MCI AD LBD
PD PDD
98
Sensibilitagrave
74
Specificitagrave
per
RBD
A clinically probable RBD was diagnosed in
patients presenting during sleep about 1 h after
falling asleep rude movements andor
vocalizations as if they were enacting terrifying
nightmares sometimes provoking harm to self or
to their bed partner these episodes do not
necessarily cause the complete awakening of the
subject
Guarnieri B et al 2012
REM senza atonia ( RSWA)
u RSWA is a requisite diagnostic
feature of RBD but may also be
seen in patients without clinical
symptoms or signs of dream
enactment as an incidental finding in
neurologically normal individuals
especially in patients receiving
antidepressant therapy
u RSWA non vuol dire RBD
RBDdecorso clinico
cronico
RBD
alcohol (sospensione)
meprobamate (sospensione)
TCA I-MAO SSRI
cioccolata (intoxication)
RBD inserito nel deliriumhelliphellip
idiopatico
sintomatico(neurological diseases
mostly α-synucleinopathies)
acuto
RBD e malattie neurodegenerative
α-synucleiopathies(Boeve et al 2001)
Sporadically reported in
tauopathies
(overlap LBD)
bull Parkinsonrsquos disease (PD) ++
bull Lewy Body Dementia (LBD) +++
bull Multiple System Atrophy (MSA) +++
bull Progressive Supranuclear Palsy (PSP)
bull Cortico-Basal degeneration (CBD)
bull Alzheimerrsquos disease
RBD = Positive predicting value for α-synucleinopathies gt 90
Mayo
Clinic
Neurol Sci 2012 Apr33(2)371-3
REM sleep behavior disorder in a patient
with frontotemporal dementia
Lo Coco D Cupidi C Mattaliano A Baiamonte V Realmuto S
Cannizzaro E
RBD idiopatico
u Non associato ad altre diagnosi neurologiche
u Prevalenza stimata con interviste
telefoniche ( soggetti 15-100 anni) 05 (Ohayon 1997)
u Con PSG in pz con etagrave avanzata spesso declino cognitivo che
si rivolgono a Centro del sonno 002 bias di selezione
u Prevalenza maschile (MF 91) in PD 72
In LBD72 In MSA 64
u Etagrave drsquoesordio maggiore di 50 anni
u Evoluzione verso malattie
neurodegenerative nel 65 dei casi
38 of 29 iRBD pts developed parkinsonism andor
dementia after 12 yrs from onset (and 65 after 21 yrs
from RBD onset) (Schenk 1996 and 2005)
45 developed PD MSA DLB MCI after a mean of 115
years from the RBD onset (Iranzo at al 2006)
Esiste realmente lrsquoRBD idiopatico
RBD idiopatico al follow up
Iranzo 2013 The Lancet Neurology
u idiopathic RBD represents the
prodromal phase of a Lewy body
disorder and with sufficient
follow-up most cases would
eventually be diagnosed with a
clinical defined Lewy body
disorder such as Parkinsons
disease (PD) or dementia with
Lewy bodies (DLB)
u Patients from an IRBD cohort recruited
between 1991 and 2003 and previously
assessed in 2005 were followed up
during an additional period of 7 years
u Of the 44 participants from the original
cohort 36 (82) by the 2012 assessment
16 patients were diagnosed with PD
u 14 with DLB
u 1 with multiple system atrophy
u 5 with mild cognitive impairment
Iranzo 2013
Follow-up of idiopathic RBD patients
Predicting value of PLMS
u In the study of Schenck et al 1996 the only variable that
differentiated iRBD that eventually developed PD (38)
from those remaining idiopathic was the PLMS index at
the time of RBD diagnosis (852 vs 359)
u In a serie of 100 patients with RBD diagnosed at the Sleep
Disorders Center of San Raffaele H the PLMS index was
significantly higher in the symptomatic RBD compared to
the idiopathic ones (86 vs 58 with a PLMS indexgt10) (Zucconi et al 2003)
Risk 5-year 177 10-year 406 12-year 524
( 14PD i 1MSA 11 dementia- 7LBD 4 AD )
Cohort of
93 IRBD (
PSG) pts
Neurology 2009
u Ann Neurol 2012 Jan71(1)49-56 doi
101002ana22655
u Probable rapid eye movement sleep behavior
disorder increases risk for mild cognitive
impairment and Parkinson disease a
population-based studyu Boot BP Boeve BF et al
u Cognitively normal subjects aged 70 to 89
years in a population-based study of aging who screened
positive for probable RBD using the Mayo Sleep
Questionnaire were followed at 15-month intervals
u INTERPRETATION
u In this population-based cohort study RBD confers a
22-fold increased risk of developing MCIPD over 4
years
Neurology 2007
3 YEARS
Follow-up
Mov Dis 2012 (early view)
u Lancet Neurol 2013 May12(5)417-9
u REM sleep behaviour disorder a markerof synucleinopathy
u Mahowald MW Schenck CH
u Lancet Neurol 2013 May 12 (5) 469-82
u Idiopathic RBD in the development of PD
u Boeve BF
u Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder anobservational cohort study
Inclusion of RBD improves the diagnostic
classification of dementia with Lewy
bodiesTJ Ferman PhD BF Boeve MD et al
u cohort of 234 autopsy-confirmed dementia
patients followed longitudinally
u a history of definite or probable RBD was
present in 76 of 98 autopsy-confirmed DLB
indicating it is a frequent feature of DLB
u A history of RBD improves clinical diagnostic
accuracy and increases the odds of autopsy-
confirmed DLB by 6-fold9u Neurology 201177875ndash88
RBD ndashdemenza a corpi di Lewy
u the presence of RBD may reflect a distinct subtype of DLB suggestive of a bottom-up disease progression
u while DLB without RBD has additional features suggestive of a top-down progression
u Does RBD define clinicopathologic subtypes of DLB with distinct patterns of disease progression and treatment response It could help the development of biomarkers that may assist in differential diagnosis early detection and prognosis of DLBhelliphelliphelliphelliphellip
RBD e allucinazioni
u Iniziali report hanno esaltato
lrsquoassociazione tra rbd e allucinazioni
visive (Pacchetti Sinforiani Onofrij)
u Alcuni le hanno considerate intrusioni
di sonno REMhelliphellip
u Studi piugrave recenti non hanno trovato
chiare associazioni (Postuma hellip)
uLa latenza di conversione da
RBD idiopatico a RBD in
malattia neurodegenerativa
cambia negli anni
u Maggior attenzione e capacitagrave
diagnostica
u Studi non solo retrospettivi
u Studi non piugrave limitati solo o
prevalentemente ai centri del sonno
Idiopathic RBD
Multiple subtle abnormalities
Slowing of waking EEG (Fantini 2003)
Neuropsicological deficits (Ferini-Strambi et al 2003 Vendette M 2000
Fantini et al 2011)
Subtle parkinsonism (motor and gait speed) (Postuma 2006)h
Autonomic impairment (Ferini-Strambi 1996 Lanfranchi 2007 Postuma
2010
Olfactory deficit (Fantini 2006 Postuma 2006)
Color vision impairment (Postuma 2006)
Neuroimaging
abilitagrave visuospaziali logiche non verbali attenzione funzioni esecutive
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Descrizioni fondamentali
Schenk C Manhowald M
ldquo REM sleep beahvior disorder clinical
developmental and neuroscience
perspective 16 years after its formal
identification in SLEEPrdquo Sleep 2002
Schenk C
rdquo Paradox lost-Midnight in the battleground
of sleep and dreamsviolent moving
nightmares REM sleep behavior
disorderrdquo Extreme nights LLC 2005
REM SLEEP BEHAVIOR DISORDER (RBD)
u Parasonnia formalmente identificata nel 1986 da Schenck e
Mahowald
u Comportamenti motori vigorosi e spesso violenti di solito
associati a sogni spiacevoli e vividi (ldquo dream enacting behaviorsrdquo)
u PSG perdita intermittente o completa dellrsquoatonia muscolare del
milo-ioideo e o un incremento dellrsquoattivitagrave muscolare fasica ( milo
ioideo e muscoli degli arti) durante sonno R senza evidente
attivazione vegetativa
u Lrsquoincubo tipico dellrsquoRBD essere attaccati da animali o persone
sconosciute e anche combattere per autodifesa o tentativo di fuggire
International Classification of Sleep Disorders
AASM 2005- criteri diagnostici di RBD definito
u A-Presence of RSWA on PSG
u B- At least one of the following
sleep-related injurious potentially injurious or
disruptive behaviors by history (ie dream enactment
behavior) andor
abnormal REM sleep behavior documented during
polysomnographic monitoring
u Absence of EEG epileptiform activity during REM sleep
unless RBD can be clearly distinguished from any
concurrent REM sleep related seizure disorder
u The sleep disorder is not better explained by another sleep
disorder medical or neurological disorder mental
disorder medication use or substance use disorder
RBD clinicamente probabile
u In assenza di polisonnografia o in chi
non riesce a collaborare o in chi ha
pochissimo o assente sonno REM in
PSG per la diagnosi
u Anamnesi di eventi motorio-
comportamentali tipici
u Risposte congrue a specifici
questionari possibilmente validati
Mayo RBD questionnaire for PD
and cognitive
declined patients
2011
validato su 176
soggetti (normal
MCI AD LBD
PD PDD
98
Sensibilitagrave
74
Specificitagrave
per
RBD
A clinically probable RBD was diagnosed in
patients presenting during sleep about 1 h after
falling asleep rude movements andor
vocalizations as if they were enacting terrifying
nightmares sometimes provoking harm to self or
to their bed partner these episodes do not
necessarily cause the complete awakening of the
subject
Guarnieri B et al 2012
REM senza atonia ( RSWA)
u RSWA is a requisite diagnostic
feature of RBD but may also be
seen in patients without clinical
symptoms or signs of dream
enactment as an incidental finding in
neurologically normal individuals
especially in patients receiving
antidepressant therapy
u RSWA non vuol dire RBD
RBDdecorso clinico
cronico
RBD
alcohol (sospensione)
meprobamate (sospensione)
TCA I-MAO SSRI
cioccolata (intoxication)
RBD inserito nel deliriumhelliphellip
idiopatico
sintomatico(neurological diseases
mostly α-synucleinopathies)
acuto
RBD e malattie neurodegenerative
α-synucleiopathies(Boeve et al 2001)
Sporadically reported in
tauopathies
(overlap LBD)
bull Parkinsonrsquos disease (PD) ++
bull Lewy Body Dementia (LBD) +++
bull Multiple System Atrophy (MSA) +++
bull Progressive Supranuclear Palsy (PSP)
bull Cortico-Basal degeneration (CBD)
bull Alzheimerrsquos disease
RBD = Positive predicting value for α-synucleinopathies gt 90
Mayo
Clinic
Neurol Sci 2012 Apr33(2)371-3
REM sleep behavior disorder in a patient
with frontotemporal dementia
Lo Coco D Cupidi C Mattaliano A Baiamonte V Realmuto S
Cannizzaro E
RBD idiopatico
u Non associato ad altre diagnosi neurologiche
u Prevalenza stimata con interviste
telefoniche ( soggetti 15-100 anni) 05 (Ohayon 1997)
u Con PSG in pz con etagrave avanzata spesso declino cognitivo che
si rivolgono a Centro del sonno 002 bias di selezione
u Prevalenza maschile (MF 91) in PD 72
In LBD72 In MSA 64
u Etagrave drsquoesordio maggiore di 50 anni
u Evoluzione verso malattie
neurodegenerative nel 65 dei casi
38 of 29 iRBD pts developed parkinsonism andor
dementia after 12 yrs from onset (and 65 after 21 yrs
from RBD onset) (Schenk 1996 and 2005)
45 developed PD MSA DLB MCI after a mean of 115
years from the RBD onset (Iranzo at al 2006)
Esiste realmente lrsquoRBD idiopatico
RBD idiopatico al follow up
Iranzo 2013 The Lancet Neurology
u idiopathic RBD represents the
prodromal phase of a Lewy body
disorder and with sufficient
follow-up most cases would
eventually be diagnosed with a
clinical defined Lewy body
disorder such as Parkinsons
disease (PD) or dementia with
Lewy bodies (DLB)
u Patients from an IRBD cohort recruited
between 1991 and 2003 and previously
assessed in 2005 were followed up
during an additional period of 7 years
u Of the 44 participants from the original
cohort 36 (82) by the 2012 assessment
16 patients were diagnosed with PD
u 14 with DLB
u 1 with multiple system atrophy
u 5 with mild cognitive impairment
Iranzo 2013
Follow-up of idiopathic RBD patients
Predicting value of PLMS
u In the study of Schenck et al 1996 the only variable that
differentiated iRBD that eventually developed PD (38)
from those remaining idiopathic was the PLMS index at
the time of RBD diagnosis (852 vs 359)
u In a serie of 100 patients with RBD diagnosed at the Sleep
Disorders Center of San Raffaele H the PLMS index was
significantly higher in the symptomatic RBD compared to
the idiopathic ones (86 vs 58 with a PLMS indexgt10) (Zucconi et al 2003)
Risk 5-year 177 10-year 406 12-year 524
( 14PD i 1MSA 11 dementia- 7LBD 4 AD )
Cohort of
93 IRBD (
PSG) pts
Neurology 2009
u Ann Neurol 2012 Jan71(1)49-56 doi
101002ana22655
u Probable rapid eye movement sleep behavior
disorder increases risk for mild cognitive
impairment and Parkinson disease a
population-based studyu Boot BP Boeve BF et al
u Cognitively normal subjects aged 70 to 89
years in a population-based study of aging who screened
positive for probable RBD using the Mayo Sleep
Questionnaire were followed at 15-month intervals
u INTERPRETATION
u In this population-based cohort study RBD confers a
22-fold increased risk of developing MCIPD over 4
years
Neurology 2007
3 YEARS
Follow-up
Mov Dis 2012 (early view)
u Lancet Neurol 2013 May12(5)417-9
u REM sleep behaviour disorder a markerof synucleinopathy
u Mahowald MW Schenck CH
u Lancet Neurol 2013 May 12 (5) 469-82
u Idiopathic RBD in the development of PD
u Boeve BF
u Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder anobservational cohort study
Inclusion of RBD improves the diagnostic
classification of dementia with Lewy
bodiesTJ Ferman PhD BF Boeve MD et al
u cohort of 234 autopsy-confirmed dementia
patients followed longitudinally
u a history of definite or probable RBD was
present in 76 of 98 autopsy-confirmed DLB
indicating it is a frequent feature of DLB
u A history of RBD improves clinical diagnostic
accuracy and increases the odds of autopsy-
confirmed DLB by 6-fold9u Neurology 201177875ndash88
RBD ndashdemenza a corpi di Lewy
u the presence of RBD may reflect a distinct subtype of DLB suggestive of a bottom-up disease progression
u while DLB without RBD has additional features suggestive of a top-down progression
u Does RBD define clinicopathologic subtypes of DLB with distinct patterns of disease progression and treatment response It could help the development of biomarkers that may assist in differential diagnosis early detection and prognosis of DLBhelliphelliphelliphelliphellip
RBD e allucinazioni
u Iniziali report hanno esaltato
lrsquoassociazione tra rbd e allucinazioni
visive (Pacchetti Sinforiani Onofrij)
u Alcuni le hanno considerate intrusioni
di sonno REMhelliphellip
u Studi piugrave recenti non hanno trovato
chiare associazioni (Postuma hellip)
uLa latenza di conversione da
RBD idiopatico a RBD in
malattia neurodegenerativa
cambia negli anni
u Maggior attenzione e capacitagrave
diagnostica
u Studi non solo retrospettivi
u Studi non piugrave limitati solo o
prevalentemente ai centri del sonno
Idiopathic RBD
Multiple subtle abnormalities
Slowing of waking EEG (Fantini 2003)
Neuropsicological deficits (Ferini-Strambi et al 2003 Vendette M 2000
Fantini et al 2011)
Subtle parkinsonism (motor and gait speed) (Postuma 2006)h
Autonomic impairment (Ferini-Strambi 1996 Lanfranchi 2007 Postuma
2010
Olfactory deficit (Fantini 2006 Postuma 2006)
Color vision impairment (Postuma 2006)
Neuroimaging
abilitagrave visuospaziali logiche non verbali attenzione funzioni esecutive
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
REM SLEEP BEHAVIOR DISORDER (RBD)
u Parasonnia formalmente identificata nel 1986 da Schenck e
Mahowald
u Comportamenti motori vigorosi e spesso violenti di solito
associati a sogni spiacevoli e vividi (ldquo dream enacting behaviorsrdquo)
u PSG perdita intermittente o completa dellrsquoatonia muscolare del
milo-ioideo e o un incremento dellrsquoattivitagrave muscolare fasica ( milo
ioideo e muscoli degli arti) durante sonno R senza evidente
attivazione vegetativa
u Lrsquoincubo tipico dellrsquoRBD essere attaccati da animali o persone
sconosciute e anche combattere per autodifesa o tentativo di fuggire
International Classification of Sleep Disorders
AASM 2005- criteri diagnostici di RBD definito
u A-Presence of RSWA on PSG
u B- At least one of the following
sleep-related injurious potentially injurious or
disruptive behaviors by history (ie dream enactment
behavior) andor
abnormal REM sleep behavior documented during
polysomnographic monitoring
u Absence of EEG epileptiform activity during REM sleep
unless RBD can be clearly distinguished from any
concurrent REM sleep related seizure disorder
u The sleep disorder is not better explained by another sleep
disorder medical or neurological disorder mental
disorder medication use or substance use disorder
RBD clinicamente probabile
u In assenza di polisonnografia o in chi
non riesce a collaborare o in chi ha
pochissimo o assente sonno REM in
PSG per la diagnosi
u Anamnesi di eventi motorio-
comportamentali tipici
u Risposte congrue a specifici
questionari possibilmente validati
Mayo RBD questionnaire for PD
and cognitive
declined patients
2011
validato su 176
soggetti (normal
MCI AD LBD
PD PDD
98
Sensibilitagrave
74
Specificitagrave
per
RBD
A clinically probable RBD was diagnosed in
patients presenting during sleep about 1 h after
falling asleep rude movements andor
vocalizations as if they were enacting terrifying
nightmares sometimes provoking harm to self or
to their bed partner these episodes do not
necessarily cause the complete awakening of the
subject
Guarnieri B et al 2012
REM senza atonia ( RSWA)
u RSWA is a requisite diagnostic
feature of RBD but may also be
seen in patients without clinical
symptoms or signs of dream
enactment as an incidental finding in
neurologically normal individuals
especially in patients receiving
antidepressant therapy
u RSWA non vuol dire RBD
RBDdecorso clinico
cronico
RBD
alcohol (sospensione)
meprobamate (sospensione)
TCA I-MAO SSRI
cioccolata (intoxication)
RBD inserito nel deliriumhelliphellip
idiopatico
sintomatico(neurological diseases
mostly α-synucleinopathies)
acuto
RBD e malattie neurodegenerative
α-synucleiopathies(Boeve et al 2001)
Sporadically reported in
tauopathies
(overlap LBD)
bull Parkinsonrsquos disease (PD) ++
bull Lewy Body Dementia (LBD) +++
bull Multiple System Atrophy (MSA) +++
bull Progressive Supranuclear Palsy (PSP)
bull Cortico-Basal degeneration (CBD)
bull Alzheimerrsquos disease
RBD = Positive predicting value for α-synucleinopathies gt 90
Mayo
Clinic
Neurol Sci 2012 Apr33(2)371-3
REM sleep behavior disorder in a patient
with frontotemporal dementia
Lo Coco D Cupidi C Mattaliano A Baiamonte V Realmuto S
Cannizzaro E
RBD idiopatico
u Non associato ad altre diagnosi neurologiche
u Prevalenza stimata con interviste
telefoniche ( soggetti 15-100 anni) 05 (Ohayon 1997)
