Nonmotor manifestations of dystonia: A systematic review

Nonmotor Manifestations of Dystonia: A Systematic Review

Daniel J. Kuyper, MD,1 Veronica Parra,2 Shanae Aerts,2 Michael S. Okun, MD,3 and Benzi M. Kluger, MD, MS2*

1Department of Neurology, University of Colorado, Denver, Colorado, USA2Departments of Neurology. and Psychiatry, University of Colorado, Denver, Colorado, USA

3Departments of Neurology, Neurosurgery, Psychiatry and History, University of Florida, Gainesville, Florida, USA

ABSTRACT: Nonmotor symptoms are increasinglyrecognized as important determinants of quality of lifeand disability in a wide range of movement disorders.There is a limited body of research suggesting thatmany of these symptoms are also commonly associ-ated with primary and other genetic forms of dystonia.However, the significance, etiology, pathophysiology,and treatment of these symptoms remain poorlydescribed. The following is a review of the literature

that focuses primarily on the association of these typesof dystonia with psychiatric disorders, cognition, sleep,pain, and autonomic symptoms. We will also discusspotential mechanisms and approaches to treatmentfor nonmotor features of dystonia. VC 2011 MovementDisorder Society

Key Words: dystonia; nonmotor; depression; anxiety;cognition; pain; sleep

Nonmotor symptoms are increasingly recognized asan important determinant of quality of life (QOL) anddisability in movement disorders. Nonmotor symp-toms include alterations of mood, cognition, sleep, au-tonomic function, and/or pain that cannot be directlyattributed to a secondary consequence of motor symp-toms. These symptoms are described most commonlyin Huntington’s disease1 and Parkinson’s disease(PD),2 but have also been reported in other movementdisorders including dystonia.3,4

The etiology of dystonia can be either primaryor secondary. In primary dystonia, no abnormalityis present other than the dystonia itself. Secondarydystonia is the result of neurodegenerative disease,metabolic disorders, or other acquired causes.5 Dysto-nia-plus syndromes are inherited forms of secondarydystonia that are accompanied by other neurologic

abnormalities. These, as well as other heterogeneitiesin dystonia populations, make for significant chal-lenges in assessing nonmotor symptoms across studiesthat may sample very different patient populations.Although psychological and other nonmotor symp-

toms have been reported to occur in primary andother genetic forms of dystonia, their significance andcauses are still debated. This article will summarizethe current literature on this topic, review the poten-tial relationship to pathophysiological data, and finallysuggest areas where further research is needed.

Methods

A search strategy was used to reference English-lan-guage articles in Medline from 1966 to December2009. A total of 1902 records were retrieved, and theabstracts were reviewed. In the absence of an abstract,the title was considered. Studies were included if theparticipants had primary dystonia or dystonia-plussyndromes and if the focus was related to nonmotorsymptomatology. Reference lists of all initiallyincluded studies were searched for additional publica-tions. Search terms were selected based on commonnonmotor features of other movement disorders (ie,PD) and terms associated with mood disorders, thecategory of nonmotor symptoms that has been studiedmost thoroughly in dystonia. The following searchterms were used: dystonia, torticollis, dysphonia,

CME

------------------------------------------------------------*Correspondence to: Dr. Benzi M. Kluger, Mail Stop B185, 12631 East17th Avenue, Aurora, CO 80045, USA; [email protected]

Funding agencies: This work was supported by the LABCOATSprogram at the University of Colorado, Denver.Relevant conflicts of interest/financial disclosures: Nothing to report.Full financial disclosures and author roles may be found in the onlineversion of this article.

Received: 3 June 2010; Revised: 7 February 2011; Accepted: 15February 2011Published online 11 April 2011 in Wiley Online Library(wileyonlinelibrary.com). DOI: 10.1002/mds.23709

R E V I E W

1206 Movement Disorders, Vol. 26, No. 7, 2011

blepharospasm, depression, bipolar, mood, anxiety,psychiatric, substance abuse, phobia, personality, deepbrain stimulation, anticholinergic medications, neuroi-maging, psychosis, hallucinations, memory, cognition,neuropsychology, sleep, fatigue, energy, pain, auto-nomic, sweating, blood pressure, orthostatic, constipa-tion, urinary, urination, sexual, erectile.

