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Demyelinating Diseases
TA Yousry
Institute of Neurology
Queen Square
Acknowledgment
Jackie Palace (Oxford) A Rovira (Barcelona)
F Barkhof (Amsterdam) N de Stefano (Siena)
F Fazekas (Graz) E Enzinger (Graz)
V Sethi D Chard (London)
R Jaeger H Chandrashekar (London)
A Thompson D Miller (London)
Overview • Autoantibodies associated CNS diseases
Neuromyelitis optica
Limbic encephalitis
NMDAR encephalitis
• ADEM
• Neuropsychiatric SLE
1. NMO Pathology
• Inflammation
• Astrocytopathy
• Myelin relatively preserved, damage 2ry
Epidemiology
Uzawa Journal of Clinical Neuroscience 2013 Prevalence (per 100,000)
Diagnosis
• Optic neuritis initial event in the young
• Acute myelitis initial event in the older
• AQP4 AB –ve 20-30%
NMO
NMO
Aquaporin 4 • most abundant CNS water channel • concentrated in astrocytic foot
processes
Lennon et al Lancet 2004; J Ex Med 2005 Antibodies to AQP4 → astrocytopathy
AQP4 Channelopathy AB Disease’ NMO
• Female > 80%
• Non-Caucasian predominance
• Relapsing if untreated
• Severe disability and high mortality
• Associated with other auto-immunity
• Onset with both ON + TM uncommon
Lennon et al Lancet 2004; J Ex Med 2005
NMO
M ON
10% - monophasic
M ON ON M
NMO
90% - relapsing
AQP4 Channelopathy’
1.AQP4-Ab-positive classical NMO
2.AQP4-Ab-positive high-risk syndromes
for NMO’ (HRS)
NMO
Isolated LETM (lesions spanning > 3segments)
Monophasic or recurrent isolated ON
Certain types of brainstem encephalitis (particularly if the
diencephalon or medulla oblongata is involved)
NMOSD
Autoimmune AQP4 Channelopathy’ NMO Revised diagnostic criteria (Wingerchuk 2006)
• Optic neuritis
• Acute myelitis
• At least 2 of 3 supportive criteria
1. SC MRI Contiguous over 3 segments
2. Onset brain MRI not meeting MS* criteria
3. NMO-IgG/AQP4 AB seropositive
Some NMO patients remain seronegative for NMO-IgG (12-24%)
• Male predominance
• Younger patients
• Milder clinical presentation: lower relapse rate, lower disability,
lower number of severe attacks
• Simultaneous occurrence of ON and transverse myelitis (33% vs 6%)
• No differences in brain MRI
• Shorter SC lesions
• Spinal cord confinement
• Some NMOneg could suffer either atypical ADEM or MS. Hyun et al. Mukt Scler J 2014; Bernard-Valnet et al. Eur J Neurol 2015
NMO-IgG Seronegative’
Jarius Journal of Neuroinflammation 2012
NMO
NMO
Jarius Journal of Neuroinflammation 2012
NMO
Jarius Journal of Neuroinflammation 2012
SC lesions
• Extent > 3 segments
• Central grey matter
• Swelling
• Partial enhancement
• Atrophy & cavity formation
Uzawa Journal of Clinical Neuroscience 2013
NMO Devic Neuromyelitis optica
Multiple sclerosis
Nakamura et al. J Neurol 2008
Preferential spinal central gray matter
involvement in neuromyelitis optica
Courtesy A Rovira
Jarius Journal of Neuroinflammation 2012
NMO
Bot et al. Radiology 2004
Nakamura et al. J Neurol 2008
Spinal cord MRI in NMO Central necrosis: pseudosyringomyelia
Courtesy A Rovira
Neuromyelitis optica
Multiple sclerosis
Courtesy A Rovira
Specific brain lesions
• Medullary periaqueductal grey
• Bilat hypothalamus
Uzawa Journal of Clinical Neuroscience 2013
NMO
Brain lesions • Present 60%