u Con PSG in pz con etagrave avanzata spesso declino cognitivo che
si rivolgono a Centro del sonno 002 bias di selezione
u Prevalenza maschile (MF 91) in PD 72
In LBD72 In MSA 64
u Etagrave drsquoesordio maggiore di 50 anni
u Evoluzione verso malattie
neurodegenerative nel 65 dei casi
38 of 29 iRBD pts developed parkinsonism andor
dementia after 12 yrs from onset (and 65 after 21 yrs
from RBD onset) (Schenk 1996 and 2005)
45 developed PD MSA DLB MCI after a mean of 115
years from the RBD onset (Iranzo at al 2006)
Esiste realmente lrsquoRBD idiopatico
RBD idiopatico al follow up
Iranzo 2013 The Lancet Neurology
u idiopathic RBD represents the
prodromal phase of a Lewy body
disorder and with sufficient
follow-up most cases would
eventually be diagnosed with a
clinical defined Lewy body
disorder such as Parkinsons
disease (PD) or dementia with
Lewy bodies (DLB)
u Patients from an IRBD cohort recruited
between 1991 and 2003 and previously
assessed in 2005 were followed up
during an additional period of 7 years
u Of the 44 participants from the original
cohort 36 (82) by the 2012 assessment
16 patients were diagnosed with PD
u 14 with DLB
u 1 with multiple system atrophy
u 5 with mild cognitive impairment
Iranzo 2013
Follow-up of idiopathic RBD patients
Predicting value of PLMS
u In the study of Schenck et al 1996 the only variable that
differentiated iRBD that eventually developed PD (38)
from those remaining idiopathic was the PLMS index at
the time of RBD diagnosis (852 vs 359)
u In a serie of 100 patients with RBD diagnosed at the Sleep
Disorders Center of San Raffaele H the PLMS index was
significantly higher in the symptomatic RBD compared to
the idiopathic ones (86 vs 58 with a PLMS indexgt10) (Zucconi et al 2003)
Risk 5-year 177 10-year 406 12-year 524
( 14PD i 1MSA 11 dementia- 7LBD 4 AD )
Cohort of
93 IRBD (
PSG) pts
Neurology 2009
u Ann Neurol 2012 Jan71(1)49-56 doi
101002ana22655
u Probable rapid eye movement sleep behavior
disorder increases risk for mild cognitive
impairment and Parkinson disease a
population-based studyu Boot BP Boeve BF et al
u Cognitively normal subjects aged 70 to 89
years in a population-based study of aging who screened
positive for probable RBD using the Mayo Sleep
Questionnaire were followed at 15-month intervals
u INTERPRETATION
u In this population-based cohort study RBD confers a
22-fold increased risk of developing MCIPD over 4
years
Neurology 2007
3 YEARS
Follow-up
Mov Dis 2012 (early view)
u Lancet Neurol 2013 May12(5)417-9
u REM sleep behaviour disorder a markerof synucleinopathy
u Mahowald MW Schenck CH
u Lancet Neurol 2013 May 12 (5) 469-82
u Idiopathic RBD in the development of PD
u Boeve BF
u Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder anobservational cohort study
Inclusion of RBD improves the diagnostic
classification of dementia with Lewy
bodiesTJ Ferman PhD BF Boeve MD et al
u cohort of 234 autopsy-confirmed dementia
patients followed longitudinally
u a history of definite or probable RBD was
present in 76 of 98 autopsy-confirmed DLB
indicating it is a frequent feature of DLB
u A history of RBD improves clinical diagnostic
accuracy and increases the odds of autopsy-
confirmed DLB by 6-fold9u Neurology 201177875ndash88
RBD ndashdemenza a corpi di Lewy
u the presence of RBD may reflect a distinct subtype of DLB suggestive of a bottom-up disease progression
u while DLB without RBD has additional features suggestive of a top-down progression
u Does RBD define clinicopathologic subtypes of DLB with distinct patterns of disease progression and treatment response It could help the development of biomarkers that may assist in differential diagnosis early detection and prognosis of DLBhelliphelliphelliphelliphellip
RBD e allucinazioni
u Iniziali report hanno esaltato
lrsquoassociazione tra rbd e allucinazioni
visive (Pacchetti Sinforiani Onofrij)
u Alcuni le hanno considerate intrusioni
di sonno REMhelliphellip
u Studi piugrave recenti non hanno trovato
chiare associazioni (Postuma hellip)
uLa latenza di conversione da
RBD idiopatico a RBD in
malattia neurodegenerativa
cambia negli anni
u Maggior attenzione e capacitagrave
diagnostica
u Studi non solo retrospettivi
u Studi non piugrave limitati solo o
prevalentemente ai centri del sonno
Idiopathic RBD
Multiple subtle abnormalities
Slowing of waking EEG (Fantini 2003)
Neuropsicological deficits (Ferini-Strambi et al 2003 Vendette M 2000
Fantini et al 2011)
Subtle parkinsonism (motor and gait speed) (Postuma 2006)h
Autonomic impairment (Ferini-Strambi 1996 Lanfranchi 2007 Postuma
2010
Olfactory deficit (Fantini 2006 Postuma 2006)
Color vision impairment (Postuma 2006)
Neuroimaging
abilitagrave visuospaziali logiche non verbali attenzione funzioni esecutive
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
International Classification of Sleep Disorders
AASM 2005- criteri diagnostici di RBD definito
u A-Presence of RSWA on PSG
u B- At least one of the following
sleep-related injurious potentially injurious or
disruptive behaviors by history (ie dream enactment
behavior) andor
abnormal REM sleep behavior documented during
polysomnographic monitoring
u Absence of EEG epileptiform activity during REM sleep
unless RBD can be clearly distinguished from any
concurrent REM sleep related seizure disorder
u The sleep disorder is not better explained by another sleep
disorder medical or neurological disorder mental
disorder medication use or substance use disorder
RBD clinicamente probabile
u In assenza di polisonnografia o in chi
non riesce a collaborare o in chi ha
pochissimo o assente sonno REM in
PSG per la diagnosi
u Anamnesi di eventi motorio-
comportamentali tipici
u Risposte congrue a specifici
questionari possibilmente validati
Mayo RBD questionnaire for PD
and cognitive
declined patients
2011
validato su 176
soggetti (normal
MCI AD LBD
PD PDD
98
Sensibilitagrave
74
Specificitagrave
per
RBD
A clinically probable RBD was diagnosed in
patients presenting during sleep about 1 h after
falling asleep rude movements andor
vocalizations as if they were enacting terrifying
nightmares sometimes provoking harm to self or
to their bed partner these episodes do not
necessarily cause the complete awakening of the
subject
Guarnieri B et al 2012
REM senza atonia ( RSWA)
u RSWA is a requisite diagnostic
feature of RBD but may also be
seen in patients without clinical
symptoms or signs of dream
enactment as an incidental finding in
neurologically normal individuals
especially in patients receiving
antidepressant therapy
u RSWA non vuol dire RBD
RBDdecorso clinico
cronico
RBD
alcohol (sospensione)
meprobamate (sospensione)
TCA I-MAO SSRI
cioccolata (intoxication)
RBD inserito nel deliriumhelliphellip
idiopatico
sintomatico(neurological diseases
mostly α-synucleinopathies)
acuto
RBD e malattie neurodegenerative
α-synucleiopathies(Boeve et al 2001)
Sporadically reported in
tauopathies
(overlap LBD)
bull Parkinsonrsquos disease (PD) ++
bull Lewy Body Dementia (LBD) +++
bull Multiple System Atrophy (MSA) +++
bull Progressive Supranuclear Palsy (PSP)
bull Cortico-Basal degeneration (CBD)
bull Alzheimerrsquos disease
RBD = Positive predicting value for α-synucleinopathies gt 90
Mayo
Clinic
Neurol Sci 2012 Apr33(2)371-3
REM sleep behavior disorder in a patient
with frontotemporal dementia
Lo Coco D Cupidi C Mattaliano A Baiamonte V Realmuto S
Cannizzaro E
RBD idiopatico
u Non associato ad altre diagnosi neurologiche
u Prevalenza stimata con interviste
telefoniche ( soggetti 15-100 anni) 05 (Ohayon 1997)
u Con PSG in pz con etagrave avanzata spesso declino cognitivo che
si rivolgono a Centro del sonno 002 bias di selezione
u Prevalenza maschile (MF 91) in PD 72
In LBD72 In MSA 64
u Etagrave drsquoesordio maggiore di 50 anni
u Evoluzione verso malattie
neurodegenerative nel 65 dei casi
38 of 29 iRBD pts developed parkinsonism andor
dementia after 12 yrs from onset (and 65 after 21 yrs
from RBD onset) (Schenk 1996 and 2005)
45 developed PD MSA DLB MCI after a mean of 115
years from the RBD onset (Iranzo at al 2006)
Esiste realmente lrsquoRBD idiopatico
RBD idiopatico al follow up
Iranzo 2013 The Lancet Neurology
u idiopathic RBD represents the
prodromal phase of a Lewy body
disorder and with sufficient
follow-up most cases would
eventually be diagnosed with a
clinical defined Lewy body
disorder such as Parkinsons
disease (PD) or dementia with
Lewy bodies (DLB)
u Patients from an IRBD cohort recruited
between 1991 and 2003 and previously
assessed in 2005 were followed up
during an additional period of 7 years
u Of the 44 participants from the original
cohort 36 (82) by the 2012 assessment
16 patients were diagnosed with PD
u 14 with DLB
u 1 with multiple system atrophy
u 5 with mild cognitive impairment
Iranzo 2013
Follow-up of idiopathic RBD patients
Predicting value of PLMS
u In the study of Schenck et al 1996 the only variable that
differentiated iRBD that eventually developed PD (38)
from those remaining idiopathic was the PLMS index at
the time of RBD diagnosis (852 vs 359)
u In a serie of 100 patients with RBD diagnosed at the Sleep
Disorders Center of San Raffaele H the PLMS index was
significantly higher in the symptomatic RBD compared to
the idiopathic ones (86 vs 58 with a PLMS indexgt10) (Zucconi et al 2003)
Risk 5-year 177 10-year 406 12-year 524
( 14PD i 1MSA 11 dementia- 7LBD 4 AD )
Cohort of
93 IRBD (
PSG) pts
Neurology 2009
u Ann Neurol 2012 Jan71(1)49-56 doi
101002ana22655
u Probable rapid eye movement sleep behavior
disorder increases risk for mild cognitive
impairment and Parkinson disease a
population-based studyu Boot BP Boeve BF et al
u Cognitively normal subjects aged 70 to 89
years in a population-based study of aging who screened
positive for probable RBD using the Mayo Sleep
Questionnaire were followed at 15-month intervals
u INTERPRETATION
u In this population-based cohort study RBD confers a
22-fold increased risk of developing MCIPD over 4
years
Neurology 2007
3 YEARS
Follow-up
Mov Dis 2012 (early view)
u Lancet Neurol 2013 May12(5)417-9
u REM sleep behaviour disorder a markerof synucleinopathy
u Mahowald MW Schenck CH
u Lancet Neurol 2013 May 12 (5) 469-82
u Idiopathic RBD in the development of PD
u Boeve BF
u Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder anobservational cohort study
Inclusion of RBD improves the diagnostic
classification of dementia with Lewy
bodiesTJ Ferman PhD BF Boeve MD et al
u cohort of 234 autopsy-confirmed dementia
patients followed longitudinally
u a history of definite or probable RBD was
present in 76 of 98 autopsy-confirmed DLB
indicating it is a frequent feature of DLB
u A history of RBD improves clinical diagnostic
accuracy and increases the odds of autopsy-
confirmed DLB by 6-fold9u Neurology 201177875ndash88
RBD ndashdemenza a corpi di Lewy
u the presence of RBD may reflect a distinct subtype of DLB suggestive of a bottom-up disease progression
u while DLB without RBD has additional features suggestive of a top-down progression
u Does RBD define clinicopathologic subtypes of DLB with distinct patterns of disease progression and treatment response It could help the development of biomarkers that may assist in differential diagnosis early detection and prognosis of DLBhelliphelliphelliphelliphellip
RBD e allucinazioni
u Iniziali report hanno esaltato
lrsquoassociazione tra rbd e allucinazioni
visive (Pacchetti Sinforiani Onofrij)
u Alcuni le hanno considerate intrusioni
di sonno REMhelliphellip
u Studi piugrave recenti non hanno trovato
chiare associazioni (Postuma hellip)
uLa latenza di conversione da
RBD idiopatico a RBD in
malattia neurodegenerativa
cambia negli anni
u Maggior attenzione e capacitagrave
diagnostica
u Studi non solo retrospettivi
u Studi non piugrave limitati solo o
prevalentemente ai centri del sonno
Idiopathic RBD
Multiple subtle abnormalities
Slowing of waking EEG (Fantini 2003)
Neuropsicological deficits (Ferini-Strambi et al 2003 Vendette M 2000
Fantini et al 2011)
Subtle parkinsonism (motor and gait speed) (Postuma 2006)h
Autonomic impairment (Ferini-Strambi 1996 Lanfranchi 2007 Postuma
2010
Olfactory deficit (Fantini 2006 Postuma 2006)
Color vision impairment (Postuma 2006)
Neuroimaging
abilitagrave visuospaziali logiche non verbali attenzione funzioni esecutive
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
RBD clinicamente probabile
u In assenza di polisonnografia o in chi
non riesce a collaborare o in chi ha
pochissimo o assente sonno REM in
PSG per la diagnosi
u Anamnesi di eventi motorio-
comportamentali tipici
u Risposte congrue a specifici
questionari possibilmente validati
Mayo RBD questionnaire for PD
and cognitive
declined patients
2011
validato su 176
soggetti (normal
MCI AD LBD
PD PDD
98
Sensibilitagrave
74
Specificitagrave
per
RBD
A clinically probable RBD was diagnosed in
patients presenting during sleep about 1 h after
falling asleep rude movements andor
vocalizations as if they were enacting terrifying
nightmares sometimes provoking harm to self or
to their bed partner these episodes do not
necessarily cause the complete awakening of the
subject
Guarnieri B et al 2012
REM senza atonia ( RSWA)
u RSWA is a requisite diagnostic
feature of RBD but may also be
seen in patients without clinical
symptoms or signs of dream
enactment as an incidental finding in
neurologically normal individuals
especially in patients receiving
antidepressant therapy
u RSWA non vuol dire RBD
RBDdecorso clinico
cronico
RBD
alcohol (sospensione)
meprobamate (sospensione)
TCA I-MAO SSRI
cioccolata (intoxication)
RBD inserito nel deliriumhelliphellip
idiopatico
sintomatico(neurological diseases
mostly α-synucleinopathies)
acuto
RBD e malattie neurodegenerative
α-synucleiopathies(Boeve et al 2001)
Sporadically reported in
tauopathies
(overlap LBD)
bull Parkinsonrsquos disease (PD) ++
bull Lewy Body Dementia (LBD) +++
bull Multiple System Atrophy (MSA) +++
bull Progressive Supranuclear Palsy (PSP)
bull Cortico-Basal degeneration (CBD)
bull Alzheimerrsquos disease
RBD = Positive predicting value for α-synucleinopathies gt 90
Mayo
Clinic
Neurol Sci 2012 Apr33(2)371-3
REM sleep behavior disorder in a patient
with frontotemporal dementia
Lo Coco D Cupidi C Mattaliano A Baiamonte V Realmuto S
Cannizzaro E
RBD idiopatico
u Non associato ad altre diagnosi neurologiche
u Prevalenza stimata con interviste
telefoniche ( soggetti 15-100 anni) 05 (Ohayon 1997)
u Con PSG in pz con etagrave avanzata spesso declino cognitivo che
si rivolgono a Centro del sonno 002 bias di selezione
u Prevalenza maschile (MF 91) in PD 72
In LBD72 In MSA 64
u Etagrave drsquoesordio maggiore di 50 anni
u Evoluzione verso malattie
neurodegenerative nel 65 dei casi
38 of 29 iRBD pts developed parkinsonism andor
dementia after 12 yrs from onset (and 65 after 21 yrs
from RBD onset) (Schenk 1996 and 2005)
45 developed PD MSA DLB MCI after a mean of 115
years from the RBD onset (Iranzo at al 2006)
Esiste realmente lrsquoRBD idiopatico
RBD idiopatico al follow up
Iranzo 2013 The Lancet Neurology
u idiopathic RBD represents the
prodromal phase of a Lewy body
disorder and with sufficient
follow-up most cases would
eventually be diagnosed with a
clinical defined Lewy body
disorder such as Parkinsons
disease (PD) or dementia with
Lewy bodies (DLB)
u Patients from an IRBD cohort recruited
between 1991 and 2003 and previously
assessed in 2005 were followed up
during an additional period of 7 years
u Of the 44 participants from the original
cohort 36 (82) by the 2012 assessment
16 patients were diagnosed with PD
u 14 with DLB
u 1 with multiple system atrophy
u 5 with mild cognitive impairment
Iranzo 2013
Follow-up of idiopathic RBD patients
Predicting value of PLMS
u In the study of Schenck et al 1996 the only variable that
differentiated iRBD that eventually developed PD (38)
from those remaining idiopathic was the PLMS index at
the time of RBD diagnosis (852 vs 359)
u In a serie of 100 patients with RBD diagnosed at the Sleep
Disorders Center of San Raffaele H the PLMS index was
significantly higher in the symptomatic RBD compared to
the idiopathic ones (86 vs 58 with a PLMS indexgt10) (Zucconi et al 2003)
Risk 5-year 177 10-year 406 12-year 524
( 14PD i 1MSA 11 dementia- 7LBD 4 AD )
Cohort of
93 IRBD (
PSG) pts
Neurology 2009
u Ann Neurol 2012 Jan71(1)49-56 doi
101002ana22655
u Probable rapid eye movement sleep behavior
disorder increases risk for mild cognitive
impairment and Parkinson disease a
population-based studyu Boot BP Boeve BF et al
u Cognitively normal subjects aged 70 to 89
years in a population-based study of aging who screened
positive for probable RBD using the Mayo Sleep
Questionnaire were followed at 15-month intervals
u INTERPRETATION
u In this population-based cohort study RBD confers a
22-fold increased risk of developing MCIPD over 4
years
Neurology 2007
3 YEARS
Follow-up
Mov Dis 2012 (early view)
u Lancet Neurol 2013 May12(5)417-9
u REM sleep behaviour disorder a markerof synucleinopathy
u Mahowald MW Schenck CH
u Lancet Neurol 2013 May 12 (5) 469-82
u Idiopathic RBD in the development of PD
u Boeve BF
u Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder anobservational cohort study
Inclusion of RBD improves the diagnostic
classification of dementia with Lewy
bodiesTJ Ferman PhD BF Boeve MD et al
u cohort of 234 autopsy-confirmed dementia
patients followed longitudinally
u a history of definite or probable RBD was
present in 76 of 98 autopsy-confirmed DLB
indicating it is a frequent feature of DLB
u A history of RBD improves clinical diagnostic
accuracy and increases the odds of autopsy-
confirmed DLB by 6-fold9u Neurology 201177875ndash88
RBD ndashdemenza a corpi di Lewy
u the presence of RBD may reflect a distinct subtype of DLB suggestive of a bottom-up disease progression
u while DLB without RBD has additional features suggestive of a top-down progression
u Does RBD define clinicopathologic subtypes of DLB with distinct patterns of disease progression and treatment response It could help the development of biomarkers that may assist in differential diagnosis early detection and prognosis of DLBhelliphelliphelliphelliphellip
RBD e allucinazioni
u Iniziali report hanno esaltato
lrsquoassociazione tra rbd e allucinazioni
visive (Pacchetti Sinforiani Onofrij)
u Alcuni le hanno considerate intrusioni