Results

Mood (n 5 25 Studies)

There are numerous reports in the literature indicat-ing that patients with primary and other genetic formsof dystonia have higher than expected rates of depres-sion and anxiety (see Table 1). The prevalence ofdepression and anxiety in patients with dystonia variesbased on the study and on sample size, but cohortsanalyzed in this article indicate that 12%–71% ofpatients with focal or generalized dystonia suffer fromdepression and anxiety over the course of a lifetime,with most studies falling in the range of about 25%–50%. This percentage is similar to that for Parkinson’sdisease, which also disturbs frontal-subcortical cir-cuits.6,7 It is increased compared with those who arehealthy8–11 and those with other medical condi-tions.12–14

There is conflicting epidemiological evidence aboutwhether depression and anxiety are secondary tomotor manifestations and subsequent psychosocialimpairment or are a primary feature of the disease.On the one hand, studies have reported a higher pre-morbid incidence of depression and anxiety in patientswith dystonia,15 suggesting that, similar to PD, thismay be an independent manifestation of dystonia. Inaddition, a study of manifesting and nonmanifestingcarriers of the DYT1 gene showed that carriers (withor without symptoms) had a significantly higher rateand earlier onset of major depressive disorder thannoncarrier controls.10 Although these studies mayhave been prone to recall bias, they suggest that theunderlying pathophysiology of dystonia may predis-pose patients to mood disorders. Striatofrontal circuitsthat help regulate mood and behavior have beenshown to be disordered in dystonia patients based onfunctional imaging16–18 and may act as a pathologicsubstrate. Functional imaging studies have shown thatthese nonmanifesting carriers have decreased D2receptor binding in the basal ganglia and hypermetab-olism in the putamen, anterior cingulate, and cerebel-lar hemispheres.19,20 Patients with GTP cyclohydrolasedeficiency (DYT5 dystonia) may also have higher ratesof depression than the general population, perhapsbecause of reduced conversion of tryptophan toserotonin.21

There is mixed evidence to suggest that depressionand anxiety symptoms are associated with disease

severity, with some studies showing correlation7,22,23

and others no correlation.9,24 Of note, a 2-year longi-tudinal follow-up of patients with spasmodic torticol-lis showed that changes in the severity of the dystoniawere closely linked to subsequent changes in mood,disability, and body concept.14,25 Other factors thathave been correlated with higher depression scoresinclude marital status (higher scores for separated/divorced patients) and body parts affected (higherscores for cervical dystonia versus spasmodic dyspho-nia or hemifacial spasm).22 Self-esteem, body concept,and QOL have also contributed to the variance ofdepression.22 Finally, the degree of psychopathologymay also be associated with triggering events. Scheidtet al reported that cervical dystonia patients weremore likely to have psychopathology if symptomswere triggered by a stressful life event.23

Deep brain stimulation (DBS) of the internal globuspallidus, an emerging procedure for selected primarydystonias, deserves special attention for its effect onmood. Although most studies suggest that DBS fordystonia results in mildly improved or unchangedmeasures of depression,26–29 worsened mood and sui-cide have also been reported.30,31 The majority ofthese patients had a previous history of depression orother risk factors for suicide prior to surgery. Interest-ingly, most of the patients who committed suicide alsohad an excellent motoric response from stimulation,providing further evidence that severity of dystoniamay not correlate with symptoms of low mood.In dystonia, dysfunctional mood is one of the most

important predictors of a patient’s QOL.25 Werecently reported the results of a large retrospectivecase series of patients with dystonia who were givenquestionnaires assessing QOL, depression, anxiety,and other mood variables.4 Both physical and mentalaspects of QOL were strongly associated with depres-sion and anxiety. Treatment of the motor symptomsof dystonia may or may not32–34 lead to improvementin depression and health-related QOL. Other factorsin addition to motor symptoms—long-standing dis-ability, pain, deformity, and lifestyle changes—mayalso contribute to depression and poor QOL.Several areas of future research may prove useful.