• Location PV ( AQP4 expression)
• Extensive
• Multiple, patchy, enhancing (cloud-like enhancement) in 90% of pat with CE
• CC Splenium; diffuse; oedematous, heterogenous
NMO
Jarius Journal of Neuroinflammation 2012
NMO
NMO
Sato Arq Neuropsiquiatr 2011
NMO
Sato Arq Neuropsiquiatr 2011
NMO
Nakamura, Multiple Sclerosis 2009
Cloud-like
enhancement
Ito Ann Neurol 2009
NMO 90%
MS 8%
Cortical
lesions
Calabrese Neurol 2012
NMO 0
MS 67%
NMO
7T
Kister MSInternational 2013
7T
Sinnecker Neurology 2012
7T
Sinnecker Neurology 2012 Sinnecker Neurology 2012
Central Vein Sign
Cortese Neurology 2018
Class III evidence CVS accurately
distinguishes
MS vs sero+ve NMOSD
Central vein sign (3 T) MS vs NMO
Cortese et al. Neurology 2018
•The clinical value of the CVS in the context of the differential diagnosis between MS and NMOSD is now extended to clinical 3T scanners •Step towards the use of CVS in clinical practice. •Class III evidence that the CVS on 3T MRI accurately distinguishes patients with MS from those with seropositive NMOSD.
•Cutoff value of 54% of lesions with CVS was optimal in differentiating MS from NMOSD in the groups with high lesion numbers (sensitivity 94%; specificity 100%; accuracy 94%). •In patients with low lesion numbers, the cutoff point rose to 80% of lesions with CVS and produced less convincing results (sensitivity 50%; specificity 93%; accuracy 88%).
MS
NMOSD
Atypical
lesions
Pittock Arch Neurol 2006
Kim MSJ
2011
NMO
Uzawa Journal of Clinical Neuroscience 2013
NMO-Spectrum Disorders
In addition to NMO, AQP4-Ab is found in •Isolated LETM (lesions > three segments) •Monophasic or recurrent isolated ON •Certain types of brainstem encephalitis (particularly if diencephalon or medulla oblongata involved) •Most develop NMO •Classify these symptoms—as ‘high-risk syndromes for NMO’ (HRS)
Wingerchuk DM, et al.
Neurology. 2015
NMO: 2015 diagnostic criteria
Wingerchuk DM, et al. Neurology. 2015
+ AQP4-IgG - AQP4-IgG
NMOSD with unknown AQP4-IgG status
Emphasis on clinical diagnosis rather than solely AQP4-IgG positivity:
integration of clinical, serologic, and MR imaging data
NMO: 2015 diagnostic criteria
NMO
Wingerchuk et al Neurology 2015
MR requirements (AQP4-IgG -ve/unknown)
Acute optic neuritis
Brain Normal / unspecific
Optic nerve >1/2 ON length or optic chiasm
NMO: 2015 diagnostic criteria NMO
Wingerchuk et al Neurology 2015
Intramedullary lesions ≥ 3 contiguos segments (LETM)
≥ 3 contiguous segments SC atrophy (history of myelitis)
NMO: 2015 diagnostic criteria
MR requirements (AQP4-IgG -ve/unknown)
Acute myelitis
NMO
Wingerchuk et al Neurology 2015
Dorsal medulla/area postrema
lesions
Area postrema syndrome
NMO: 2015 diagnostic criteria
MR requirements (AQP4-IgG -ve/unknown)
NMO
Wingerchuk et al Neurology 2015
Periependymal brainstem lesions
Acute brainstem syndrom
NMO: 2015 diagnostic criteria
MR requirements (AQP4-IgG -ve/unknown)
NMO NMOSD 2015
NMOSD
AQP4-Ab positive
disease
AQP4-Ab
negative
Attack(s) involves ≥ 2 sites with typical MRI:
≥ 1 from ON, SC, area postrema. Other: brainstem, diencephalic, cerebral relapsing or monophasic
1 site
ON or LETM relapsing or monophasic
Multiple sclerosis
Ab negative MOG-Ab disease
25%
Wingerchuk et al Neurology 2015