di sonno REMhelliphellip
u Studi piugrave recenti non hanno trovato
chiare associazioni (Postuma hellip)
uLa latenza di conversione da
RBD idiopatico a RBD in
malattia neurodegenerativa
cambia negli anni
u Maggior attenzione e capacitagrave
diagnostica
u Studi non solo retrospettivi
u Studi non piugrave limitati solo o
prevalentemente ai centri del sonno
Idiopathic RBD
Multiple subtle abnormalities
Slowing of waking EEG (Fantini 2003)
Neuropsicological deficits (Ferini-Strambi et al 2003 Vendette M 2000
Fantini et al 2011)
Subtle parkinsonism (motor and gait speed) (Postuma 2006)h
Autonomic impairment (Ferini-Strambi 1996 Lanfranchi 2007 Postuma
2010
Olfactory deficit (Fantini 2006 Postuma 2006)
Color vision impairment (Postuma 2006)
Neuroimaging
abilitagrave visuospaziali logiche non verbali attenzione funzioni esecutive
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Mayo RBD questionnaire for PD
and cognitive
declined patients
2011
validato su 176
soggetti (normal
MCI AD LBD
PD PDD
98
Sensibilitagrave
74
Specificitagrave
per
RBD
A clinically probable RBD was diagnosed in
patients presenting during sleep about 1 h after
falling asleep rude movements andor
vocalizations as if they were enacting terrifying
nightmares sometimes provoking harm to self or
to their bed partner these episodes do not
necessarily cause the complete awakening of the
subject
Guarnieri B et al 2012
REM senza atonia ( RSWA)
u RSWA is a requisite diagnostic
feature of RBD but may also be
seen in patients without clinical
symptoms or signs of dream
enactment as an incidental finding in
neurologically normal individuals
especially in patients receiving
antidepressant therapy
u RSWA non vuol dire RBD
RBDdecorso clinico
cronico
RBD
alcohol (sospensione)
meprobamate (sospensione)
TCA I-MAO SSRI
cioccolata (intoxication)
RBD inserito nel deliriumhelliphellip
idiopatico
sintomatico(neurological diseases
mostly α-synucleinopathies)
acuto
RBD e malattie neurodegenerative
α-synucleiopathies(Boeve et al 2001)
Sporadically reported in
tauopathies
(overlap LBD)
bull Parkinsonrsquos disease (PD) ++
bull Lewy Body Dementia (LBD) +++
bull Multiple System Atrophy (MSA) +++
bull Progressive Supranuclear Palsy (PSP)
bull Cortico-Basal degeneration (CBD)
bull Alzheimerrsquos disease
RBD = Positive predicting value for α-synucleinopathies gt 90
Mayo
Clinic
Neurol Sci 2012 Apr33(2)371-3
REM sleep behavior disorder in a patient
with frontotemporal dementia
Lo Coco D Cupidi C Mattaliano A Baiamonte V Realmuto S
Cannizzaro E
RBD idiopatico
u Non associato ad altre diagnosi neurologiche
u Prevalenza stimata con interviste
telefoniche ( soggetti 15-100 anni) 05 (Ohayon 1997)
u Con PSG in pz con etagrave avanzata spesso declino cognitivo che
si rivolgono a Centro del sonno 002 bias di selezione
u Prevalenza maschile (MF 91) in PD 72
In LBD72 In MSA 64
u Etagrave drsquoesordio maggiore di 50 anni
u Evoluzione verso malattie
neurodegenerative nel 65 dei casi
38 of 29 iRBD pts developed parkinsonism andor
dementia after 12 yrs from onset (and 65 after 21 yrs
from RBD onset) (Schenk 1996 and 2005)
45 developed PD MSA DLB MCI after a mean of 115
years from the RBD onset (Iranzo at al 2006)
Esiste realmente lrsquoRBD idiopatico
RBD idiopatico al follow up
Iranzo 2013 The Lancet Neurology
u idiopathic RBD represents the
prodromal phase of a Lewy body
disorder and with sufficient
follow-up most cases would
eventually be diagnosed with a
clinical defined Lewy body
disorder such as Parkinsons
disease (PD) or dementia with
Lewy bodies (DLB)
u Patients from an IRBD cohort recruited
between 1991 and 2003 and previously
assessed in 2005 were followed up
during an additional period of 7 years
u Of the 44 participants from the original
cohort 36 (82) by the 2012 assessment
16 patients were diagnosed with PD
u 14 with DLB
u 1 with multiple system atrophy
u 5 with mild cognitive impairment
Iranzo 2013
Follow-up of idiopathic RBD patients
Predicting value of PLMS
u In the study of Schenck et al 1996 the only variable that
differentiated iRBD that eventually developed PD (38)
from those remaining idiopathic was the PLMS index at
the time of RBD diagnosis (852 vs 359)
u In a serie of 100 patients with RBD diagnosed at the Sleep
Disorders Center of San Raffaele H the PLMS index was
significantly higher in the symptomatic RBD compared to
the idiopathic ones (86 vs 58 with a PLMS indexgt10) (Zucconi et al 2003)
Risk 5-year 177 10-year 406 12-year 524
( 14PD i 1MSA 11 dementia- 7LBD 4 AD )
Cohort of
93 IRBD (
PSG) pts
Neurology 2009
u Ann Neurol 2012 Jan71(1)49-56 doi
101002ana22655
u Probable rapid eye movement sleep behavior
disorder increases risk for mild cognitive
impairment and Parkinson disease a
population-based studyu Boot BP Boeve BF et al
u Cognitively normal subjects aged 70 to 89
years in a population-based study of aging who screened
positive for probable RBD using the Mayo Sleep
Questionnaire were followed at 15-month intervals
u INTERPRETATION
u In this population-based cohort study RBD confers a
22-fold increased risk of developing MCIPD over 4
years
Neurology 2007
3 YEARS
Follow-up
Mov Dis 2012 (early view)
u Lancet Neurol 2013 May12(5)417-9
u REM sleep behaviour disorder a markerof synucleinopathy
u Mahowald MW Schenck CH
u Lancet Neurol 2013 May 12 (5) 469-82
u Idiopathic RBD in the development of PD
u Boeve BF
u Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder anobservational cohort study
Inclusion of RBD improves the diagnostic
classification of dementia with Lewy
bodiesTJ Ferman PhD BF Boeve MD et al
u cohort of 234 autopsy-confirmed dementia
patients followed longitudinally
u a history of definite or probable RBD was
present in 76 of 98 autopsy-confirmed DLB
indicating it is a frequent feature of DLB
u A history of RBD improves clinical diagnostic
accuracy and increases the odds of autopsy-
confirmed DLB by 6-fold9u Neurology 201177875ndash88
RBD ndashdemenza a corpi di Lewy
u the presence of RBD may reflect a distinct subtype of DLB suggestive of a bottom-up disease progression
u while DLB without RBD has additional features suggestive of a top-down progression
u Does RBD define clinicopathologic subtypes of DLB with distinct patterns of disease progression and treatment response It could help the development of biomarkers that may assist in differential diagnosis early detection and prognosis of DLBhelliphelliphelliphelliphellip
RBD e allucinazioni
u Iniziali report hanno esaltato
lrsquoassociazione tra rbd e allucinazioni
visive (Pacchetti Sinforiani Onofrij)
u Alcuni le hanno considerate intrusioni
di sonno REMhelliphellip
u Studi piugrave recenti non hanno trovato
chiare associazioni (Postuma hellip)
uLa latenza di conversione da
RBD idiopatico a RBD in
malattia neurodegenerativa
cambia negli anni
u Maggior attenzione e capacitagrave
diagnostica
u Studi non solo retrospettivi
u Studi non piugrave limitati solo o
prevalentemente ai centri del sonno
Idiopathic RBD
Multiple subtle abnormalities
Slowing of waking EEG (Fantini 2003)
Neuropsicological deficits (Ferini-Strambi et al 2003 Vendette M 2000
Fantini et al 2011)
Subtle parkinsonism (motor and gait speed) (Postuma 2006)h
Autonomic impairment (Ferini-Strambi 1996 Lanfranchi 2007 Postuma
2010
Olfactory deficit (Fantini 2006 Postuma 2006)
Color vision impairment (Postuma 2006)
Neuroimaging
abilitagrave visuospaziali logiche non verbali attenzione funzioni esecutive
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
A clinically probable RBD was diagnosed in
patients presenting during sleep about 1 h after
falling asleep rude movements andor
vocalizations as if they were enacting terrifying
nightmares sometimes provoking harm to self or
to their bed partner these episodes do not
necessarily cause the complete awakening of the
subject
Guarnieri B et al 2012
REM senza atonia ( RSWA)
u RSWA is a requisite diagnostic
feature of RBD but may also be
seen in patients without clinical
symptoms or signs of dream
enactment as an incidental finding in
neurologically normal individuals
especially in patients receiving
antidepressant therapy
u RSWA non vuol dire RBD
RBDdecorso clinico
cronico
RBD
alcohol (sospensione)
meprobamate (sospensione)
TCA I-MAO SSRI
cioccolata (intoxication)
RBD inserito nel deliriumhelliphellip
idiopatico
sintomatico(neurological diseases
mostly α-synucleinopathies)
acuto
RBD e malattie neurodegenerative
α-synucleiopathies(Boeve et al 2001)
Sporadically reported in
tauopathies
(overlap LBD)
bull Parkinsonrsquos disease (PD) ++
bull Lewy Body Dementia (LBD) +++
bull Multiple System Atrophy (MSA) +++
bull Progressive Supranuclear Palsy (PSP)
bull Cortico-Basal degeneration (CBD)
bull Alzheimerrsquos disease
RBD = Positive predicting value for α-synucleinopathies gt 90
Mayo
Clinic
Neurol Sci 2012 Apr33(2)371-3
REM sleep behavior disorder in a patient
with frontotemporal dementia
Lo Coco D Cupidi C Mattaliano A Baiamonte V Realmuto S
Cannizzaro E
RBD idiopatico
u Non associato ad altre diagnosi neurologiche
u Prevalenza stimata con interviste
telefoniche ( soggetti 15-100 anni) 05 (Ohayon 1997)
u Con PSG in pz con etagrave avanzata spesso declino cognitivo che
si rivolgono a Centro del sonno 002 bias di selezione
u Prevalenza maschile (MF 91) in PD 72
In LBD72 In MSA 64
u Etagrave drsquoesordio maggiore di 50 anni
u Evoluzione verso malattie
neurodegenerative nel 65 dei casi
38 of 29 iRBD pts developed parkinsonism andor
dementia after 12 yrs from onset (and 65 after 21 yrs
from RBD onset) (Schenk 1996 and 2005)
45 developed PD MSA DLB MCI after a mean of 115
years from the RBD onset (Iranzo at al 2006)
Esiste realmente lrsquoRBD idiopatico
RBD idiopatico al follow up
Iranzo 2013 The Lancet Neurology
u idiopathic RBD represents the
prodromal phase of a Lewy body
disorder and with sufficient
follow-up most cases would
eventually be diagnosed with a
clinical defined Lewy body
disorder such as Parkinsons
disease (PD) or dementia with
Lewy bodies (DLB)
u Patients from an IRBD cohort recruited
between 1991 and 2003 and previously
assessed in 2005 were followed up
during an additional period of 7 years
u Of the 44 participants from the original
cohort 36 (82) by the 2012 assessment
16 patients were diagnosed with PD
u 14 with DLB
u 1 with multiple system atrophy
u 5 with mild cognitive impairment
Iranzo 2013
Follow-up of idiopathic RBD patients
Predicting value of PLMS
u In the study of Schenck et al 1996 the only variable that
differentiated iRBD that eventually developed PD (38)
from those remaining idiopathic was the PLMS index at
the time of RBD diagnosis (852 vs 359)
u In a serie of 100 patients with RBD diagnosed at the Sleep
Disorders Center of San Raffaele H the PLMS index was
significantly higher in the symptomatic RBD compared to
the idiopathic ones (86 vs 58 with a PLMS indexgt10) (Zucconi et al 2003)
Risk 5-year 177 10-year 406 12-year 524
( 14PD i 1MSA 11 dementia- 7LBD 4 AD )
Cohort of
93 IRBD (
PSG) pts
Neurology 2009
u Ann Neurol 2012 Jan71(1)49-56 doi
101002ana22655
u Probable rapid eye movement sleep behavior
disorder increases risk for mild cognitive
impairment and Parkinson disease a
population-based studyu Boot BP Boeve BF et al
u Cognitively normal subjects aged 70 to 89
years in a population-based study of aging who screened
positive for probable RBD using the Mayo Sleep
Questionnaire were followed at 15-month intervals
u INTERPRETATION
u In this population-based cohort study RBD confers a
22-fold increased risk of developing MCIPD over 4
years
Neurology 2007
3 YEARS
Follow-up
Mov Dis 2012 (early view)
u Lancet Neurol 2013 May12(5)417-9
u REM sleep behaviour disorder a markerof synucleinopathy
u Mahowald MW Schenck CH
u Lancet Neurol 2013 May 12 (5) 469-82
u Idiopathic RBD in the development of PD
u Boeve BF
u Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder anobservational cohort study
Inclusion of RBD improves the diagnostic
classification of dementia with Lewy
bodiesTJ Ferman PhD BF Boeve MD et al
u cohort of 234 autopsy-confirmed dementia
patients followed longitudinally
u a history of definite or probable RBD was
present in 76 of 98 autopsy-confirmed DLB
indicating it is a frequent feature of DLB
u A history of RBD improves clinical diagnostic
accuracy and increases the odds of autopsy-
confirmed DLB by 6-fold9u Neurology 201177875ndash88
RBD ndashdemenza a corpi di Lewy
u the presence of RBD may reflect a distinct subtype of DLB suggestive of a bottom-up disease progression
u while DLB without RBD has additional features suggestive of a top-down progression
u Does RBD define clinicopathologic subtypes of DLB with distinct patterns of disease progression and treatment response It could help the development of biomarkers that may assist in differential diagnosis early detection and prognosis of DLBhelliphelliphelliphelliphellip
RBD e allucinazioni
u Iniziali report hanno esaltato
lrsquoassociazione tra rbd e allucinazioni
visive (Pacchetti Sinforiani Onofrij)
u Alcuni le hanno considerate intrusioni
di sonno REMhelliphellip
u Studi piugrave recenti non hanno trovato
chiare associazioni (Postuma hellip)
uLa latenza di conversione da
RBD idiopatico a RBD in
malattia neurodegenerativa
cambia negli anni
u Maggior attenzione e capacitagrave
diagnostica
u Studi non solo retrospettivi
u Studi non piugrave limitati solo o
prevalentemente ai centri del sonno
Idiopathic RBD
Multiple subtle abnormalities
Slowing of waking EEG (Fantini 2003)
Neuropsicological deficits (Ferini-Strambi et al 2003 Vendette M 2000
Fantini et al 2011)
Subtle parkinsonism (motor and gait speed) (Postuma 2006)h
Autonomic impairment (Ferini-Strambi 1996 Lanfranchi 2007 Postuma
2010
Olfactory deficit (Fantini 2006 Postuma 2006)
Color vision impairment (Postuma 2006)
Neuroimaging
abilitagrave visuospaziali logiche non verbali attenzione funzioni esecutive
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
REM senza atonia ( RSWA)
u RSWA is a requisite diagnostic
feature of RBD but may also be
seen in patients without clinical
symptoms or signs of dream
enactment as an incidental finding in
neurologically normal individuals
especially in patients receiving
antidepressant therapy
u RSWA non vuol dire RBD
RBDdecorso clinico
cronico
RBD
alcohol (sospensione)
meprobamate (sospensione)
TCA I-MAO SSRI
cioccolata (intoxication)
RBD inserito nel deliriumhelliphellip
idiopatico
sintomatico(neurological diseases
mostly α-synucleinopathies)
acuto
RBD e malattie neurodegenerative
α-synucleiopathies(Boeve et al 2001)
Sporadically reported in
tauopathies
(overlap LBD)
bull Parkinsonrsquos disease (PD) ++
bull Lewy Body Dementia (LBD) +++
bull Multiple System Atrophy (MSA) +++
bull Progressive Supranuclear Palsy (PSP)
bull Cortico-Basal degeneration (CBD)
bull Alzheimerrsquos disease
RBD = Positive predicting value for α-synucleinopathies gt 90
Mayo
Clinic
Neurol Sci 2012 Apr33(2)371-3
REM sleep behavior disorder in a patient
with frontotemporal dementia
Lo Coco D Cupidi C Mattaliano A Baiamonte V Realmuto S
Cannizzaro E
RBD idiopatico
u Non associato ad altre diagnosi neurologiche
u Prevalenza stimata con interviste
telefoniche ( soggetti 15-100 anni) 05 (Ohayon 1997)
u Con PSG in pz con etagrave avanzata spesso declino cognitivo che
si rivolgono a Centro del sonno 002 bias di selezione
u Prevalenza maschile (MF 91) in PD 72
In LBD72 In MSA 64
u Etagrave drsquoesordio maggiore di 50 anni
u Evoluzione verso malattie
neurodegenerative nel 65 dei casi
38 of 29 iRBD pts developed parkinsonism andor
dementia after 12 yrs from onset (and 65 after 21 yrs
from RBD onset) (Schenk 1996 and 2005)
45 developed PD MSA DLB MCI after a mean of 115
years from the RBD onset (Iranzo at al 2006)
Esiste realmente lrsquoRBD idiopatico
RBD idiopatico al follow up
Iranzo 2013 The Lancet Neurology
u idiopathic RBD represents the
prodromal phase of a Lewy body
disorder and with sufficient
follow-up most cases would
eventually be diagnosed with a
clinical defined Lewy body
disorder such as Parkinsons
disease (PD) or dementia with
Lewy bodies (DLB)
u Patients from an IRBD cohort recruited
between 1991 and 2003 and previously
assessed in 2005 were followed up
during an additional period of 7 years
u Of the 44 participants from the original
cohort 36 (82) by the 2012 assessment
16 patients were diagnosed with PD
u 14 with DLB
u 1 with multiple system atrophy
u 5 with mild cognitive impairment
Iranzo 2013
Follow-up of idiopathic RBD patients
Predicting value of PLMS
u In the study of Schenck et al 1996 the only variable that
differentiated iRBD that eventually developed PD (38)
from those remaining idiopathic was the PLMS index at
the time of RBD diagnosis (852 vs 359)
u In a serie of 100 patients with RBD diagnosed at the Sleep
Disorders Center of San Raffaele H the PLMS index was
significantly higher in the symptomatic RBD compared to
the idiopathic ones (86 vs 58 with a PLMS indexgt10) (Zucconi et al 2003)
Risk 5-year 177 10-year 406 12-year 524
( 14PD i 1MSA 11 dementia- 7LBD 4 AD )
Cohort of
93 IRBD (
PSG) pts
Neurology 2009
u Ann Neurol 2012 Jan71(1)49-56 doi
101002ana22655
u Probable rapid eye movement sleep behavior
disorder increases risk for mild cognitive
impairment and Parkinson disease a
population-based studyu Boot BP Boeve BF et al
u Cognitively normal subjects aged 70 to 89
years in a population-based study of aging who screened
positive for probable RBD using the Mayo Sleep
Questionnaire were followed at 15-month intervals
u INTERPRETATION
u In this population-based cohort study RBD confers a
22-fold increased risk of developing MCIPD over 4
years
Neurology 2007
3 YEARS
Follow-up
Mov Dis 2012 (early view)
u Lancet Neurol 2013 May12(5)417-9
u REM sleep behaviour disorder a markerof synucleinopathy
u Mahowald MW Schenck CH
u Lancet Neurol 2013 May 12 (5) 469-82
u Idiopathic RBD in the development of PD
u Boeve BF
u Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder anobservational cohort study
Inclusion of RBD improves the diagnostic
classification of dementia with Lewy
bodiesTJ Ferman PhD BF Boeve MD et al
u cohort of 234 autopsy-confirmed dementia
patients followed longitudinally
u a history of definite or probable RBD was
present in 76 of 98 autopsy-confirmed DLB
indicating it is a frequent feature of DLB