Routine screening of patients with dystonia, or thosewho have genetic mutations predisposing to dystonia,for depression and anxiety would seem to be war-ranted. Development of a nonmotor screening tool forpatients with dystonia could make this process moreefficient. Identifying those who are most at risk formood dysfunction would be helpful to the clinicianscaring for these patients. For instance, does the side ofmotor symptom onset make someone more likely todevelop depression with their dystonia? Studies in thehealthy brain indicate that the right forebrain plays alarge role in mood processing.35 Also, patients withleft-sided onset of their parkinsonian motor symptoms

N O N M O T O R M A N I F E S T A T I O N S O F D Y S T O N I A

Movement Disorders, Vol. 26, No. 7, 2011 1207

TABLE1.Depression/anxiety

studiesin

dystonia

Author,year

Studytype

Sample

size

Findings

Comments

Aronson,

1968

77Case–control

31Spasmodicdysphonia

Nostatisticallysignificant

differencebetweenthe

3groups

onMMPI

50,000

Controls(generaloutpatient

medicalpopulation)

18Psychogenicaphonia

VanHoof,1987

78Retrospectivecase–control

17Spasmodictorticollis

Nodifferenceinpersonality

inventory;2of

17spasmodictorticollispatientshaddepression

Healthycontrols(unspecified)

Harrington,1988


22Writer’scram

pNo

differenceinanxietyindices;3subjectshad

symptom

sof

generalized

anxiety.

22Healthycontrols

Naber,1988

3Case–control


MMPI

scores,specifically

hypochondriasis,

depression,andhysteria,wereelevated

in50%

ofpatients

MMPI

scores

correlated

with

severityof

neurologicsymptom

sandweresimilarto

PDcontrols

32Controlswith

Parkinson’sdisease

Jahanshahi,1988

12Case–control


NodifferenceinMMPI,anxiety,or

obsessive

symptom

s7ST

patientswith

priorpsychiatric

histories

wereexcluded

49Controls(cervicalspondylosis)

Jahanshahi,1989

81Case

series


36%

hadnorm

alMMPI

profiles;conversion

‘‘V’’

profileswereseen

in9%

58.5%

hadMMPI

pattern

consistent

with

mild

depression

Jahanshahi,1990

142-Year

longitudinalcohort


25%

ofpatientsdepressedat

both

times

Depression

improved

inpatientswith

successfulBotoxtreatment

Jahanshahi,1990



STpatientshadhigher

prevalence

(54%

)and

severityof

depression,disability,andnegative

body

concept.

Body

image,

neuroticism,pain,anddisability

correlated

with

depression

Jahanshahi,1988

8049

Controls(cervicalspondylosis)

Grafman,1991

24Case

series

20Focalhanddystonia

Four

of20

hadmild

depression,30%

with

elevated

anxietyinventoryscores.

MMPI

andpsychiatric

historieswere

unremarkableanddidnotcorrelatewith

dystoniaseverity

Cannito,1991



SDhadhigher

ratesof

clinicaldepression

and

anxiety(both39%)

18Healthycontrols

Jahanshahi,1992

Longitudinalcohort


Improved

depression

anddisabilityafterBotox

injections

in22

patientswhose

torticollis

improved.

Body

conceptalso

improved

butnot

significantly

Murry,1994

11Case–control


SDhadhigher

ratings

ofdepression,stateand

traitanxiety

Improvem

entsnotedindepression

andanxiety

followingBotoxtreatment.