Attack 1 site:ON / TM / brainstem / area
postrema Or diencephalic / narcolepsy / cerebral w typical MRI
NMOSD 2015 NMO
MOG
• Female : Male equal
• No non-caucasian predominance
• ~ 50% monophasic
• Better outcome than AQP4-Ab disease
• Not associated with other auto-immunity
• Onset with both ON + TM common
• Overlap with ADEM (monophasic & relapsing)
Myelin Oligodendrocyte
Glycoprotein (MOG)-AB Disease
NMO
Reindl et al. Nat Rev Neurol 2014
MOG-AB Disease
MOG-AB Disease
Jurynczyk Brain 2017
MOG-AB Disease
Jurynczyk Brain 2017
Summary
• NMOSD is a distinct entity
• Diagnosis based on clinical, lab and MRI findings
• MRI findings play a role in the Diagnostic criteria
• Overlap with ADEM, MS
• Neuroradiologist must be familiar with the radiological spectrum of
NMOSD, in order to properly distinguish this disorder from MD (different
prognosis and treatment)
Brain lesions as initial manifestation
De Seze Brain 2017
AQP4-ab vs MOG-ab NMO
MOG-ab Similar to AQP4-ab
Additionally
• conus involvement (left w isolated sphincter and
erectile dysfunction)
• fluffy lesions (adults, or ADEM attacks childhood)
• bilateral cerebellar peduncle lesions
Lechner et al. JNNP 2015
AQP4-ab vs MOG-ab
NMO
Jurynczyk Brain 2017
• Acute monophasic course
• Immune-mediated inflammatory disorder, triggered by
inflammatory response to viral infections and vaccination
• Affects children more commonly than adults
• Best viewed as a “syndrome” rather than a specific disorder
Clinical presentation
• Headaches, vomiting, drowsiness, fever, lethargy (uncommon MS)
• Self-limiting, good outcome
Acute Disseminated Encephalomyelitis
ADEM
ADEM MS
Age Gender Prior flu Encephalopathy Symptoms Attacks CSF white blood cell count >50 CSF oligoclonal bands
≤10 years (rare in adults) male=female very frequent
required multifocal
fluctuate over 3 months frequent variable
>10 years male<female
variable rare
monofocal separated by >1 month
very rare frequent
ADEM vs MS ADEM
Periventricular lesions
Isolated subcortical lesions
Deep grey matter lesions
Poorly marginated lesions
Contrast-enhancement
Symmetrical white matter lesions
Symmetrical grey matter lesions
New lesions on follow-up
Hemorrhagic lesions
Same appearance lesions
Large and confluent lesions
Resolution of lesions
Hypointense lesions (ne)
MS
+
++
++
++
+
+
++
+
+
++
++
++
-
+++
-
+/-
+
++
++
-
+++
-
+
+
+
++
ADEM
ADEM vs MS
Evolution
ADEM
MS
ADEM vs MS
8 years old boy
SC involvement in ~30% Large and tumefactive lesions Variable enhancement
ADEM
MS if ≥ 2
• 2 or more PV lesions
• Black holes
• Absence of diffuse bilateral lesions
Callen et al. Neurology 2009
ADEM MS
ADEM
Verhey et al. Lancet Neurol 2011
•PV lesions •T1-hypointense lesions
Predictive Parameteres: Time to MS
• First polyfocal, clinical CNS event (presumend inflammatory demyelinating) • Encephalopathy (cannot be explained by fever) • No new clinical and MRI findings ≥ 3 months after onset • Brain MRI abnormal in acute phase (3 months) Typical MRI
• Diffuse, poorly demarcated, large (>1-2 cm) lesions (cerebral WM) • T1 hipointense lesions rare • Deep GM lesions can be present Krupp et al. Mult Scler J 2013
Proposed 2012 IPMSSG criteria Pediatric ADEM