u A history of RBD improves clinical diagnostic
accuracy and increases the odds of autopsy-
confirmed DLB by 6-fold9u Neurology 201177875ndash88
RBD ndashdemenza a corpi di Lewy
u the presence of RBD may reflect a distinct subtype of DLB suggestive of a bottom-up disease progression
u while DLB without RBD has additional features suggestive of a top-down progression
u Does RBD define clinicopathologic subtypes of DLB with distinct patterns of disease progression and treatment response It could help the development of biomarkers that may assist in differential diagnosis early detection and prognosis of DLBhelliphelliphelliphelliphellip
RBD e allucinazioni
u Iniziali report hanno esaltato
lrsquoassociazione tra rbd e allucinazioni
visive (Pacchetti Sinforiani Onofrij)
u Alcuni le hanno considerate intrusioni
di sonno REMhelliphellip
u Studi piugrave recenti non hanno trovato
chiare associazioni (Postuma hellip)
uLa latenza di conversione da
RBD idiopatico a RBD in
malattia neurodegenerativa
cambia negli anni
u Maggior attenzione e capacitagrave
diagnostica
u Studi non solo retrospettivi
u Studi non piugrave limitati solo o
prevalentemente ai centri del sonno
Idiopathic RBD
Multiple subtle abnormalities
Slowing of waking EEG (Fantini 2003)
Neuropsicological deficits (Ferini-Strambi et al 2003 Vendette M 2000
Fantini et al 2011)
Subtle parkinsonism (motor and gait speed) (Postuma 2006)h
Autonomic impairment (Ferini-Strambi 1996 Lanfranchi 2007 Postuma
2010
Olfactory deficit (Fantini 2006 Postuma 2006)
Color vision impairment (Postuma 2006)
Neuroimaging
abilitagrave visuospaziali logiche non verbali attenzione funzioni esecutive
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
RBDdecorso clinico
cronico
RBD
alcohol (sospensione)
meprobamate (sospensione)
TCA I-MAO SSRI
cioccolata (intoxication)
RBD inserito nel deliriumhelliphellip
idiopatico
sintomatico(neurological diseases
mostly α-synucleinopathies)
acuto
RBD e malattie neurodegenerative
α-synucleiopathies(Boeve et al 2001)
Sporadically reported in
tauopathies
(overlap LBD)
bull Parkinsonrsquos disease (PD) ++
bull Lewy Body Dementia (LBD) +++
bull Multiple System Atrophy (MSA) +++
bull Progressive Supranuclear Palsy (PSP)
bull Cortico-Basal degeneration (CBD)
bull Alzheimerrsquos disease
RBD = Positive predicting value for α-synucleinopathies gt 90
Mayo
Clinic
Neurol Sci 2012 Apr33(2)371-3
REM sleep behavior disorder in a patient
with frontotemporal dementia
Lo Coco D Cupidi C Mattaliano A Baiamonte V Realmuto S
Cannizzaro E
RBD idiopatico
u Non associato ad altre diagnosi neurologiche
u Prevalenza stimata con interviste
telefoniche ( soggetti 15-100 anni) 05 (Ohayon 1997)
u Con PSG in pz con etagrave avanzata spesso declino cognitivo che
si rivolgono a Centro del sonno 002 bias di selezione
u Prevalenza maschile (MF 91) in PD 72
In LBD72 In MSA 64
u Etagrave drsquoesordio maggiore di 50 anni
u Evoluzione verso malattie
neurodegenerative nel 65 dei casi
38 of 29 iRBD pts developed parkinsonism andor
dementia after 12 yrs from onset (and 65 after 21 yrs
from RBD onset) (Schenk 1996 and 2005)
45 developed PD MSA DLB MCI after a mean of 115
years from the RBD onset (Iranzo at al 2006)
Esiste realmente lrsquoRBD idiopatico
RBD idiopatico al follow up
Iranzo 2013 The Lancet Neurology
u idiopathic RBD represents the
prodromal phase of a Lewy body
disorder and with sufficient
follow-up most cases would
eventually be diagnosed with a
clinical defined Lewy body
disorder such as Parkinsons
disease (PD) or dementia with
Lewy bodies (DLB)
u Patients from an IRBD cohort recruited
between 1991 and 2003 and previously
assessed in 2005 were followed up
during an additional period of 7 years
u Of the 44 participants from the original
cohort 36 (82) by the 2012 assessment
16 patients were diagnosed with PD
u 14 with DLB
u 1 with multiple system atrophy
u 5 with mild cognitive impairment
Iranzo 2013
Follow-up of idiopathic RBD patients
Predicting value of PLMS
u In the study of Schenck et al 1996 the only variable that
differentiated iRBD that eventually developed PD (38)
from those remaining idiopathic was the PLMS index at
the time of RBD diagnosis (852 vs 359)
u In a serie of 100 patients with RBD diagnosed at the Sleep
Disorders Center of San Raffaele H the PLMS index was
significantly higher in the symptomatic RBD compared to
the idiopathic ones (86 vs 58 with a PLMS indexgt10) (Zucconi et al 2003)
Risk 5-year 177 10-year 406 12-year 524
( 14PD i 1MSA 11 dementia- 7LBD 4 AD )
Cohort of
93 IRBD (
PSG) pts
Neurology 2009
u Ann Neurol 2012 Jan71(1)49-56 doi
101002ana22655
u Probable rapid eye movement sleep behavior
disorder increases risk for mild cognitive
impairment and Parkinson disease a
population-based studyu Boot BP Boeve BF et al
u Cognitively normal subjects aged 70 to 89
years in a population-based study of aging who screened
positive for probable RBD using the Mayo Sleep
Questionnaire were followed at 15-month intervals
u INTERPRETATION
u In this population-based cohort study RBD confers a
22-fold increased risk of developing MCIPD over 4
years
Neurology 2007
3 YEARS
Follow-up
Mov Dis 2012 (early view)
u Lancet Neurol 2013 May12(5)417-9
u REM sleep behaviour disorder a markerof synucleinopathy
u Mahowald MW Schenck CH
u Lancet Neurol 2013 May 12 (5) 469-82
u Idiopathic RBD in the development of PD
u Boeve BF
u Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder anobservational cohort study
Inclusion of RBD improves the diagnostic
classification of dementia with Lewy
bodiesTJ Ferman PhD BF Boeve MD et al
u cohort of 234 autopsy-confirmed dementia
patients followed longitudinally
u a history of definite or probable RBD was
present in 76 of 98 autopsy-confirmed DLB
indicating it is a frequent feature of DLB
u A history of RBD improves clinical diagnostic
accuracy and increases the odds of autopsy-
confirmed DLB by 6-fold9u Neurology 201177875ndash88
RBD ndashdemenza a corpi di Lewy
u the presence of RBD may reflect a distinct subtype of DLB suggestive of a bottom-up disease progression
u while DLB without RBD has additional features suggestive of a top-down progression
u Does RBD define clinicopathologic subtypes of DLB with distinct patterns of disease progression and treatment response It could help the development of biomarkers that may assist in differential diagnosis early detection and prognosis of DLBhelliphelliphelliphelliphellip
RBD e allucinazioni
u Iniziali report hanno esaltato
lrsquoassociazione tra rbd e allucinazioni
visive (Pacchetti Sinforiani Onofrij)
u Alcuni le hanno considerate intrusioni
di sonno REMhelliphellip
u Studi piugrave recenti non hanno trovato
chiare associazioni (Postuma hellip)
uLa latenza di conversione da
RBD idiopatico a RBD in
malattia neurodegenerativa
cambia negli anni
u Maggior attenzione e capacitagrave
diagnostica
u Studi non solo retrospettivi
u Studi non piugrave limitati solo o
prevalentemente ai centri del sonno
Idiopathic RBD
Multiple subtle abnormalities
Slowing of waking EEG (Fantini 2003)
Neuropsicological deficits (Ferini-Strambi et al 2003 Vendette M 2000
Fantini et al 2011)
Subtle parkinsonism (motor and gait speed) (Postuma 2006)h
Autonomic impairment (Ferini-Strambi 1996 Lanfranchi 2007 Postuma
2010
Olfactory deficit (Fantini 2006 Postuma 2006)
Color vision impairment (Postuma 2006)
Neuroimaging
abilitagrave visuospaziali logiche non verbali attenzione funzioni esecutive
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
RBD e malattie neurodegenerative
α-synucleiopathies(Boeve et al 2001)
Sporadically reported in
tauopathies
(overlap LBD)
bull Parkinsonrsquos disease (PD) ++
bull Lewy Body Dementia (LBD) +++
bull Multiple System Atrophy (MSA) +++
bull Progressive Supranuclear Palsy (PSP)
bull Cortico-Basal degeneration (CBD)
bull Alzheimerrsquos disease
RBD = Positive predicting value for α-synucleinopathies gt 90
Mayo
Clinic
Neurol Sci 2012 Apr33(2)371-3
REM sleep behavior disorder in a patient
with frontotemporal dementia
Lo Coco D Cupidi C Mattaliano A Baiamonte V Realmuto S
Cannizzaro E
RBD idiopatico
u Non associato ad altre diagnosi neurologiche
u Prevalenza stimata con interviste
telefoniche ( soggetti 15-100 anni) 05 (Ohayon 1997)
u Con PSG in pz con etagrave avanzata spesso declino cognitivo che
si rivolgono a Centro del sonno 002 bias di selezione
u Prevalenza maschile (MF 91) in PD 72
In LBD72 In MSA 64
u Etagrave drsquoesordio maggiore di 50 anni
u Evoluzione verso malattie
neurodegenerative nel 65 dei casi
38 of 29 iRBD pts developed parkinsonism andor
dementia after 12 yrs from onset (and 65 after 21 yrs
from RBD onset) (Schenk 1996 and 2005)
45 developed PD MSA DLB MCI after a mean of 115
years from the RBD onset (Iranzo at al 2006)
Esiste realmente lrsquoRBD idiopatico
RBD idiopatico al follow up
Iranzo 2013 The Lancet Neurology
u idiopathic RBD represents the
prodromal phase of a Lewy body
disorder and with sufficient
follow-up most cases would
eventually be diagnosed with a
clinical defined Lewy body
disorder such as Parkinsons
disease (PD) or dementia with
Lewy bodies (DLB)
u Patients from an IRBD cohort recruited
between 1991 and 2003 and previously
assessed in 2005 were followed up
during an additional period of 7 years
u Of the 44 participants from the original
cohort 36 (82) by the 2012 assessment
16 patients were diagnosed with PD
u 14 with DLB
u 1 with multiple system atrophy
u 5 with mild cognitive impairment
Iranzo 2013
Follow-up of idiopathic RBD patients
Predicting value of PLMS
u In the study of Schenck et al 1996 the only variable that
differentiated iRBD that eventually developed PD (38)
from those remaining idiopathic was the PLMS index at
the time of RBD diagnosis (852 vs 359)
u In a serie of 100 patients with RBD diagnosed at the Sleep
Disorders Center of San Raffaele H the PLMS index was
significantly higher in the symptomatic RBD compared to
the idiopathic ones (86 vs 58 with a PLMS indexgt10) (Zucconi et al 2003)
Risk 5-year 177 10-year 406 12-year 524
( 14PD i 1MSA 11 dementia- 7LBD 4 AD )
Cohort of
93 IRBD (
PSG) pts
Neurology 2009
u Ann Neurol 2012 Jan71(1)49-56 doi
101002ana22655
u Probable rapid eye movement sleep behavior
disorder increases risk for mild cognitive
impairment and Parkinson disease a
population-based studyu Boot BP Boeve BF et al
u Cognitively normal subjects aged 70 to 89
years in a population-based study of aging who screened
positive for probable RBD using the Mayo Sleep
Questionnaire were followed at 15-month intervals
u INTERPRETATION
u In this population-based cohort study RBD confers a
22-fold increased risk of developing MCIPD over 4
years
Neurology 2007
3 YEARS
Follow-up
Mov Dis 2012 (early view)
u Lancet Neurol 2013 May12(5)417-9
u REM sleep behaviour disorder a markerof synucleinopathy
u Mahowald MW Schenck CH
u Lancet Neurol 2013 May 12 (5) 469-82
u Idiopathic RBD in the development of PD
u Boeve BF
u Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder anobservational cohort study
Inclusion of RBD improves the diagnostic
classification of dementia with Lewy
bodiesTJ Ferman PhD BF Boeve MD et al
u cohort of 234 autopsy-confirmed dementia
patients followed longitudinally
u a history of definite or probable RBD was
present in 76 of 98 autopsy-confirmed DLB
indicating it is a frequent feature of DLB
u A history of RBD improves clinical diagnostic
accuracy and increases the odds of autopsy-
confirmed DLB by 6-fold9u Neurology 201177875ndash88
RBD ndashdemenza a corpi di Lewy
u the presence of RBD may reflect a distinct subtype of DLB suggestive of a bottom-up disease progression
u while DLB without RBD has additional features suggestive of a top-down progression
u Does RBD define clinicopathologic subtypes of DLB with distinct patterns of disease progression and treatment response It could help the development of biomarkers that may assist in differential diagnosis early detection and prognosis of DLBhelliphelliphelliphelliphellip
RBD e allucinazioni
u Iniziali report hanno esaltato
lrsquoassociazione tra rbd e allucinazioni
visive (Pacchetti Sinforiani Onofrij)
u Alcuni le hanno considerate intrusioni
di sonno REMhelliphellip
u Studi piugrave recenti non hanno trovato
chiare associazioni (Postuma hellip)
uLa latenza di conversione da
RBD idiopatico a RBD in
malattia neurodegenerativa
cambia negli anni
u Maggior attenzione e capacitagrave
diagnostica
u Studi non solo retrospettivi
u Studi non piugrave limitati solo o
prevalentemente ai centri del sonno
Idiopathic RBD
Multiple subtle abnormalities
Slowing of waking EEG (Fantini 2003)
Neuropsicological deficits (Ferini-Strambi et al 2003 Vendette M 2000
Fantini et al 2011)
Subtle parkinsonism (motor and gait speed) (Postuma 2006)h
Autonomic impairment (Ferini-Strambi 1996 Lanfranchi 2007 Postuma
2010
Olfactory deficit (Fantini 2006 Postuma 2006)
Color vision impairment (Postuma 2006)
Neuroimaging
abilitagrave visuospaziali logiche non verbali attenzione funzioni esecutive
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Mayo
Clinic
Neurol Sci 2012 Apr33(2)371-3
REM sleep behavior disorder in a patient
with frontotemporal dementia
Lo Coco D Cupidi C Mattaliano A Baiamonte V Realmuto S
Cannizzaro E
RBD idiopatico
u Non associato ad altre diagnosi neurologiche
u Prevalenza stimata con interviste
telefoniche ( soggetti 15-100 anni) 05 (Ohayon 1997)
u Con PSG in pz con etagrave avanzata spesso declino cognitivo che
si rivolgono a Centro del sonno 002 bias di selezione
u Prevalenza maschile (MF 91) in PD 72
In LBD72 In MSA 64
u Etagrave drsquoesordio maggiore di 50 anni
u Evoluzione verso malattie
neurodegenerative nel 65 dei casi
38 of 29 iRBD pts developed parkinsonism andor
dementia after 12 yrs from onset (and 65 after 21 yrs
from RBD onset) (Schenk 1996 and 2005)
45 developed PD MSA DLB MCI after a mean of 115
years from the RBD onset (Iranzo at al 2006)
Esiste realmente lrsquoRBD idiopatico
RBD idiopatico al follow up
Iranzo 2013 The Lancet Neurology
u idiopathic RBD represents the
prodromal phase of a Lewy body
disorder and with sufficient
follow-up most cases would
eventually be diagnosed with a
clinical defined Lewy body
disorder such as Parkinsons
disease (PD) or dementia with
Lewy bodies (DLB)
u Patients from an IRBD cohort recruited
between 1991 and 2003 and previously
assessed in 2005 were followed up
during an additional period of 7 years
u Of the 44 participants from the original
cohort 36 (82) by the 2012 assessment
16 patients were diagnosed with PD
u 14 with DLB
u 1 with multiple system atrophy
u 5 with mild cognitive impairment
Iranzo 2013
Follow-up of idiopathic RBD patients
Predicting value of PLMS
u In the study of Schenck et al 1996 the only variable that
differentiated iRBD that eventually developed PD (38)
from those remaining idiopathic was the PLMS index at
the time of RBD diagnosis (852 vs 359)
u In a serie of 100 patients with RBD diagnosed at the Sleep
Disorders Center of San Raffaele H the PLMS index was
significantly higher in the symptomatic RBD compared to
the idiopathic ones (86 vs 58 with a PLMS indexgt10) (Zucconi et al 2003)
Risk 5-year 177 10-year 406 12-year 524
( 14PD i 1MSA 11 dementia- 7LBD 4 AD )
Cohort of
93 IRBD (
PSG) pts
Neurology 2009
u Ann Neurol 2012 Jan71(1)49-56 doi
101002ana22655
u Probable rapid eye movement sleep behavior
disorder increases risk for mild cognitive
impairment and Parkinson disease a
population-based studyu Boot BP Boeve BF et al
u Cognitively normal subjects aged 70 to 89
years in a population-based study of aging who screened
positive for probable RBD using the Mayo Sleep
Questionnaire were followed at 15-month intervals
u INTERPRETATION
u In this population-based cohort study RBD confers a
22-fold increased risk of developing MCIPD over 4
years
Neurology 2007
3 YEARS
Follow-up
Mov Dis 2012 (early view)
u Lancet Neurol 2013 May12(5)417-9
u REM sleep behaviour disorder a markerof synucleinopathy
u Mahowald MW Schenck CH
u Lancet Neurol 2013 May 12 (5) 469-82
u Idiopathic RBD in the development of PD
u Boeve BF
u Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder anobservational cohort study
Inclusion of RBD improves the diagnostic
classification of dementia with Lewy
bodiesTJ Ferman PhD BF Boeve MD et al
u cohort of 234 autopsy-confirmed dementia
patients followed longitudinally
u a history of definite or probable RBD was
present in 76 of 98 autopsy-confirmed DLB
indicating it is a frequent feature of DLB
u A history of RBD improves clinical diagnostic
accuracy and increases the odds of autopsy-
confirmed DLB by 6-fold9u Neurology 201177875ndash88
RBD ndashdemenza a corpi di Lewy
u the presence of RBD may reflect a distinct subtype of DLB suggestive of a bottom-up disease progression
u while DLB without RBD has additional features suggestive of a top-down progression
u Does RBD define clinicopathologic subtypes of DLB with distinct patterns of disease progression and treatment response It could help the development of biomarkers that may assist in differential diagnosis early detection and prognosis of DLBhelliphelliphelliphelliphellip
RBD e allucinazioni
u Iniziali report hanno esaltato
lrsquoassociazione tra rbd e allucinazioni
visive (Pacchetti Sinforiani Onofrij)
u Alcuni le hanno considerate intrusioni
di sonno REMhelliphellip
u Studi piugrave recenti non hanno trovato
chiare associazioni (Postuma hellip)
uLa latenza di conversione da
RBD idiopatico a RBD in
malattia neurodegenerativa
cambia negli anni
u Maggior attenzione e capacitagrave
diagnostica
u Studi non solo retrospettivi
u Studi non piugrave limitati solo o
prevalentemente ai centri del sonno
Idiopathic RBD
Multiple subtle abnormalities
Slowing of waking EEG (Fantini 2003)
Neuropsicological deficits (Ferini-Strambi et al 2003 Vendette M 2000
Fantini et al 2011)
Subtle parkinsonism (motor and gait speed) (Postuma 2006)h
Autonomic impairment (Ferini-Strambi 1996 Lanfranchi 2007 Postuma
2010
Olfactory deficit (Fantini 2006 Postuma 2006)
Color vision impairment (Postuma 2006)
Neuroimaging
abilitagrave visuospaziali logiche non verbali attenzione funzioni esecutive
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Neurol Sci 2012 Apr33(2)371-3
REM sleep behavior disorder in a patient
with frontotemporal dementia
Lo Coco D Cupidi C Mattaliano A Baiamonte V Realmuto S
Cannizzaro E
RBD idiopatico