28Healthycontrols

Scheidt,1996

I-IV2



27%

ofST

patientshadpsychopathology

including23%

with

clinicaldepression

Depression

correlated

with

severity

HC(unspecified)

Wenzel,1998

39Case

series


High

lifetimeprevalence

ofpsychiatric

disorders

(66%

)especiallyanxietydisorders(34%

),includingpanicdisorder

(20%

)andMDD

(25%

)

43%

ofpatientsreportedpsychopathology

preceded

motor

symptom

s

Gundel,2001

9Case–control


Higher

lifetimeprevalence

ofMDD

(46%

)and

anxietyd/o,

especiallysocialphobia(71%

)Psychopathologydidnotcorrelatewith

dystoniaseverity;socialphobiacorrelated

with

body

image

483Healthycontrols

Moraru,

2002

15Case

series


40%

with

anxiety,37.5%

with

major

depressive

disorder

Criteria

for1lifetimepsychiatric

diagnosis

fulfilledpriorto

onsetof

STin42.5%

Muller,2002

33Longitudinalcohort


47%

depression

inST

patients,37%

inBL

patients;health-related

QOLsignificantly

worse

inalldom

ains

comparedwith

controls

Botoximproved

clinicalsymptom

sbutminimal

improvem

entinhealth-related

QOL.

89Blepharospasm

K U Y P E R E T A L .


may have more prominent mood and pain symp-toms.36 Last, studies utilizing more standardized scalesof depression and anxiety would clarify the true inci-dence of mood disorders and make comparisonseasier.

Other Psychiatric Disorders and Symptoms(n 5 10)

A small group of studies have looked specificallyfor obsessive–compulsive symptoms in dystonia (seeTable 2). In 1 of the larger cohorts, 19.7% of patientswith idiopathic focal dystonia met DSM-IV criteriafor obsessive–compulsive disorder.37 This percentageis slightly higher than that in other studiesreviewed.15,38,40 No significant differences in obses-sive–compulsive symptoms emerged in a study com-paring DYT1 carriers with a control population.40 Incontrast, symptomatic carriers of DYT11, the gene formyoclonus-dystonia, had a higher rate of obsessive–compulsive symptoms than asymptomatic carriers andcontrol populations.38,41

Alcohol abuse and dependence has been reported inthe DYT11 mutation (myoclonus-dystonia) as well asin idiopathic generalized and focal dystonia, albeit toa lesser extent. In DYT11, a study of carriers versusnoncarriers revealed no significant differences in alco-hol dependence. However, some38,41 but not all42

studies have shown that symptomatic carriers demon-strate more alcohol dependence than unaffected car-riers. Given the typical sensitivity of myoclonus toalcohol, the alcohol dependence seen in certainpatients may be the result of alcohol’s symptomaticeffects rather than a manifestation of the gene itself.38

Aside from the connection to DYT11, alcohol abusewas found to be significantly higher than healthy con-trols in a small cohort of patients with primary gener-alized dystonia and spasmodic torticollis.6

Social phobia in dystonia is often comorbid andassociated with other anxiety symptoms. In 1 largerstudy of 116 patients with spasmodic torticollis, a71% lifetime prevalence of social phobia was foundby using the Social Phobia and Social Interaction Anx-iety scales.9 This prevalence correlated with bodyimage and a ‘‘maladaptive attitude’’ toward their ill-ness, not with the objective severity of the dystonia.9

It can be hypothesized that self-esteem and body con-cept play an important role in the development ofsocial phobia, much like depression and other formsof anxiety..Screening for these conditions in patients with dys-

tonia is of great importance. This is particularly truewith the association of alcoholism in patients withDYT11 dystonia. Physicians should consider counsel-ing patients, specifically adolescents, about the risks ofusing alcohol to treat their symptoms. Furtherresearch verifying the possible association between

TABLE1.(Continued)