• Rare (less than 4%)
• Multiphasic ADEM
2 episodes consistent with ADEM separated by 3 months,
not followed by any further events
Second episode can be new or re-emergence of first
episode
• Relapsing ADEM following ADEM beyond a 2nd episode
leads to the diagnosis of MS or NMO
Krupp et al. Mult Scler J 2013
Proposed 2012 IPMSSG criteria Pediatric ADEM
baseline 1 m
• Viral upper respiratory tract infection & fever
(38ºC)
• Cephalea and irritability
• Bilateral optic neuritis
Krupp et al. Mult Scler J 2013
3 requirements for 2nd clinical event • Nonencephalopathic • ≥ 3 months after incident neurologic illness •Associated with new MRI findings (disseminated in space)
MS Diagnostic Criteria After ADEM
baseline 1 m
Krupp et al. Mult Scler J 2013
1 year
•Right optic neuritis
3 requirements for 2nd clinical event • Nonencephalopathic • ≥ 3 months after incident neurologic illness •Associated with new MRI findings (disseminated in space)
MS Diagnostic Criteria After ADEM
3 requirements for 2nd clinical event • Nonencephalopathic • ≥ 3 months after incident neurologic illness •Associated with new MRI findings (disseminated in space)
Krupp et al. Mult Scler J 2013
MS Diagnostic Criteria After ADEM
•Internuclear opthalmoplejia
baseline 1 m 1 year 3 years
2-18% of children with MS present with clinical/MR features suggestive of ADEM
ADEM MS NMOSD
Age at onset Children. Median of 5–8 years. Uncommon in adults
Young adults. Median of 29 years, uncommon in children and >50 years
Middle age adults. Mean of 40–45 years, with wide distribution from young children to elderly
Gender No gender predominance Moderate female predominance: 2-3/1
High female predominance: 3-9/1
Incidence/Prevalence Incidence of 0.3 to 0.6 per 100,000 per year
Global prevalence 33 per 100,000 (91-203 (108) in Europe; 2.2 East Asia) Incidence: 3,6-9,6
Global prevalence 1-2.6 per 100,000 (1/100,000 Europe; 2.2 Asia) Incidence 0.05-0.4
Prior viral or bacterial infections, vaccination
Common May trigger relapse Not seen
Course Monophasic, rarely multiphasic (4%) Relapsing, progressive Usually relapsing (80-90%)
Serum AQP4 antibodies: not seen MOG antibodies: in up to 40% of patients; commonly transient (in monophasic ADEM) and most frequent in children between age 3 and 8 years
AQP4 antibodies: not seen
AQP4 antibodies: Sensitive and specific MOG antibodies 30% of AQP4 Ab negative cases
CSF analysis Oligoclonal bands: present in up to 29% of cases
Oligoclonal bands: Common and persistent (90-95%)
Oligoclonal bands: Rare; if present at presentation tend to disappear later on
Differences between MS, ADEM and NMOSD
MS-NMO-MOG
Weber TAND 2018
Weber TAND 2018
Diagnostic Algorithm
Hacohen Neurology 2017
MS
NMOSD (NMO/LETM/atyp
ON)
AQP4-
Ab
disease ADE
M
Autoantibodies Associated CNS Diseases
• Onconeural AB Paraneoplastic No improvement with immunotherapies
• Neuronal “cell surface” protein AB Improve with immunotherapies Prev “autoimmune channelopathies”
Vincent Lancet Neurol 2011 Rosenfeld Neurol Clin Practice 2012
Vincent Lancet Neurol 2011
Vincent Lancet
Neurol 2011
3. Limbic Encephalitis
Inflammatory process
• 1960 rare paraneoplastic syn
• 1980s onconeural AB
• 2000s Cell-surface AB