u Non associato ad altre diagnosi neurologiche
u Prevalenza stimata con interviste
telefoniche ( soggetti 15-100 anni) 05 (Ohayon 1997)
u Con PSG in pz con etagrave avanzata spesso declino cognitivo che
si rivolgono a Centro del sonno 002 bias di selezione
u Prevalenza maschile (MF 91) in PD 72
In LBD72 In MSA 64
u Etagrave drsquoesordio maggiore di 50 anni
u Evoluzione verso malattie
neurodegenerative nel 65 dei casi
38 of 29 iRBD pts developed parkinsonism andor
dementia after 12 yrs from onset (and 65 after 21 yrs
from RBD onset) (Schenk 1996 and 2005)
45 developed PD MSA DLB MCI after a mean of 115
years from the RBD onset (Iranzo at al 2006)
Esiste realmente lrsquoRBD idiopatico
RBD idiopatico al follow up
Iranzo 2013 The Lancet Neurology
u idiopathic RBD represents the
prodromal phase of a Lewy body
disorder and with sufficient
follow-up most cases would
eventually be diagnosed with a
clinical defined Lewy body
disorder such as Parkinsons
disease (PD) or dementia with
Lewy bodies (DLB)
u Patients from an IRBD cohort recruited
between 1991 and 2003 and previously
assessed in 2005 were followed up
during an additional period of 7 years
u Of the 44 participants from the original
cohort 36 (82) by the 2012 assessment
16 patients were diagnosed with PD
u 14 with DLB
u 1 with multiple system atrophy
u 5 with mild cognitive impairment
Iranzo 2013
Follow-up of idiopathic RBD patients
Predicting value of PLMS
u In the study of Schenck et al 1996 the only variable that
differentiated iRBD that eventually developed PD (38)
from those remaining idiopathic was the PLMS index at
the time of RBD diagnosis (852 vs 359)
u In a serie of 100 patients with RBD diagnosed at the Sleep
Disorders Center of San Raffaele H the PLMS index was
significantly higher in the symptomatic RBD compared to
the idiopathic ones (86 vs 58 with a PLMS indexgt10) (Zucconi et al 2003)
Risk 5-year 177 10-year 406 12-year 524
( 14PD i 1MSA 11 dementia- 7LBD 4 AD )
Cohort of
93 IRBD (
PSG) pts
Neurology 2009
u Ann Neurol 2012 Jan71(1)49-56 doi
101002ana22655
u Probable rapid eye movement sleep behavior
disorder increases risk for mild cognitive
impairment and Parkinson disease a
population-based studyu Boot BP Boeve BF et al
u Cognitively normal subjects aged 70 to 89
years in a population-based study of aging who screened
positive for probable RBD using the Mayo Sleep
Questionnaire were followed at 15-month intervals
u INTERPRETATION
u In this population-based cohort study RBD confers a
22-fold increased risk of developing MCIPD over 4
years
Neurology 2007
3 YEARS
Follow-up
Mov Dis 2012 (early view)
u Lancet Neurol 2013 May12(5)417-9
u REM sleep behaviour disorder a markerof synucleinopathy
u Mahowald MW Schenck CH
u Lancet Neurol 2013 May 12 (5) 469-82
u Idiopathic RBD in the development of PD
u Boeve BF
u Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder anobservational cohort study
Inclusion of RBD improves the diagnostic
classification of dementia with Lewy
bodiesTJ Ferman PhD BF Boeve MD et al
u cohort of 234 autopsy-confirmed dementia
patients followed longitudinally
u a history of definite or probable RBD was
present in 76 of 98 autopsy-confirmed DLB
indicating it is a frequent feature of DLB
u A history of RBD improves clinical diagnostic
accuracy and increases the odds of autopsy-
confirmed DLB by 6-fold9u Neurology 201177875ndash88
RBD ndashdemenza a corpi di Lewy
u the presence of RBD may reflect a distinct subtype of DLB suggestive of a bottom-up disease progression
u while DLB without RBD has additional features suggestive of a top-down progression
u Does RBD define clinicopathologic subtypes of DLB with distinct patterns of disease progression and treatment response It could help the development of biomarkers that may assist in differential diagnosis early detection and prognosis of DLBhelliphelliphelliphelliphellip
RBD e allucinazioni
u Iniziali report hanno esaltato
lrsquoassociazione tra rbd e allucinazioni
visive (Pacchetti Sinforiani Onofrij)
u Alcuni le hanno considerate intrusioni
di sonno REMhelliphellip
u Studi piugrave recenti non hanno trovato
chiare associazioni (Postuma hellip)
uLa latenza di conversione da
RBD idiopatico a RBD in
malattia neurodegenerativa
cambia negli anni
u Maggior attenzione e capacitagrave
diagnostica
u Studi non solo retrospettivi
u Studi non piugrave limitati solo o
prevalentemente ai centri del sonno
Idiopathic RBD
Multiple subtle abnormalities
Slowing of waking EEG (Fantini 2003)
Neuropsicological deficits (Ferini-Strambi et al 2003 Vendette M 2000
Fantini et al 2011)
Subtle parkinsonism (motor and gait speed) (Postuma 2006)h
Autonomic impairment (Ferini-Strambi 1996 Lanfranchi 2007 Postuma
2010
Olfactory deficit (Fantini 2006 Postuma 2006)
Color vision impairment (Postuma 2006)
Neuroimaging
abilitagrave visuospaziali logiche non verbali attenzione funzioni esecutive
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
RBD idiopatico
u Non associato ad altre diagnosi neurologiche
u Prevalenza stimata con interviste
telefoniche ( soggetti 15-100 anni) 05 (Ohayon 1997)
u Con PSG in pz con etagrave avanzata spesso declino cognitivo che
si rivolgono a Centro del sonno 002 bias di selezione
u Prevalenza maschile (MF 91) in PD 72
In LBD72 In MSA 64
u Etagrave drsquoesordio maggiore di 50 anni
u Evoluzione verso malattie
neurodegenerative nel 65 dei casi
38 of 29 iRBD pts developed parkinsonism andor
dementia after 12 yrs from onset (and 65 after 21 yrs
from RBD onset) (Schenk 1996 and 2005)
45 developed PD MSA DLB MCI after a mean of 115
years from the RBD onset (Iranzo at al 2006)
Esiste realmente lrsquoRBD idiopatico
RBD idiopatico al follow up
Iranzo 2013 The Lancet Neurology
u idiopathic RBD represents the
prodromal phase of a Lewy body
disorder and with sufficient
follow-up most cases would
eventually be diagnosed with a
clinical defined Lewy body
disorder such as Parkinsons
disease (PD) or dementia with
Lewy bodies (DLB)
u Patients from an IRBD cohort recruited
between 1991 and 2003 and previously
assessed in 2005 were followed up
during an additional period of 7 years
u Of the 44 participants from the original
cohort 36 (82) by the 2012 assessment
16 patients were diagnosed with PD
u 14 with DLB
u 1 with multiple system atrophy
u 5 with mild cognitive impairment
Iranzo 2013
Follow-up of idiopathic RBD patients
Predicting value of PLMS
u In the study of Schenck et al 1996 the only variable that
differentiated iRBD that eventually developed PD (38)
from those remaining idiopathic was the PLMS index at
the time of RBD diagnosis (852 vs 359)
u In a serie of 100 patients with RBD diagnosed at the Sleep
Disorders Center of San Raffaele H the PLMS index was
significantly higher in the symptomatic RBD compared to
the idiopathic ones (86 vs 58 with a PLMS indexgt10) (Zucconi et al 2003)
Risk 5-year 177 10-year 406 12-year 524
( 14PD i 1MSA 11 dementia- 7LBD 4 AD )
Cohort of
93 IRBD (
PSG) pts
Neurology 2009
u Ann Neurol 2012 Jan71(1)49-56 doi
101002ana22655
u Probable rapid eye movement sleep behavior
disorder increases risk for mild cognitive
impairment and Parkinson disease a
population-based studyu Boot BP Boeve BF et al
u Cognitively normal subjects aged 70 to 89
years in a population-based study of aging who screened
positive for probable RBD using the Mayo Sleep
Questionnaire were followed at 15-month intervals
u INTERPRETATION
u In this population-based cohort study RBD confers a
22-fold increased risk of developing MCIPD over 4
years
Neurology 2007
3 YEARS
Follow-up
Mov Dis 2012 (early view)
u Lancet Neurol 2013 May12(5)417-9
u REM sleep behaviour disorder a markerof synucleinopathy
u Mahowald MW Schenck CH
u Lancet Neurol 2013 May 12 (5) 469-82
u Idiopathic RBD in the development of PD
u Boeve BF
u Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder anobservational cohort study
Inclusion of RBD improves the diagnostic
classification of dementia with Lewy
bodiesTJ Ferman PhD BF Boeve MD et al
u cohort of 234 autopsy-confirmed dementia
patients followed longitudinally
u a history of definite or probable RBD was
present in 76 of 98 autopsy-confirmed DLB
indicating it is a frequent feature of DLB
u A history of RBD improves clinical diagnostic
accuracy and increases the odds of autopsy-
confirmed DLB by 6-fold9u Neurology 201177875ndash88
RBD ndashdemenza a corpi di Lewy
u the presence of RBD may reflect a distinct subtype of DLB suggestive of a bottom-up disease progression
u while DLB without RBD has additional features suggestive of a top-down progression
u Does RBD define clinicopathologic subtypes of DLB with distinct patterns of disease progression and treatment response It could help the development of biomarkers that may assist in differential diagnosis early detection and prognosis of DLBhelliphelliphelliphelliphellip
RBD e allucinazioni
u Iniziali report hanno esaltato
lrsquoassociazione tra rbd e allucinazioni
visive (Pacchetti Sinforiani Onofrij)
u Alcuni le hanno considerate intrusioni
di sonno REMhelliphellip
u Studi piugrave recenti non hanno trovato
chiare associazioni (Postuma hellip)
uLa latenza di conversione da
RBD idiopatico a RBD in
malattia neurodegenerativa
cambia negli anni
u Maggior attenzione e capacitagrave
diagnostica
u Studi non solo retrospettivi
u Studi non piugrave limitati solo o
prevalentemente ai centri del sonno
Idiopathic RBD
Multiple subtle abnormalities
Slowing of waking EEG (Fantini 2003)
Neuropsicological deficits (Ferini-Strambi et al 2003 Vendette M 2000
Fantini et al 2011)
Subtle parkinsonism (motor and gait speed) (Postuma 2006)h
Autonomic impairment (Ferini-Strambi 1996 Lanfranchi 2007 Postuma
2010
Olfactory deficit (Fantini 2006 Postuma 2006)
Color vision impairment (Postuma 2006)
Neuroimaging
abilitagrave visuospaziali logiche non verbali attenzione funzioni esecutive
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
u Evoluzione verso malattie
neurodegenerative nel 65 dei casi
38 of 29 iRBD pts developed parkinsonism andor
dementia after 12 yrs from onset (and 65 after 21 yrs
from RBD onset) (Schenk 1996 and 2005)
45 developed PD MSA DLB MCI after a mean of 115
years from the RBD onset (Iranzo at al 2006)
Esiste realmente lrsquoRBD idiopatico
RBD idiopatico al follow up
Iranzo 2013 The Lancet Neurology
u idiopathic RBD represents the
prodromal phase of a Lewy body
disorder and with sufficient
follow-up most cases would
eventually be diagnosed with a
clinical defined Lewy body
disorder such as Parkinsons
disease (PD) or dementia with
Lewy bodies (DLB)
u Patients from an IRBD cohort recruited
between 1991 and 2003 and previously
assessed in 2005 were followed up
during an additional period of 7 years
u Of the 44 participants from the original
cohort 36 (82) by the 2012 assessment
16 patients were diagnosed with PD
u 14 with DLB
u 1 with multiple system atrophy
u 5 with mild cognitive impairment
Iranzo 2013
Follow-up of idiopathic RBD patients
Predicting value of PLMS
u In the study of Schenck et al 1996 the only variable that
differentiated iRBD that eventually developed PD (38)
from those remaining idiopathic was the PLMS index at
the time of RBD diagnosis (852 vs 359)
u In a serie of 100 patients with RBD diagnosed at the Sleep
Disorders Center of San Raffaele H the PLMS index was
significantly higher in the symptomatic RBD compared to
the idiopathic ones (86 vs 58 with a PLMS indexgt10) (Zucconi et al 2003)
Risk 5-year 177 10-year 406 12-year 524
( 14PD i 1MSA 11 dementia- 7LBD 4 AD )
Cohort of
93 IRBD (
PSG) pts
Neurology 2009
u Ann Neurol 2012 Jan71(1)49-56 doi
101002ana22655
u Probable rapid eye movement sleep behavior
disorder increases risk for mild cognitive
impairment and Parkinson disease a
population-based studyu Boot BP Boeve BF et al
u Cognitively normal subjects aged 70 to 89
years in a population-based study of aging who screened
positive for probable RBD using the Mayo Sleep
Questionnaire were followed at 15-month intervals
u INTERPRETATION
u In this population-based cohort study RBD confers a
22-fold increased risk of developing MCIPD over 4
years
Neurology 2007
3 YEARS
Follow-up
Mov Dis 2012 (early view)
u Lancet Neurol 2013 May12(5)417-9
u REM sleep behaviour disorder a markerof synucleinopathy
u Mahowald MW Schenck CH
u Lancet Neurol 2013 May 12 (5) 469-82
u Idiopathic RBD in the development of PD
u Boeve BF
u Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder anobservational cohort study
Inclusion of RBD improves the diagnostic
classification of dementia with Lewy
bodiesTJ Ferman PhD BF Boeve MD et al
u cohort of 234 autopsy-confirmed dementia
patients followed longitudinally
u a history of definite or probable RBD was
present in 76 of 98 autopsy-confirmed DLB
indicating it is a frequent feature of DLB
u A history of RBD improves clinical diagnostic
accuracy and increases the odds of autopsy-
confirmed DLB by 6-fold9u Neurology 201177875ndash88
RBD ndashdemenza a corpi di Lewy
u the presence of RBD may reflect a distinct subtype of DLB suggestive of a bottom-up disease progression
u while DLB without RBD has additional features suggestive of a top-down progression
u Does RBD define clinicopathologic subtypes of DLB with distinct patterns of disease progression and treatment response It could help the development of biomarkers that may assist in differential diagnosis early detection and prognosis of DLBhelliphelliphelliphelliphellip
RBD e allucinazioni
u Iniziali report hanno esaltato
lrsquoassociazione tra rbd e allucinazioni
visive (Pacchetti Sinforiani Onofrij)
u Alcuni le hanno considerate intrusioni
di sonno REMhelliphellip
u Studi piugrave recenti non hanno trovato
chiare associazioni (Postuma hellip)
uLa latenza di conversione da
RBD idiopatico a RBD in
malattia neurodegenerativa
cambia negli anni
u Maggior attenzione e capacitagrave
diagnostica
u Studi non solo retrospettivi
u Studi non piugrave limitati solo o
prevalentemente ai centri del sonno
Idiopathic RBD
Multiple subtle abnormalities
Slowing of waking EEG (Fantini 2003)
Neuropsicological deficits (Ferini-Strambi et al 2003 Vendette M 2000
Fantini et al 2011)
Subtle parkinsonism (motor and gait speed) (Postuma 2006)h
Autonomic impairment (Ferini-Strambi 1996 Lanfranchi 2007 Postuma
2010
Olfactory deficit (Fantini 2006 Postuma 2006)
Color vision impairment (Postuma 2006)
Neuroimaging
abilitagrave visuospaziali logiche non verbali attenzione funzioni esecutive
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Iranzo 2013 The Lancet Neurology
u idiopathic RBD represents the
prodromal phase of a Lewy body
disorder and with sufficient
follow-up most cases would
eventually be diagnosed with a
clinical defined Lewy body
disorder such as Parkinsons
disease (PD) or dementia with
Lewy bodies (DLB)
u Patients from an IRBD cohort recruited
between 1991 and 2003 and previously
assessed in 2005 were followed up
during an additional period of 7 years
u Of the 44 participants from the original
cohort 36 (82) by the 2012 assessment
16 patients were diagnosed with PD
u 14 with DLB
u 1 with multiple system atrophy
u 5 with mild cognitive impairment
Iranzo 2013
Follow-up of idiopathic RBD patients
Predicting value of PLMS
u In the study of Schenck et al 1996 the only variable that
differentiated iRBD that eventually developed PD (38)
from those remaining idiopathic was the PLMS index at
the time of RBD diagnosis (852 vs 359)
u In a serie of 100 patients with RBD diagnosed at the Sleep
Disorders Center of San Raffaele H the PLMS index was
significantly higher in the symptomatic RBD compared to
the idiopathic ones (86 vs 58 with a PLMS indexgt10) (Zucconi et al 2003)
Risk 5-year 177 10-year 406 12-year 524
( 14PD i 1MSA 11 dementia- 7LBD 4 AD )
Cohort of
93 IRBD (
PSG) pts
Neurology 2009
u Ann Neurol 2012 Jan71(1)49-56 doi
101002ana22655
u Probable rapid eye movement sleep behavior
disorder increases risk for mild cognitive
impairment and Parkinson disease a
population-based studyu Boot BP Boeve BF et al
u Cognitively normal subjects aged 70 to 89
years in a population-based study of aging who screened
positive for probable RBD using the Mayo Sleep
Questionnaire were followed at 15-month intervals
u INTERPRETATION
u In this population-based cohort study RBD confers a
22-fold increased risk of developing MCIPD over 4
years
Neurology 2007
3 YEARS
Follow-up
Mov Dis 2012 (early view)
u Lancet Neurol 2013 May12(5)417-9
u REM sleep behaviour disorder a markerof synucleinopathy
u Mahowald MW Schenck CH
u Lancet Neurol 2013 May 12 (5) 469-82
u Idiopathic RBD in the development of PD
u Boeve BF
u Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder anobservational cohort study
Inclusion of RBD improves the diagnostic
classification of dementia with Lewy
bodiesTJ Ferman PhD BF Boeve MD et al
u cohort of 234 autopsy-confirmed dementia
patients followed longitudinally
u a history of definite or probable RBD was
present in 76 of 98 autopsy-confirmed DLB
indicating it is a frequent feature of DLB
u A history of RBD improves clinical diagnostic
accuracy and increases the odds of autopsy-
confirmed DLB by 6-fold9u Neurology 201177875ndash88
RBD ndashdemenza a corpi di Lewy
u the presence of RBD may reflect a distinct subtype of DLB suggestive of a bottom-up disease progression
u while DLB without RBD has additional features suggestive of a top-down progression
u Does RBD define clinicopathologic subtypes of DLB with distinct patterns of disease progression and treatment response It could help the development of biomarkers that may assist in differential diagnosis early detection and prognosis of DLBhelliphelliphelliphelliphellip
RBD e allucinazioni
u Iniziali report hanno esaltato
lrsquoassociazione tra rbd e allucinazioni
visive (Pacchetti Sinforiani Onofrij)
u Alcuni le hanno considerate intrusioni
di sonno REMhelliphellip
u Studi piugrave recenti non hanno trovato
chiare associazioni (Postuma hellip)
uLa latenza di conversione da
RBD idiopatico a RBD in
malattia neurodegenerativa
cambia negli anni
u Maggior attenzione e capacitagrave
diagnostica
u Studi non solo retrospettivi
u Studi non piugrave limitati solo o
prevalentemente ai centri del sonno
Idiopathic RBD
Multiple subtle abnormalities
Slowing of waking EEG (Fantini 2003)
Neuropsicological deficits (Ferini-Strambi et al 2003 Vendette M 2000