Author,year

Studytype

Sample

size

Findings

Comments

Gundel,2003



Higher

prevalence

ofpsychiatric

diagnosis(77%

)includinganxiety(69%

)andmood(19%

)disorders

Socialphobia(54%

)was

themostcommon

anxietydisorder

48Controls(alopeciaareata)

Heiman,2004

10Case

control

96Manifestingcarriers

ofDY

T1,

Risk

forrecurrentmajor

depressive

disorder

increasedinboth

NMC(RR,

4.95)andMC

(RR,

3.62)comparedwith

noncarriers

Mutationcarriers

also

hadearlier

onset

depression

than

noncarriers

60Nonm

anifestingcarriers

ofDY

T165

Noncarriers

Lauterbach,2004

6Retrospectivecase

control

28Primarygeneralized

dystoniaandspasmodic

torticollis

Higher

prevalence

ofMDD

(25%

),BM

D(7%),

phobias(39%

),GA

D(25%

),andalcoholabuse

(11%

)than

inHC

53%

ofdystoniapatientswereon

GABA

agonists;phobiasandGA

Dfrequently

preceded

motor

symptom

s1:128Matchingwith

healthycontrols

Lewis,2008

22Case

series

329Focaland

generalized

dystonia

30%

reportedmoderateto

severe

depression;

disfigurement,negativebody

concept,low

self-esteem

,andQO

Lwereimportant

contributorsto

depression

BL,blepharospasm;BMD,bipolarmooddisorder;FHD,focalhanddystonia;GAD,generalizedanxiety

disorder;HC,healthycontrols;MC,manifestingcarriers;MDD,majordepressivedisorder;MMPI,Minnesota

Multiphasic

Personality

Inventory;NMC,nonmanifesting

carriers;PA,psychogenic

aphonia;PD,Parkinson’s

disease;PG,primary

generalized

dystonia;QOL,quality

oflife;SD,spasmodic

dysphonia;ST,

spasmodic

torticollis;WC

–writer’scramp.



TABLE2.Obsessivecompulsivesymptoms

Author,year

Studytype

Sample

size

Findings

Comments

Meares,1971

82Case–control


SThadhigher

than

expected

obsessionalpersonality

traits

butnotsymptom

s.Ob

sessioncorrelated

with

neuroticism.

Healthycontrols(unspecifiedN)

Bindman,1977

83Case

series

10Writer’scram

p9of

10WChadobsessivepersonalities.

Mathews,1978

Case

series


Neuroticism,obsessionalsym

ptom

s,intropunitive

hostilityunchangedfrom

generalpopulation.

23of

29with

‘‘adverse

socialeffects’’and9of

21with

moderate–severe

maritaldiscord

Bihari,

1992


21Blepharospasm

BLpatientshadhigher

scores

onobsessive–com-

pulsiveinventory.

Didnotassess

forclinicalOC

D.19

Healthycontrols

Broocks,1998

85Case

series

13Blepharospasm

Significantlymoreobsessive-compulsivesymptom

sinBL

groupthan

inHFSgroup.

13Hemifacialspasm

Kubota,2001


12Writer’scram

pWChadsignificantlyhigher

obsessivecompulsive

symptom

sscorethan

either

controlgroup

Therewereno

differences

betweendiseased

and

healthycontrols.

12Diseasecontrol(includingCTS)

12Healthycontrols

Cavallaro,2002

37Case

series

76Idiopathicfocaldystonia

19.7%

satisfiedDS

M-IV

criteria

forOC

D;morbidity

riskforfirst-degreefamily

mem

bers

ofOC

Dpatientswas

13.8%,significantlyhigher

than

generalpopulation

Heiman,2007

40Case–control


ofDY

T1No

differenceinOC

Dor

obsessive–compulsive

symptom

sbetweencontrolsandcarriers.