LGI1LE most common Autoimmune E
Asztely Acta Neurol Scand 2012
Graus Lancet Neurol 2012
Association with
• Onconeural AB (intracellular) Often tu
• Surface/synaptic surface AB Often no tu
• No known AB Often tu
Asztely Acta Neurol Scand 2012
Limbic Encephalitis
VGKC AB POSITIVE
Limbic Encephalitis Anti-NMDAR (N-methyl D-aspartate receptor) Encephalitis
Autoimmune disorder 1st described in 2005
• Prominent psychiatric symptoms
• 2nd most common cause of autoimmune encephalitis (after ADEM)
• 80% improve after immunotherapy a/or tumour removal
Titulaer Lancet Neurol 2013
NMDAR Encephalitis
• 80% females
• 37% <18y
• 38% tumour (97% f)
• 94% ovarian teratomas
• Higher frequency of teratomas in Asian
Titulaer, Lancet Neurol 2013
NMDAR Encephalitis MR
• 50% normal
• 50% T2/FLAIR hyperintensity hippocampi, cortex, cerebellar cortex, BG, BS, insula, fronto-basal, cord
mild/transient
focal meningeal enhancement
Ho Dev Med Child Neurol 2017
NMDAR Encephalitis First Criterion
• Rapid onset (<3mo) of at least 4/6
• (1) psychiatric behaviour or cog dysfunction
• (2) speech dysfunction
• (3) seizures
• (4) movement disorders
• (5) decreased level of consciousness
• (6) autonomic dysfunction or central hypoventilation. Ho Dev Med Child Neurol 2017
Diagnostic Criteria
Second criterion
At least one of the following lab results
• (1) abnormal EEG or
• (2) CSF with pleocytosis or oligoclonal bands.
Ho Dev Med Child Neurol 2017
Diagnostic Criteria Third criterion
• Reasonable exclusion of other disorders
All three criteria should be fulfilled for a probable diagnosis of anti-NMDAR encephalitis.
Ho Dev Med Child Neurol 2017
Diagnostic Criteria
• Cumulative % of patients satisfying anti-
NMDAR encephalitis diagnostic criteria over
time
Ho Dev Med Child Neurol 2017
Diagnostic Criteria
Ho Dev Med Child Neurol 2017
Diagnostic Criteria
Encephalitis
New Disease
•Novel cell surface auto antigen
• DPPX antibodies
Boronat Ann Neurol 2013
NMDAR Encephalitis
Boronat Ann Neurol 2013
4. SLE Primary pathophysiology
• Rheumatic disorder; Autoantibodies
• Inflammation
• Small vessel infarction
• Thrombosis
Scolding Neuropath App Neurobio 2002
• Chronic relapsing-remitting
• Neuropsychiatric SLE in 50%
• Woman>man
Scolding Neuropath App Neurobio 2002
SLE
Diagnostic criteria • Malar rash Discoid rash
• Photosensitivity Oral ulcers
• Arthritis Serositis
• Renal disorder Neurological disorder
• Haematological disorder Immunological dis
• Antinuclear AB
Scolding Neuropath App Neurobio 2002
SLE Clinical presentation (112)
• Woman 92%
• Age 41 (±14)
• Headache 28%
• CV disease 16%
• Cog dysfunction 12% Multicentre study 2014
SLE
MR abnormalities in 60%
• SVD 56%
• LVD 13%
• Inflammation 7%
• Atrophy 19%
Multicentre study 2014
SLE MR –Clinical correlation
• Headache Normal MR
• CV syndrome LVD, WML, MicroH
• Cog dysfunction WML
• Low C4 Inflammatory pattern
Multicentre study 2014
SLE
Conclusions
NPSLE (6M diagnosis)
• T2 lesions (SVD+LVD) 48%
• Inflammatory only 6%
• MRI is important for monitoring active NPSLE
Summary • NMOSD/AQP4/MOG
± typical MR pattern
• NMDAR E Frequent; ± tumours
• Membrane surface encephalitis are a growing field ± typical MR pattern
• SLE Inflammatory changes possible