Fantini et al 2011)
Subtle parkinsonism (motor and gait speed) (Postuma 2006)h
Autonomic impairment (Ferini-Strambi 1996 Lanfranchi 2007 Postuma
2010
Olfactory deficit (Fantini 2006 Postuma 2006)
Color vision impairment (Postuma 2006)
Neuroimaging
abilitagrave visuospaziali logiche non verbali attenzione funzioni esecutive
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
u Patients from an IRBD cohort recruited
between 1991 and 2003 and previously
assessed in 2005 were followed up
during an additional period of 7 years
u Of the 44 participants from the original
cohort 36 (82) by the 2012 assessment
16 patients were diagnosed with PD
u 14 with DLB
u 1 with multiple system atrophy
u 5 with mild cognitive impairment
Iranzo 2013
Follow-up of idiopathic RBD patients
Predicting value of PLMS
u In the study of Schenck et al 1996 the only variable that
differentiated iRBD that eventually developed PD (38)
from those remaining idiopathic was the PLMS index at
the time of RBD diagnosis (852 vs 359)
u In a serie of 100 patients with RBD diagnosed at the Sleep
Disorders Center of San Raffaele H the PLMS index was
significantly higher in the symptomatic RBD compared to
the idiopathic ones (86 vs 58 with a PLMS indexgt10) (Zucconi et al 2003)
Risk 5-year 177 10-year 406 12-year 524
( 14PD i 1MSA 11 dementia- 7LBD 4 AD )
Cohort of
93 IRBD (
PSG) pts
Neurology 2009
u Ann Neurol 2012 Jan71(1)49-56 doi
101002ana22655
u Probable rapid eye movement sleep behavior
disorder increases risk for mild cognitive
impairment and Parkinson disease a
population-based studyu Boot BP Boeve BF et al
u Cognitively normal subjects aged 70 to 89
years in a population-based study of aging who screened
positive for probable RBD using the Mayo Sleep
Questionnaire were followed at 15-month intervals
u INTERPRETATION
u In this population-based cohort study RBD confers a
22-fold increased risk of developing MCIPD over 4
years
Neurology 2007
3 YEARS
Follow-up
Mov Dis 2012 (early view)
u Lancet Neurol 2013 May12(5)417-9
u REM sleep behaviour disorder a markerof synucleinopathy
u Mahowald MW Schenck CH
u Lancet Neurol 2013 May 12 (5) 469-82
u Idiopathic RBD in the development of PD
u Boeve BF
u Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder anobservational cohort study
Inclusion of RBD improves the diagnostic
classification of dementia with Lewy
bodiesTJ Ferman PhD BF Boeve MD et al
u cohort of 234 autopsy-confirmed dementia
patients followed longitudinally
u a history of definite or probable RBD was
present in 76 of 98 autopsy-confirmed DLB
indicating it is a frequent feature of DLB
u A history of RBD improves clinical diagnostic
accuracy and increases the odds of autopsy-
confirmed DLB by 6-fold9u Neurology 201177875ndash88
RBD ndashdemenza a corpi di Lewy
u the presence of RBD may reflect a distinct subtype of DLB suggestive of a bottom-up disease progression
u while DLB without RBD has additional features suggestive of a top-down progression
u Does RBD define clinicopathologic subtypes of DLB with distinct patterns of disease progression and treatment response It could help the development of biomarkers that may assist in differential diagnosis early detection and prognosis of DLBhelliphelliphelliphelliphellip
RBD e allucinazioni
u Iniziali report hanno esaltato
lrsquoassociazione tra rbd e allucinazioni
visive (Pacchetti Sinforiani Onofrij)
u Alcuni le hanno considerate intrusioni
di sonno REMhelliphellip
u Studi piugrave recenti non hanno trovato
chiare associazioni (Postuma hellip)
uLa latenza di conversione da
RBD idiopatico a RBD in
malattia neurodegenerativa
cambia negli anni
u Maggior attenzione e capacitagrave
diagnostica
u Studi non solo retrospettivi
u Studi non piugrave limitati solo o
prevalentemente ai centri del sonno
Idiopathic RBD
Multiple subtle abnormalities
Slowing of waking EEG (Fantini 2003)
Neuropsicological deficits (Ferini-Strambi et al 2003 Vendette M 2000
Fantini et al 2011)
Subtle parkinsonism (motor and gait speed) (Postuma 2006)h
Autonomic impairment (Ferini-Strambi 1996 Lanfranchi 2007 Postuma
2010
Olfactory deficit (Fantini 2006 Postuma 2006)
Color vision impairment (Postuma 2006)
Neuroimaging
abilitagrave visuospaziali logiche non verbali attenzione funzioni esecutive
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Follow-up of idiopathic RBD patients
Predicting value of PLMS
u In the study of Schenck et al 1996 the only variable that
differentiated iRBD that eventually developed PD (38)
from those remaining idiopathic was the PLMS index at
the time of RBD diagnosis (852 vs 359)
u In a serie of 100 patients with RBD diagnosed at the Sleep
Disorders Center of San Raffaele H the PLMS index was
significantly higher in the symptomatic RBD compared to
the idiopathic ones (86 vs 58 with a PLMS indexgt10) (Zucconi et al 2003)
Risk 5-year 177 10-year 406 12-year 524
( 14PD i 1MSA 11 dementia- 7LBD 4 AD )
Cohort of
93 IRBD (
PSG) pts
Neurology 2009
u Ann Neurol 2012 Jan71(1)49-56 doi
101002ana22655
u Probable rapid eye movement sleep behavior
disorder increases risk for mild cognitive
impairment and Parkinson disease a
population-based studyu Boot BP Boeve BF et al
u Cognitively normal subjects aged 70 to 89
years in a population-based study of aging who screened
positive for probable RBD using the Mayo Sleep
Questionnaire were followed at 15-month intervals
u INTERPRETATION
u In this population-based cohort study RBD confers a
22-fold increased risk of developing MCIPD over 4
years
Neurology 2007
3 YEARS
Follow-up
Mov Dis 2012 (early view)
u Lancet Neurol 2013 May12(5)417-9
u REM sleep behaviour disorder a markerof synucleinopathy
u Mahowald MW Schenck CH
u Lancet Neurol 2013 May 12 (5) 469-82
u Idiopathic RBD in the development of PD
u Boeve BF
u Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder anobservational cohort study
Inclusion of RBD improves the diagnostic
classification of dementia with Lewy
bodiesTJ Ferman PhD BF Boeve MD et al
u cohort of 234 autopsy-confirmed dementia
patients followed longitudinally
u a history of definite or probable RBD was
present in 76 of 98 autopsy-confirmed DLB
indicating it is a frequent feature of DLB
u A history of RBD improves clinical diagnostic
accuracy and increases the odds of autopsy-
confirmed DLB by 6-fold9u Neurology 201177875ndash88
RBD ndashdemenza a corpi di Lewy
u the presence of RBD may reflect a distinct subtype of DLB suggestive of a bottom-up disease progression
u while DLB without RBD has additional features suggestive of a top-down progression
u Does RBD define clinicopathologic subtypes of DLB with distinct patterns of disease progression and treatment response It could help the development of biomarkers that may assist in differential diagnosis early detection and prognosis of DLBhelliphelliphelliphelliphellip
RBD e allucinazioni
u Iniziali report hanno esaltato
lrsquoassociazione tra rbd e allucinazioni
visive (Pacchetti Sinforiani Onofrij)
u Alcuni le hanno considerate intrusioni
di sonno REMhelliphellip
u Studi piugrave recenti non hanno trovato
chiare associazioni (Postuma hellip)
uLa latenza di conversione da
RBD idiopatico a RBD in
malattia neurodegenerativa
cambia negli anni
u Maggior attenzione e capacitagrave
diagnostica
u Studi non solo retrospettivi
u Studi non piugrave limitati solo o
prevalentemente ai centri del sonno
Idiopathic RBD
Multiple subtle abnormalities
Slowing of waking EEG (Fantini 2003)
Neuropsicological deficits (Ferini-Strambi et al 2003 Vendette M 2000
Fantini et al 2011)
Subtle parkinsonism (motor and gait speed) (Postuma 2006)h
Autonomic impairment (Ferini-Strambi 1996 Lanfranchi 2007 Postuma
2010
Olfactory deficit (Fantini 2006 Postuma 2006)
Color vision impairment (Postuma 2006)
Neuroimaging
abilitagrave visuospaziali logiche non verbali attenzione funzioni esecutive
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Risk 5-year 177 10-year 406 12-year 524
( 14PD i 1MSA 11 dementia- 7LBD 4 AD )
Cohort of
93 IRBD (
PSG) pts
Neurology 2009
u Ann Neurol 2012 Jan71(1)49-56 doi
101002ana22655
u Probable rapid eye movement sleep behavior
disorder increases risk for mild cognitive
impairment and Parkinson disease a
population-based studyu Boot BP Boeve BF et al
u Cognitively normal subjects aged 70 to 89
years in a population-based study of aging who screened
positive for probable RBD using the Mayo Sleep
Questionnaire were followed at 15-month intervals
u INTERPRETATION
u In this population-based cohort study RBD confers a
22-fold increased risk of developing MCIPD over 4
years
Neurology 2007
3 YEARS
Follow-up
Mov Dis 2012 (early view)
u Lancet Neurol 2013 May12(5)417-9
u REM sleep behaviour disorder a markerof synucleinopathy
u Mahowald MW Schenck CH
u Lancet Neurol 2013 May 12 (5) 469-82
u Idiopathic RBD in the development of PD
u Boeve BF
u Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder anobservational cohort study
Inclusion of RBD improves the diagnostic
classification of dementia with Lewy
bodiesTJ Ferman PhD BF Boeve MD et al
u cohort of 234 autopsy-confirmed dementia
patients followed longitudinally
u a history of definite or probable RBD was
present in 76 of 98 autopsy-confirmed DLB
indicating it is a frequent feature of DLB
u A history of RBD improves clinical diagnostic
accuracy and increases the odds of autopsy-
confirmed DLB by 6-fold9u Neurology 201177875ndash88
RBD ndashdemenza a corpi di Lewy
u the presence of RBD may reflect a distinct subtype of DLB suggestive of a bottom-up disease progression
u while DLB without RBD has additional features suggestive of a top-down progression
u Does RBD define clinicopathologic subtypes of DLB with distinct patterns of disease progression and treatment response It could help the development of biomarkers that may assist in differential diagnosis early detection and prognosis of DLBhelliphelliphelliphelliphellip
RBD e allucinazioni
u Iniziali report hanno esaltato
lrsquoassociazione tra rbd e allucinazioni
visive (Pacchetti Sinforiani Onofrij)
u Alcuni le hanno considerate intrusioni
di sonno REMhelliphellip
u Studi piugrave recenti non hanno trovato
chiare associazioni (Postuma hellip)
uLa latenza di conversione da
RBD idiopatico a RBD in
malattia neurodegenerativa
cambia negli anni
u Maggior attenzione e capacitagrave
diagnostica
u Studi non solo retrospettivi
u Studi non piugrave limitati solo o
prevalentemente ai centri del sonno
Idiopathic RBD
Multiple subtle abnormalities
Slowing of waking EEG (Fantini 2003)
Neuropsicological deficits (Ferini-Strambi et al 2003 Vendette M 2000
Fantini et al 2011)
Subtle parkinsonism (motor and gait speed) (Postuma 2006)h
Autonomic impairment (Ferini-Strambi 1996 Lanfranchi 2007 Postuma
2010
Olfactory deficit (Fantini 2006 Postuma 2006)
Color vision impairment (Postuma 2006)
Neuroimaging
abilitagrave visuospaziali logiche non verbali attenzione funzioni esecutive
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
u Ann Neurol 2012 Jan71(1)49-56 doi
101002ana22655
u Probable rapid eye movement sleep behavior
disorder increases risk for mild cognitive
impairment and Parkinson disease a
population-based studyu Boot BP Boeve BF et al
u Cognitively normal subjects aged 70 to 89
years in a population-based study of aging who screened
positive for probable RBD using the Mayo Sleep
Questionnaire were followed at 15-month intervals
u INTERPRETATION
u In this population-based cohort study RBD confers a
22-fold increased risk of developing MCIPD over 4
years
Neurology 2007
3 YEARS
Follow-up
Mov Dis 2012 (early view)
u Lancet Neurol 2013 May12(5)417-9
u REM sleep behaviour disorder a markerof synucleinopathy
u Mahowald MW Schenck CH
u Lancet Neurol 2013 May 12 (5) 469-82
u Idiopathic RBD in the development of PD
u Boeve BF
u Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder anobservational cohort study
Inclusion of RBD improves the diagnostic
classification of dementia with Lewy
bodiesTJ Ferman PhD BF Boeve MD et al
u cohort of 234 autopsy-confirmed dementia
patients followed longitudinally
u a history of definite or probable RBD was
present in 76 of 98 autopsy-confirmed DLB
indicating it is a frequent feature of DLB
u A history of RBD improves clinical diagnostic
accuracy and increases the odds of autopsy-
confirmed DLB by 6-fold9u Neurology 201177875ndash88
RBD ndashdemenza a corpi di Lewy
u the presence of RBD may reflect a distinct subtype of DLB suggestive of a bottom-up disease progression
u while DLB without RBD has additional features suggestive of a top-down progression
u Does RBD define clinicopathologic subtypes of DLB with distinct patterns of disease progression and treatment response It could help the development of biomarkers that may assist in differential diagnosis early detection and prognosis of DLBhelliphelliphelliphelliphellip
RBD e allucinazioni
u Iniziali report hanno esaltato
lrsquoassociazione tra rbd e allucinazioni
visive (Pacchetti Sinforiani Onofrij)
u Alcuni le hanno considerate intrusioni
di sonno REMhelliphellip
u Studi piugrave recenti non hanno trovato
chiare associazioni (Postuma hellip)
uLa latenza di conversione da
RBD idiopatico a RBD in
malattia neurodegenerativa
cambia negli anni
u Maggior attenzione e capacitagrave
diagnostica
u Studi non solo retrospettivi
u Studi non piugrave limitati solo o
prevalentemente ai centri del sonno
Idiopathic RBD
Multiple subtle abnormalities
Slowing of waking EEG (Fantini 2003)
Neuropsicological deficits (Ferini-Strambi et al 2003 Vendette M 2000
Fantini et al 2011)
Subtle parkinsonism (motor and gait speed) (Postuma 2006)h
Autonomic impairment (Ferini-Strambi 1996 Lanfranchi 2007 Postuma
2010
Olfactory deficit (Fantini 2006 Postuma 2006)
Color vision impairment (Postuma 2006)
Neuroimaging
abilitagrave visuospaziali logiche non verbali attenzione funzioni esecutive
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Neurology 2007
3 YEARS
Follow-up
Mov Dis 2012 (early view)
u Lancet Neurol 2013 May12(5)417-9
u REM sleep behaviour disorder a markerof synucleinopathy
u Mahowald MW Schenck CH
u Lancet Neurol 2013 May 12 (5) 469-82
u Idiopathic RBD in the development of PD
u Boeve BF
u Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder anobservational cohort study
Inclusion of RBD improves the diagnostic
classification of dementia with Lewy
bodiesTJ Ferman PhD BF Boeve MD et al
u cohort of 234 autopsy-confirmed dementia
patients followed longitudinally
u a history of definite or probable RBD was
present in 76 of 98 autopsy-confirmed DLB
indicating it is a frequent feature of DLB
u A history of RBD improves clinical diagnostic
accuracy and increases the odds of autopsy-
confirmed DLB by 6-fold9u Neurology 201177875ndash88
RBD ndashdemenza a corpi di Lewy
u the presence of RBD may reflect a distinct subtype of DLB suggestive of a bottom-up disease progression
u while DLB without RBD has additional features suggestive of a top-down progression
u Does RBD define clinicopathologic subtypes of DLB with distinct patterns of disease progression and treatment response It could help the development of biomarkers that may assist in differential diagnosis early detection and prognosis of DLBhelliphelliphelliphelliphellip
RBD e allucinazioni
u Iniziali report hanno esaltato
lrsquoassociazione tra rbd e allucinazioni
visive (Pacchetti Sinforiani Onofrij)
u Alcuni le hanno considerate intrusioni
di sonno REMhelliphellip
u Studi piugrave recenti non hanno trovato
chiare associazioni (Postuma hellip)
uLa latenza di conversione da
RBD idiopatico a RBD in
malattia neurodegenerativa
cambia negli anni
u Maggior attenzione e capacitagrave
diagnostica
u Studi non solo retrospettivi
u Studi non piugrave limitati solo o
prevalentemente ai centri del sonno
Idiopathic RBD
Multiple subtle abnormalities
Slowing of waking EEG (Fantini 2003)
Neuropsicological deficits (Ferini-Strambi et al 2003 Vendette M 2000
Fantini et al 2011)
Subtle parkinsonism (motor and gait speed) (Postuma 2006)h
Autonomic impairment (Ferini-Strambi 1996 Lanfranchi 2007 Postuma
2010
Olfactory deficit (Fantini 2006 Postuma 2006)
Color vision impairment (Postuma 2006)
Neuroimaging
abilitagrave visuospaziali logiche non verbali attenzione funzioni esecutive
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
3 YEARS
Follow-up
Mov Dis 2012 (early view)
u Lancet Neurol 2013 May12(5)417-9
u REM sleep behaviour disorder a markerof synucleinopathy
u Mahowald MW Schenck CH
u Lancet Neurol 2013 May 12 (5) 469-82
u Idiopathic RBD in the development of PD
u Boeve BF
u Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder anobservational cohort study
Inclusion of RBD improves the diagnostic
classification of dementia with Lewy
bodiesTJ Ferman PhD BF Boeve MD et al
u cohort of 234 autopsy-confirmed dementia
patients followed longitudinally
u a history of definite or probable RBD was
present in 76 of 98 autopsy-confirmed DLB
indicating it is a frequent feature of DLB
u A history of RBD improves clinical diagnostic
accuracy and increases the odds of autopsy-
confirmed DLB by 6-fold9u Neurology 201177875ndash88
RBD ndashdemenza a corpi di Lewy
u the presence of RBD may reflect a distinct subtype of DLB suggestive of a bottom-up disease progression
u while DLB without RBD has additional features suggestive of a top-down progression
u Does RBD define clinicopathologic subtypes of DLB with distinct patterns of disease progression and treatment response It could help the development of biomarkers that may assist in differential diagnosis early detection and prognosis of DLBhelliphelliphelliphelliphellip
RBD e allucinazioni
u Iniziali report hanno esaltato
lrsquoassociazione tra rbd e allucinazioni
visive (Pacchetti Sinforiani Onofrij)
u Alcuni le hanno considerate intrusioni
di sonno REMhelliphellip
u Studi piugrave recenti non hanno trovato
chiare associazioni (Postuma hellip)
uLa latenza di conversione da
RBD idiopatico a RBD in
malattia neurodegenerativa
cambia negli anni
u Maggior attenzione e capacitagrave
diagnostica
u Studi non solo retrospettivi
u Studi non piugrave limitati solo o
prevalentemente ai centri del sonno
Idiopathic RBD
Multiple subtle abnormalities
Slowing of waking EEG (Fantini 2003)
Neuropsicological deficits (Ferini-Strambi et al 2003 Vendette M 2000
Fantini et al 2011)
Subtle parkinsonism (motor and gait speed) (Postuma 2006)h