Firststudyexam

iningOC

Dspecifically

inDY

T1carriers

60Nonm

anifestingcarriers

ofDY

T165

Healthycontrols

Saunders-Pullman,2002

38Case–control


ofDY

T11

Rate

ofOC

Dhigher

incarriers

(5of

27)than

non-

carriers

(0of

28)andgreaterinsymptom

atic(4

of16)than

innonsym

ptom

atic(1

of11)

11Nonm

anifestingcarriers

ofDY

T11

28Noncarriers

Hess,2007



ofDY

T11

Increasedrate

ofOC

D,EtOH

dependence

among

MCgroup,

notNM

Cgroup

10Nonm

anifestingcarriers

ofDY

T11

34Healthycontrols

BL,blepharospasm;CTS,carpaltunnelsyndrome;HC,healthycontrols;HFS,hemifacialspasm;IFD,idiopathic

focaldystonia;MC,manifestingcarriers;NMC,nonmanifestingcarriers;OCD,obsessive–compulsive

disorder;QOL,qualityoflife;ST,

spasmodic

torticollis;WC,writer’scramp.



different types of dystonia and alcoholism is needed.Also lacking from the literature are studies assessingthe incidence of other psychiatric disorders (ie, bipolardisorder) in dystonia patients.

Cognition (n 5 14)

Several studies of cognition have been performedin both idiopathic and genetic forms of dystonia (seeTable 3). By using detailed neuropsychological testing,many of these studies have shown statistically signifi-cant (albeit, at times subtle) deficits in executive,attentional, or visuospatial function. From the avail-able evidence, it is unclear how functionally significantthese deficits are. That certain findings such asimpaired sequence learning are not consistently repli-cated suggests that the severity of these findings maybe mild. There are several limitations of the currentliterature regarding cognition, including small samplesizes. Also notable is the variability of several factors,including age, education level, premorbid cognitivefunction, type of dystonia, and antidystonic medica-tion burden at the time of testing. The studies thataccounted most thoroughly for these confounding fac-tors showed either no difference between dystoniapatients and controls or only mild executive dysfunc-tion including set-shifting deficits, verbal learning, cat-egory fluency, and performance of dual tasks.43–46

The etiology of these cognitive deficits is not entirelyclear. One possible explanation is that antidystonicmedications play a part, particularly if a patient is onan anticholinergic agent or on a benzodiazepine.Although patients in several of these studies were onmedications at the time of testing, there has not beenclear evidence that medications are directly causative.Chronic exposure to anticholinergic medicationsaffected performance on a memory task in 1 study ofadult patients with dystonia.47 Another study showedthat cognitive processes were only mildly affected byanticholinergic medication, and this was only in el-derly patients.48 Three of 23 pediatric patientsreported being forgetful in an early study using high-dose benzhexol therapy for dystonia.49

Another possibility is that concurrent mood disor-ders may lead to impairments in executive function.Depression causing a ‘‘pseudodementia’’ is well estab-lished as a diagnostic consideration in patients withuntreated low mood. Moreover, patients with OCDare known to have deficits in organizational strategiesand executive dysfunction.50 Although disorders ofmood have not been definitively linked to cognitivedysfunction in dystonia, 1 recent study showed a pos-sible association between executive dysfunction inpatients with idiopathic focal and segmental dystoniaand obsessive compulsive symptoms.45

A third potential mechanism for cognitive impair-ment is the possibility that the disabling symptoms of

dystonia, including pain, are impairing attentionalprocesses. In a small sample of patients with primarycranial dystonia, sustained attention deficits wereshown to improve following botulinum toxin injec-tions, suggesting that dystonic activity may impairattentional processing.51 Executive function alsoimproved mildly but significantly in a group of gener-alized dystonia patients after undergoing GPi DBSsurgery.52

Although secondary effects of motor symptoms maybe partly to blame, there is evidence to suggest thatasymptomatic carriers of DYT1, the most commonform of genetic dystonia, also have mildly impairedcognition and abnormal functional imaging, particu-larly in motor and visual sequence learning.21,53 Func-tional imaging studies in this population have showncompensatory overactivation of the lateral cerebellumand right inferotemporal cortex with a lack of recruit-ment of prefrontal regions, which may be a result ofunderlying frontostriatal dysfunction.16