Autonomic impairment (Ferini-Strambi 1996 Lanfranchi 2007 Postuma
2010
Olfactory deficit (Fantini 2006 Postuma 2006)
Color vision impairment (Postuma 2006)
Neuroimaging
abilitagrave visuospaziali logiche non verbali attenzione funzioni esecutive
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
u Lancet Neurol 2013 May12(5)417-9
u REM sleep behaviour disorder a markerof synucleinopathy
u Mahowald MW Schenck CH
u Lancet Neurol 2013 May 12 (5) 469-82
u Idiopathic RBD in the development of PD
u Boeve BF
u Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder anobservational cohort study
Inclusion of RBD improves the diagnostic
classification of dementia with Lewy
bodiesTJ Ferman PhD BF Boeve MD et al
u cohort of 234 autopsy-confirmed dementia
patients followed longitudinally
u a history of definite or probable RBD was
present in 76 of 98 autopsy-confirmed DLB
indicating it is a frequent feature of DLB
u A history of RBD improves clinical diagnostic
accuracy and increases the odds of autopsy-
confirmed DLB by 6-fold9u Neurology 201177875ndash88
RBD ndashdemenza a corpi di Lewy
u the presence of RBD may reflect a distinct subtype of DLB suggestive of a bottom-up disease progression
u while DLB without RBD has additional features suggestive of a top-down progression
u Does RBD define clinicopathologic subtypes of DLB with distinct patterns of disease progression and treatment response It could help the development of biomarkers that may assist in differential diagnosis early detection and prognosis of DLBhelliphelliphelliphelliphellip
RBD e allucinazioni
u Iniziali report hanno esaltato
lrsquoassociazione tra rbd e allucinazioni
visive (Pacchetti Sinforiani Onofrij)
u Alcuni le hanno considerate intrusioni
di sonno REMhelliphellip
u Studi piugrave recenti non hanno trovato
chiare associazioni (Postuma hellip)
uLa latenza di conversione da
RBD idiopatico a RBD in
malattia neurodegenerativa
cambia negli anni
u Maggior attenzione e capacitagrave
diagnostica
u Studi non solo retrospettivi
u Studi non piugrave limitati solo o
prevalentemente ai centri del sonno
Idiopathic RBD
Multiple subtle abnormalities
Slowing of waking EEG (Fantini 2003)
Neuropsicological deficits (Ferini-Strambi et al 2003 Vendette M 2000
Fantini et al 2011)
Subtle parkinsonism (motor and gait speed) (Postuma 2006)h
Autonomic impairment (Ferini-Strambi 1996 Lanfranchi 2007 Postuma
2010
Olfactory deficit (Fantini 2006 Postuma 2006)
Color vision impairment (Postuma 2006)
Neuroimaging
abilitagrave visuospaziali logiche non verbali attenzione funzioni esecutive
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Inclusion of RBD improves the diagnostic
classification of dementia with Lewy
bodiesTJ Ferman PhD BF Boeve MD et al
u cohort of 234 autopsy-confirmed dementia
patients followed longitudinally
u a history of definite or probable RBD was
present in 76 of 98 autopsy-confirmed DLB
indicating it is a frequent feature of DLB
u A history of RBD improves clinical diagnostic
accuracy and increases the odds of autopsy-
confirmed DLB by 6-fold9u Neurology 201177875ndash88
RBD ndashdemenza a corpi di Lewy
u the presence of RBD may reflect a distinct subtype of DLB suggestive of a bottom-up disease progression
u while DLB without RBD has additional features suggestive of a top-down progression
u Does RBD define clinicopathologic subtypes of DLB with distinct patterns of disease progression and treatment response It could help the development of biomarkers that may assist in differential diagnosis early detection and prognosis of DLBhelliphelliphelliphelliphellip
RBD e allucinazioni
u Iniziali report hanno esaltato
lrsquoassociazione tra rbd e allucinazioni
visive (Pacchetti Sinforiani Onofrij)
u Alcuni le hanno considerate intrusioni
di sonno REMhelliphellip
u Studi piugrave recenti non hanno trovato
chiare associazioni (Postuma hellip)
uLa latenza di conversione da
RBD idiopatico a RBD in
malattia neurodegenerativa
cambia negli anni
u Maggior attenzione e capacitagrave
diagnostica
u Studi non solo retrospettivi
u Studi non piugrave limitati solo o
prevalentemente ai centri del sonno
Idiopathic RBD
Multiple subtle abnormalities
Slowing of waking EEG (Fantini 2003)
Neuropsicological deficits (Ferini-Strambi et al 2003 Vendette M 2000
Fantini et al 2011)
Subtle parkinsonism (motor and gait speed) (Postuma 2006)h
Autonomic impairment (Ferini-Strambi 1996 Lanfranchi 2007 Postuma
2010
Olfactory deficit (Fantini 2006 Postuma 2006)
Color vision impairment (Postuma 2006)
Neuroimaging
abilitagrave visuospaziali logiche non verbali attenzione funzioni esecutive
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
RBD ndashdemenza a corpi di Lewy
u the presence of RBD may reflect a distinct subtype of DLB suggestive of a bottom-up disease progression
u while DLB without RBD has additional features suggestive of a top-down progression
u Does RBD define clinicopathologic subtypes of DLB with distinct patterns of disease progression and treatment response It could help the development of biomarkers that may assist in differential diagnosis early detection and prognosis of DLBhelliphelliphelliphelliphellip
RBD e allucinazioni
u Iniziali report hanno esaltato
lrsquoassociazione tra rbd e allucinazioni
visive (Pacchetti Sinforiani Onofrij)
u Alcuni le hanno considerate intrusioni
di sonno REMhelliphellip
u Studi piugrave recenti non hanno trovato
chiare associazioni (Postuma hellip)
uLa latenza di conversione da
RBD idiopatico a RBD in
malattia neurodegenerativa
cambia negli anni
u Maggior attenzione e capacitagrave
diagnostica
u Studi non solo retrospettivi
u Studi non piugrave limitati solo o
prevalentemente ai centri del sonno
Idiopathic RBD
Multiple subtle abnormalities
Slowing of waking EEG (Fantini 2003)
Neuropsicological deficits (Ferini-Strambi et al 2003 Vendette M 2000
Fantini et al 2011)
Subtle parkinsonism (motor and gait speed) (Postuma 2006)h
Autonomic impairment (Ferini-Strambi 1996 Lanfranchi 2007 Postuma
2010
Olfactory deficit (Fantini 2006 Postuma 2006)
Color vision impairment (Postuma 2006)
Neuroimaging
abilitagrave visuospaziali logiche non verbali attenzione funzioni esecutive
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
RBD e allucinazioni
u Iniziali report hanno esaltato
lrsquoassociazione tra rbd e allucinazioni
visive (Pacchetti Sinforiani Onofrij)
u Alcuni le hanno considerate intrusioni
di sonno REMhelliphellip
u Studi piugrave recenti non hanno trovato
chiare associazioni (Postuma hellip)
uLa latenza di conversione da
RBD idiopatico a RBD in
malattia neurodegenerativa
cambia negli anni
u Maggior attenzione e capacitagrave
diagnostica
u Studi non solo retrospettivi
u Studi non piugrave limitati solo o
prevalentemente ai centri del sonno
Idiopathic RBD
Multiple subtle abnormalities
Slowing of waking EEG (Fantini 2003)
Neuropsicological deficits (Ferini-Strambi et al 2003 Vendette M 2000
Fantini et al 2011)
Subtle parkinsonism (motor and gait speed) (Postuma 2006)h
Autonomic impairment (Ferini-Strambi 1996 Lanfranchi 2007 Postuma
2010
Olfactory deficit (Fantini 2006 Postuma 2006)
Color vision impairment (Postuma 2006)
Neuroimaging
abilitagrave visuospaziali logiche non verbali attenzione funzioni esecutive
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
uLa latenza di conversione da
RBD idiopatico a RBD in
malattia neurodegenerativa
cambia negli anni
u Maggior attenzione e capacitagrave
diagnostica
u Studi non solo retrospettivi
u Studi non piugrave limitati solo o
prevalentemente ai centri del sonno
Idiopathic RBD
Multiple subtle abnormalities
Slowing of waking EEG (Fantini 2003)
Neuropsicological deficits (Ferini-Strambi et al 2003 Vendette M 2000
Fantini et al 2011)
Subtle parkinsonism (motor and gait speed) (Postuma 2006)h
Autonomic impairment (Ferini-Strambi 1996 Lanfranchi 2007 Postuma
2010
Olfactory deficit (Fantini 2006 Postuma 2006)
Color vision impairment (Postuma 2006)
Neuroimaging
abilitagrave visuospaziali logiche non verbali attenzione funzioni esecutive
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Idiopathic RBD
Multiple subtle abnormalities
Slowing of waking EEG (Fantini 2003)
Neuropsicological deficits (Ferini-Strambi et al 2003 Vendette M 2000
Fantini et al 2011)
Subtle parkinsonism (motor and gait speed) (Postuma 2006)h
Autonomic impairment (Ferini-Strambi 1996 Lanfranchi 2007 Postuma
2010
Olfactory deficit (Fantini 2006 Postuma 2006)
Color vision impairment (Postuma 2006)
Neuroimaging
abilitagrave visuospaziali logiche non verbali attenzione funzioni esecutive
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Deficit olfattivo in iRBD
u Deficit olfattivo in un gruppo eterogeneo di
pazienti con RBD di cui 2 idiopatici
(Stiasny-Kolster et al 2004)
u Deficit della identificazione degli odori in
un gruppo di 50 pazienti con RBD
idiopatico (Fantini et al 2005)
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Olfatto e malattie neurodegenerative
u Deficit olfattivo simile a quello osservato nel PD
Lrsquoodore del diluente (paint thinner) maggiore sensibilitagrave specificitagrave e potere statistico di detezione sia nel PD chenellrsquoiRBD
u Deficit olfattivo in 70-100 dei pazienti PD sin dagli stadi precoci(Doty 1988 Tissingh 2001 McSchane 2001 Ponsen 2004)
u Non presente in altre cause di parkinsonismo (PSP CBD parkinsonismo vascolare e PD associato a mutazione Parkin)
u Deficit olfattivo nella demenza in DLB gt AD (McShane et al2001)
u Deficit olfattivo= hallmark di Lewy body disease (Hawkes C 2003)
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
u The olfactory deficit found in 61 of RBD patients suggests
the presence of an underlying Lewy body disease in those
patients and supports the notion of a continuum between
RBD and LBD
u A great heterogeneity in olfactory scores was observed in
the RBD group
bull Follow up of iRBD patients with high and low olfactory
identification score will allow to assess the predictive value
of olfactory impairment for the development of α-
synuchleinopathy in idiopathic RBD
Deficit olfattivo e demenza a corpi
di Lewy
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
bull Deficit nelle abilitagrave costruttive visuo-spaziali
(437 dei pazienti) e nellrsquoapprendimento
visuo-spaziale (823) simile ai pazienti con
DLB (Ferini-Strambi et al Neurology 2004)
bull Deficit nelle funzioni visuo-spaziali nellrsquoRBD
idiopatico (Terzaghi et al AIMS 2005)
Neuropsicologia in RBD
idiopatico
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
u Int J Psychophysiol 2013
u Cognitive dysfunction and REM sleep behavior
disorder Key findings in the literature and
preliminary longitudinal findingsu Manni R Sinforiani E Pacchetti C Zucchella C Cremascoli R Terzaghi M
u It is unclear whether cognitive deficits in iRBD represent an associated feature or
a marker predictive of subsequent development of a synucleinopathy
u Cross-sectional studies indicate that a proportion of iRBD patients show cognitive
deficits similar to those typically found in patients with synucleinopathies
u The available longitudinal data suggest that cognitive dysfunction in iRBD
tends to progress over time with this progression probably being
underpinned by a neurodegenerative process RBD fattore di rischio per
declino cognitivo fino alla demenza
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1
Frequenc y (Hz)
-150
-100
-050
000
050
100
150
log
PO
WE
R
Controls
PD without RBD
PD with RBD
bull EEG slowing only in
PD with RBD
bull RBD in PD predictor
of dementia ( v EEG
in LBD)
Neurology 2003
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Autonomic impairment in iRBD
u Mild autonomic dysfunctions during both sleep
and wakefulness (eg abnormalities in
sympathetic and parasympathetic tests)
(Ferini-Strambi et al1996)
u A reduced cardiac activation associated with
periodic leg movements (PLMS) (Fantini et al
2002)
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Disfunzioni autonomiche non correlate a
parkinsonismo
u MIGB alterata sempre in RBD idiopatico ( ma non in
MSAhellip
u PD-nonRBD non ci sono disfunzioni autonomiche
u Un paziente aveva 20 anni di storia di RBD non sintomi
parkinsoniani e captazione MIGB molto ridotta
u Un paziente aveva 4 anni di storia di RBD e anomalie alla
MIGB al baseline ldquo anni dopo ha sviluppato un Parkinson
ma la seconda scintigrafia MIGB era identica alla prima
Forse differenti livelli di progressione attraverso gli
stadi di Braak
(Lang AE The progression of PD a hypothesis Neurology 2007)
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
49 PD patients
18 pts =clinical RBD (367)
8 pts = subclinical RBD (163)
23 pts = normal REM sleep
(469)
ldquoPD patients with clinical RBD might
suffer from a wider a-synuclein pathology
including reduced cardiac sympathetic
ganglia function as reflected by a lowered
MIBG uptakerdquo
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Idiopathic RBD Neuroimaging
SN involvement SPECT (IPTIBZM DATSCAN) PET
TCS) (Eishenser I 2000 Albin 2000 Unger 2008
Stockner 2009 Iranzo 2010 Miyamoto 2012)
Multiple perfusion abnormalities (ECD-SPECT) (Mazza
2006 Vendette 2011)
Gray and White Matter (Voxel-based MRI DTI)
(Scherfer 2011 Haniou 2011)
Cardiac innervation (I-MGBI cardiac scintigraphy)
precocious involvement (Myiamoto )
studi solo giapponesihellipridotta captazione in RBD ma
non in MSA( dove RBD egrave piugrave frequente)
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Parkinson and RBD IPT SPECT study
(Eisensehr et al Brain 2000 1231155-1160)
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
PET STUDY decrease of nigro-striatal DAergic
innervation in idiopathic RBD
(Albin et al Neurology 2000 551410-1412) density of striatal
dopaminergic terminals with [11C]dihydrotetrabenazine PET in six
elderly subjects with chronic idiopathic RBD and 19 age-appropriate
controls
Control RBD RBD
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Alterato contenuto dei sogni un altro marker
di neurodegenerazione
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
CONTENUTO DEI SOGNI IN RBD
u Compared to control subjects RBD showed
Dreams with at least one aggression (66 vs 15 plt000001)
ratio AggressionFriendliness interactions (89 vs 44 plt00001)
frequency of Animal characters (19 vs 4 p=00001)
No Dreams with at least one element of sexuality (0 vs 9 plt00001)
u A trend toward
of Dreamer as aggressor (29 vs 0 h = 114 p=0002)
of Negative emotions (82 vs 61 h = 046 p=0003)
of Familiar characters (52 vs 65 h=-026 p=0065)
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Aggressive dream content without increased
daytime aggressiveness
RBD
patients Controls p
AQ total score 699 plusmn 161 738 plusmn 203 037
Physical Aggression 165 plusmn 64 204 plusmn 83 0034
Verbal Aggression 150 plusmn 42 144 plusmn 40 059
Anger 179 plusmn 65 173 plusmn 60 067
Hostility 204 plusmn 54 216 plusmn 62 038
u No between-group difference in overall daytime aggressiveness
u Patients with RBD showed lower score on ldquoPhysical
Aggressionrdquo than controls
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
uNovitagrave sul contenuto onirico
durante RBD
Varia fenomenologia ( riso
gesticolazione piugrave quieta )
uDiagnosi differenziale tra
RBD e disturbo da incubi
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Alterato contenuto dei sogni un altro marker di
neurodegenerazione
u Increased frequency of both aggression and animals
is reported also in children dreams (Domhoff 1996)
u Developmental decrease in phasic muscle REM sleep
activity from birth to late childhood as an expression
of maturation of the brainstem motor inhibitory
systems (Kohyama et al 1990 1996 and 1999
Tachibana WASM 2005)
u Chronic RBD as a manifestation of a widespread
neurodegenerative process might lead to an
impairment of brainstem inhibitory systems and to a
release of ontogenetically early dream patterns
Fantini et al Neurology 2005651010-1015
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
RBD demenza parkinsonismi
dati anatomopatologici
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
RBD and Parkinsonrsquos disease
Gagnon JF Beacutedard MA Fantini ML et al Neurology 2002 59585-589
N=33 PD PATIENTS
At the clinical interview only 5 patients (15 )
reported RBD symptoms
At the PSG evaluation
11 patients (333 ) both PSG and
behavioral manifestations of RBD
8 patients ( 242 ) loss of atonia without
behavioral manifestation (REM sleep without
atonia =RSWA)
A total of 19 patients (58) with
PD had REM sleep without
atonia
bull Prevalence of RBD in PD patients 15-30 (Silber 1993
Comella1998 Wetter 2002 Gagnon 2002)
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
RBD in PDuno specifico sottotipo di PD
Specific motor features (akinetic-rigid form
symmetrical onset axial symptoms L-dopa-induced dyskinesiaecc)
More severe non motor signs Autonomic deficits (Postuma 2009 and 2011)
EEG impairment (Gagnon 2003)
Cognitive deficits (Vendette 2007 Postuma 2012)
Colour vision impairment (Postuma 2005)
Visuoperceptive dysfunctions (Marques 2010)
Hallucinations (controversial)
Different outcome to STN-DBS
PD_RBD sembra avere una piugrave estesa degenerazione nel sistema nervoso centrale rispetto al PD senza RBD
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
TEMPORAL PATTERN (Kumru et al 2007)
u All tremor-dominant patientsdeveloperent RBD followingmotor parkinsonism
bullAll patients whose RBD
preceded parkinsonism belonged
to the group of non- tremor
dominant type
bullRBD preceded parkinsonism
only when parkinsonism started
after the age of 50 years
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Disfunzioni autonomiche
u Invariabilmente associate ad RBD
Stesso livello di compromissione in
iRBD e in PD-RBD
u Non riscontrate in PD senza RBDndash Sistolic blood pressure drop
ndash Cardiac variability (R-R and Spectral
analysis)
ndash Cardiac innervation (MIGB)
ndash Urinary symptoms
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Postuma et al Brain 2009)
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Cardiac variability
R-R standard deviation
bullPD-RBD severely impaired
bullPD-noRBD = controls
Mov Dis 2011
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
PD a 3-phase disease
A multisystem synucleinopathy with pathology extending beyond the
confines of the central nervous system and clinical manifestations
extending beyond dopamine cell loss in the SNc
Mov Dis 2012
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Grant del Ministero della Salute
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
uRBD distingue DLB e PD
demenza dalla VaD e dallrsquo
AD e sottolinea la necessitagrave
di ricercare altri disturbi del
sonno particolarmente
frequenti nella VaD( v
apnee morfeiche)
u Guarnieri et al 2012
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
ASSOCIATIONS AMONG
DIFFERENT SLEEP
DISTURBANCES
Dement Geriatr Cogn Disord 2012
ASSOCIAZIONI TRA DISTURBI DEL SONNO
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
u La presenza di RBD nella malattia di
Parkinson e nella demenza a corpi di
Lewy va dal 38 allrsquo 83
u RBD spesso precede lrsquoinsorgenza dei
parkinsonismi e della demenza di
molti anni fino a 20
u Nelle diagnosi cliniche di AD ed RBD
in altre malattie neurodegenerative
non sinucleinopatie RBD insorge
quasi contemporaneamente o dopo i
deficit cgnitivi eo motori
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
SNC lesions associated to RBD
Type of Lesion Localisation Auteurs
Ischemic Left upper pons Kimura et al 2000
Lacunar ischemic Right pontine tegmentum Li et al 2009
Demyelinating in R-R MS Pontine white matter Plazzi et a 2002
Neurinoma Brainstem Zambelis et al 2002
Cavernoma Ponto-mesencephalic tegmentum Provini et al 2004
Demyelinating in MS Dorsal pontine tegmentum Tippmann et al 2006
Inflammatory Brainstem (pontine tegmentum) Limousin et al 2009
Inflammatory (VGKC-Ab limbic encephalitis) Amygdala (brainstem spared) Iranzo et al 2006
Inflammatory (acute aseptic LE) Amygdala Lin et al 2009
Inflammatory (Guillain-Barreacute sdr) Hypothalamus ( level of hypocretin) Cochen V 2005
(Narcolepsy) Hypothalamus Nightingale et al 2001
Degenerative (Fatal Familiar Insomnia) Anterior and dorsomedian Thalamus Lugaresi et al 2001
Post-surgery (after electrode implantation for STN-
DBS)
Upper part of SN pars compacta
(interruption of descending imputs)
Piette et al 2007
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Studio su
lesioni
nellrsquouomo
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
ldquoPseudo-RBDrdquo
ldquodream enactmentrdquo
durante Sindrome delle apnee
ostruttive in sonno ( OSAS)
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
OSAS RBD una diagnosi differenziale da
considerare sempre sia nellrsquo RBD isdiopatico che
nelle malattie neurodegenerative
RBD-OSAS con caduta
OSA-RBD
RBD in ventilazione
RLS-OSAS
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
2007
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Visual rules for adults1 TECHNICAL SPECIFICATIONS
A Electroencephalogram (EEG)
1) The racommended derivations are
[RACOMMENDED]
a F4-M1
b C4-M1
c O2-M1
Backup electrodes should be placed at F3 C3O1 and M2 to allow display of F3-
M2 C3-M2 and O1-M2 if electrodes malfunction during the study
B EMG chin
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Tonic phenomena
u Desynchronized fast EEG activity
u Suppression of muscle tone = ATONIA (paradoxical)
Phasic phenomena
u Rapid Eye Movements (REMs)
u Muscle twitch (face extremities)
u Erratic respiration and heart rate
Eye movements
Brainwaves
Muscle Tone
Eye movements
Brainwaves
Rapid Eye Movemnts (REM) sleepe
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
REM SLEEP BEHAVIOR DISORDER
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
REM sleep in four
different patients
showing
definitely normal
EMG atonia (A)
definitely
increased EMG
tone and hence
definite REM
sleep without
atonia (B) and
equivocally
increased EMG
tone (C and D)
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
REM SENZA ATONIA1) sustained muscle activity in REM sleep with 50 of
the epoch having increased chin EMG amplitude
andor
2) excessive transient muscle activity defined by the
presence of 5 or more mini-epochs (a 30 second
epoch is divided into 10 3-second mini-epochs) in an
epoch having transient muscle activity lasting at
least 05 seconds
no minimum number of epochs showing abnormal
muscle activity required for the RSWA designation ndash
this was purposefully not stated as there is little
good normative data
AASM 2007
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
u Mov Disord 2013 Jun
u Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies
u Terzaghi M Arnaldi D Rizzetti MC Minafra B Cremascoli R RustioniV Zangaglia R Pasotti C Sinforiani E Pacchetti C Manni R
u video-PSG findings in 29 consecutive subjects diagnosed with DLB
u 29 nondemented patients with Parkinsons disease (PD)
u complex mix of overlapping sleep alterations impaired sleep structure sleep comorbidities and various motor-behavioral events (not restricted to RBD)
u Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities and consider performing polysomnographic sleep investigations in selected cases
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Per lrsquoespressivitagrave clinica di RBD
uPerdita dellrsquoinibizione
muscolare in REM
uAumento del drive motorio
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
REM sleep in cats
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
RBD model in cats
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
(From Boeve BF et al Brain 2007)
RBD patophysiology in humans
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
RBD pathophysiology in PD (according to Braak staging)
(From Boeve BF et al Brain 2007)
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Staging brain pathology in PD(Braak et al 2003)
uLewy Body pathology progresses in a stereotyped fashion
Stage 1 anterior olfactory and dorsal motor nucleus of IXX n
Stage 2 upper braistem nuclei (PPN and LC) (RBD)
Stage 3 Substantia Nigra (motor PD)
Stage 4-5 Cerebral cortex (DLB)
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
ALTERNANZA NonREM-REMMODELLO DI INTERAZIONE RECIPROCA
(Mc Carley amp Hobson 1975)
REM-on
REM-off Nuclei Peduncolopontino
(PPN) e Dorsolaterale
(DLT)
(Acetilcolina)
Locus Coeruleus
(Noradrenalina)
N Dorsale del Rafe
(Serotonina)
-
+
-
+
NA
5-HT
NA
5-HT
Ach
Ach
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
u The sleep-
wake switch
u ldquo Flip-Floprdquo
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Locus coeruleus(LC) nucleo
peduncolopontino (PPN) tegmento
laterodorsale (LDT)
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Neuropathological studiesIdiopathic RBD (2 cases)
1 Incidental Lewy bodies disease with severe
neuronal loss and gliosis in the substantia nigra
(SN) and coeruleussubcoeruleus (LC) (Uchiyama
et al 1995)
2 Incidental Lewy body disease (brainstem-
predominant dorsal motor nucleus and medullary
tegmentum) but no significant degeneration of SN
LC and raphe nuclei (Boeve BF 2007)
Degeneration of the monoaminergic SN and LC is really the
primary cause of idiopathic RBD
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
u In 1 pt RBD-dementia (combined Lewy bodies + Alzheimer pathology) marked
neuronal loss within the LC but higher density of cholinergic mesopontine
neurons possible disinhibition of cholinergic neurons by reduced number of LC
neurons leading to increased REM sleep drive and RBD (Schenck et al 1996-
1997)
u in 1 pt RBD-PD severe neuronal loss of subcoeruleus nucleus with no changes
in PPTLDT nuclei (Arnulf et al 2000)
u in 4 RBD-MSA patients depletion of the cholinergic neurons in PPTLDT (Benarroch
and Schmeichel 2002)
u In 11 pt with DLB-RBD same degree of depletion in PPN-LDT as in patients DLB-
non RBD (Dugger et al 2012)
Neuropathological studiesSymptomatic RBD (a total of 17 cases)
Alterations in PPN and LDT do not fully account for
RBD pathogenesis
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Neuropathol Appl Neurobiol 2012
Neuropathological analysis of brainstem cholinergic and catecholaminergic
nuclei in relation to rapid eye movement (REM) sleep behaviour disorder
Dugger BN Murray ME Boeve BF Parisi JE Benarroch EE Ferman TJ
Dickson DW
u human brain banked tissues of
u 11 Lewy body disease (LBD) cases with RBD
u 10 LBD without RBD
u 19 Alzheimers disease (AD)
u 10 neurologically normal controls
u Tissues were stained with choline acetyl transferase
immunohistochemistry to label neurones of PPNLDT and
tyrosine hydroxylase for the LC The burden of tau and α-
synuclein pathology was measured in the same regions with
immunohistochemistry
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
2012- dati anatomopatologici
u Whether decreases in brainstem
cholinergic neurones in LBD contribute
to RBD is uncertain but our findings
indicate these neurones are highly
vulnerable to α-synuclein pathology in
LBD and tau pathology in AD The
mechanism of selective α-synuclein-
mediated neuronal loss in these nuclei
remains to be determined
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
u Sulla genetica ancora non cegrave niente di sostanziale cegrave
un lavoro sulla aumentata storia familiare nei paz con
RBD ma questo lavoro ha dei limiti poichegrave il dato egrave
ottenuto con la single question di Postuma (RBD1Q) di
cui perograve non si conosce bene la sensibilitagrave e specificitagrave
u In ogni caso la familiaritagrave nel complesso non egrave frequente
uno studio genetico egrave in corso a Montreal ma i risultati
non sono noti
u Ipotizzata da alcuni trasmissione genetica possibile a
scarsa penetranza
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
u Neurology 2013 Jun
u Family history of idiopathic REM behavior disorder A multicenter case-control study
u Dauvilliers Y Postuma RB Ferini-Strambi L Arnulf I Houmlgl B Manni R Miyamoto T Oertel W Fantini ML Puligheddu M Jennum P Sonka K Zucconi M Leu-Semenescu S Frauscher B Terzaghi M Miyamoto M Unger M Desautels A Wolfson C Pelletier A Montplaisir J
u 316 PSG -confirmed iRBD
u 316 controls
u A positive family history of dream enactment wasreported in 138 of iRBD cases compared to 48 ofcontrols
u CONCLUSION
u increased odds of proxy-reported family historyof presumed RBD among individuals withconfirmed iRBD This suggests the possibility ofa genetic contribution to RBD
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
uNUOVE
uPROSPETTIVE
uDI
u INDAGINE
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Nature and Science of Sleep giugno 2013
u Ventricular orexin-A (hypocretin-1) levelscorrelate with rapid-eye-movement sleep withoutatonia in Parkinsons disease
u Bridoux A Moutereau S Covali-Noroc A Margarit L Palfi S Nguyen JP Lefaucheur JP Ceacutesaro P drsquoOrtho MP Drouot X
u The orexin-A (hypocretin-1) hypothalamicsystem plays a central role in controllingREM sleep Loss of orexin neurons results in narcolepsy-cataplexy a condition characterized by diurnal sleepiness and REM sleep without atonia
u high levels of orexin-A in Parkinsons diseasemay be associated with loss of REM muscleatonia
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Psychiatric symptoms and
compulsive behaviors in RBD
pazienti con RBD maggiore
compulsivitagrave
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
u Tra laltro lultimissimo dato che abbiamo appena
osservato egrave che i PD-RBD hanno un rischio almeno
doppio di sviluppare un disturbo del controllo degli
impulsi rischio che diventa triplo per alcuni ICDs
dopo avere controllato per etagrave sesso durata e
severitagrave del PD e soprattutto per dose levodopa
equivalente
u Considerato che dei fattori di rischio per ICDs non si
sa granchegrave (a parte unassociazione con giovane etagrave
esordio giovanile e lieve prevalenza di sesso
maschile) egrave un dato credo interessante che puograve
anche orientare il clinico nel trattamento soprattutto
con i dopaminoagonisti
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
TRATTAMENTO
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
The goals of therapy are to minimize the
three cardinal features of the disorder ndash
decrease the frequency and severity of the
abnormal vocalizations (thereby reducing
the embarrassing nature of screams and
swearing with guests in the home when
traveling and sleeping in hotels and when
fishinghuntingcamping and sleeping in
tents) decrease the frequency and
severity of the abnormal behaviors
(thereby reducing the risk of injury to the
patient and bedpartner) and decrease the
unpleasant dreams
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
trattamento FARMACOLOGICO
u Clonazepam (05-2 mg bedtime)
90 of success (Schenck 1990)
u Melatonina (3-12 mg at bedtime)
(Kuntz1999)
u Pramipexole (Fantini 2003)
u Carbamazepine
u Donepezil (10-15 mg bedtime)
(Simmonds 2000)
u Levodopa
u Quetiapina Clozapinahellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
PRAMIPEXOLE IN IDIOPATHIC RBD
bull Five out of 8 patients sustained reduction in frequency or intensity of
sleep motor behaviors confirmed by video-recording
bull No change for of phasic EMG activity during REM sleep
bull Surprisingly a decrease in the of REM sleep muscle atonia was
observed
bull The treatment did not modify the indexes of periodic leg movements
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Trattamento
bull Agents that decrease the frequency andor severity of RBD
bull Clonazepam
bull Melatonin
bull Agents that tend to increase the frequency andor severity of RBD
bull Tricyclic antidepressants (particularly amitriptyline)
bull Chocolate
bull Selective serotonin and norepinephrine reuptake inhibitors
(particularly venlafaxine and mirtazapine)
bull Controversial effects on RBD
bull Anticholinergics (donepezil rivastigmine)
bull Dopaminergic (Levodopa pramipexole)
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Nuove opzioni terapeutiche
uSodium Oxybate forme resistenti
( 3g prima del sonno notturno e 3 g
tre ore piugrave tardi) Un paziente non responder
a 4 mg clonazepam 12 mg melatonina 100mg
quetiapinahellipha risposto a Sodium Oxybatehellip
uAgomelatina
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Effects of cholinergic drugs
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Effects of STN-DBS in RBD
u 7 studies on sleep after STN-DBS
4 with PGS measures
4 with only subjective measures of Sleep
(PSQI etc)
u 3 studies RBD after STN-DBS (tot of 14 RBD)
Arnulf 2000 no change
Iranzo 2000 no change
Cicolin 2004 no change
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
of Phasic EMG during REM sleep
PLMS index (tot nh of
sleep)
Study 1 (Arnulf et al 2000)
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
RBD and STN-DBSStudy 2 (Iranzo et al 2000)
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Maria Livia u In effetti nel campo dellRBD idiopatico le novitagrave piugrave grandi negli
ultimi anni sono state nella definizione della patogenesi con il
modello animale di RBD ottenuto con topi knockout per la
trasmissione glicinergica e gabaergica che deriva anche dalla
ridefinizione del meccanismo del sonno REM e il modello flip-flop
u e il dato di Iranzo e di Schenck sull80 di conversione
u Per il resto in questi anni si sono accumulati molti dati sul fatto
che nellambito delle mal neurodegenerative la presenza di RBD
spesso si associa a un quadro neurodegenerativo piugrave esteso e
piugrave severo soprattutto nel PD
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Prospettive future
u Necessitagrave di biomarkers precoci di
neurodegenerazione
u RBD idiopatico da solo o i associazione con altre
anomalie elettrofisiologiche puograve essere un marker
importante di neurodegenerazione ad uno stadio
preclinico
bull Studi longitudinali per affermare il valore predittivo di
questi markers
u Futuri trials farmacologici con terapie laquodisease-
modifying raquo per pazienti con RBD idiopatico ad alto
rischio
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
DOPAMINERGIC SYSTEM and RBD
u Association with PD
u Decreased striatal innervation in I-RBD (Eisensher 2000 Albin 2000)
u Reduced size of putamen in I-RBD (Ellmore et al 2010)
but
u Absence of RBD in pts with pallidopontonigraldegeneration (Boeve 2006)
u No correlation between EMG activities and DAT densities in idiopathic RBD (
u Controversial effects of DA
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
2012- LBD con e senza RBD
u Confronto tra LBD AD soggetti di
controllo
u Patologia tau ed alfa sinucleina
u LC PPN LDT vulnerabili ad alfa
syn in LBD ed AD ma perdita
neuronale signifcativa solo in LBD
u Percheacute questa perdita neuronale
alfa synucleino mediata in questi
nuclei
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
u LBD meno neuroni colinergici in PPNLDT ma
non differenze con e senza RBDeppure tali
nuclei sono coinvolti nellrsquoatonia REM hellipforse i
LBD sono diversihellip
u Tale perdita neuronale perograve correlerebbe con
andatura e controllo posturale
u Allora sono coinvolti altri nuclei nel
determinismo dellrsquo RBDhellip oppure
u DIVERSI NODI DI UNO STESSO NETWORK
COINVOLTI INDIVERSI INDIVIDUI
GENERANDO LO STESSO FENOTIPO RBD
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
PLMS and sleep disorders
u Restless Legs syndrome +++
u Narcolepsy ++
u Rem sleep behavior disorder (RBD) +++
u Insomnia +
u Ipersomnia +
Sleep Disorder
with
involvement of
the DA system
Modified from Montplaisir et al Sleep Medicine 2000
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
EPIDEMIOLOGY
u Prevalence of PLMS in the general population increases with age
(6 subjects aged 30 ndash 50 yrs 30 after 50 yrs) (Hening 1999 Coleman
1983 Ancoli-Israeli 1985)
u Prevalence in PD gt MSA gt controls (Coccagna 1985 Plazzi 1997 Vetrugno
2004 Wetter 2002)
u Frequently associated to RBD
u Evidence of an involvement of the DA system (diencephalo-spinal
DAergic system)
Pharmacological (DAagonists=potent suppressors of PLM)
Metabolic (Cohrs 2004)
Neuroimaging ( binding with striatal postsynaptic D2 receptor with SPECT or
PET studies (Staedt 1995 Turianski 1999 Michaud 2002 )
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip
Sleep disturbance in mental health problems and
neurodegenerative disease- Nature and science of sleep 2013
u ldquoComparison between the
polysomnography studies of those with
AD compared to frontotemporal
dementia showed greater REM sleep
disruption in AD again suggesting that
sleep in frontotemporal dementia may
be better preservedhelliphelliphelliphelliphelliphellip