Additional studies of cognition in dystonia that con-trol for factors such as medication burden and moodsymptoms are needed. Studying cognitive deficits inspecific forms of dystonia without combining dystoniasubtypes would also be helpful. In addition, it isunclear how medications for dystonia could poten-tially affect cognition in the long term. Anticholiner-gics, frequently used for symptomatic treatment ofdystonia, can cause delirium in the short term andlikely lead to cognitive impairment in the elderly andmemory-impaired.54,55

Sleep and Energy (n 5 13)

There are relatively few articles addressing sleep inpatients with dystonia. Recent studies have focused onpatient surveys in order to measure quality of sleepand symptoms of sleepiness. In patients with blepharo-spasm and cervical dystonia, quality of sleep wasimpaired in both groups using the Pittsburgh SleepQuality Index.56 Differences seen in the cervical dysto-nia group, however, were partly confounded by higherscores on the Beck Depression Inventory. Excessivedaytime sleepiness, using the Epworth Sleepiness Scale(ESS), was not found to be significantly more frequentwhen compared with a group of control subjects. Incontrast, another study specifically evaluating daytimesleepiness (again using the ESS) found that a signifi-cantly higher percentage of patients with cervical dys-tonia had scores > 11 when compared with patientswith other focal movement disorders or to age-matched controls.57

Although there is mixed evidence that dystonia leadsto sleepiness, several studies suggest that either sleepstructure or quality is impaired. Specific polysomno-graphic abnormalities have been reported, includingproblems with sleep initiation and maintenance,



TABLE3.Studiesofcognitionin

dystonia

Author,year

Studytype

Sample

size

Findings

Neuropsychologicaltests

Comments

Eldridge,1970

87Case–control

14Autosomalrecessive

dystonia

Statisticallysignificant

increase

inIQ

scores

forpatientsaffected

with

autosomalrecessive

dystonia

IQtest

10Siblings

24Controls

Taylor,1991

48Case–control


Onlyexplicitmem

ory,speedof

inform

ationprocessing

affected

byhigh-doseanticholinergics

NART,WAIS-R,

LP,VR,DR

T,TT,

BSRT,CA

LT,BC

,Item

99from

LNNB

,SC

WT,

VFT,

WCS

T

Vulnerabilityto

medshighlyage

dependent

20Healthycontrols

Hinse,

1996

88Case–control


STpatientsperform

edsignificantlyworse

onspatial

tasksrequiring

mental

manipulationof

personalspace

MW,HR

DT,CB

TT,VST

Nosignificant

differenceinspatial

perception

15Norm

alcontrols

Ghilardi,1999

53Case–control

4Nonm

anifestingcarriers

ofDY

T1NM

Cpatientshadsignificantly

decreasedscores

formotor

andvisualsequence

learning

comparedwith

HCgroup

ME,

MSL,VSL

5Healthycontrols

Ghilardi,2003

18Case–control

12Nonm

anifestingcarriers

ofDY

T1(nohistoryof

psychiatric

disease)

Sequence

learning

impairedin

carriers

with

preservedmotor

perform

ance

CCW,RA

N,SEQ

Overactivationof

leftPM

C,right

SMAinNM

Cpatientsduring

sequence

learning

(PET

scan);

may

becompensatingfor

striataldysfunction

12Healthycontrols

Jahanshahi,2003

46Case–control


þidiopathicgeneralized

dystonia

Significant

differenceincategory

fluency

andperform

ingdual

tasks;otherwise,

pr\eserved

executivefunctioncompared

with

controls

NART,WFT,WCS

T,SC

WT,

MDT

,SO

RNS,

RNG,

VVCA

L,PVSAT,

DTP

Only1of

10patiens

onmedications

(4mgArtane/day);

dystoniagrouphad

nonsignificantincrease

inself-reporteddepression

12Healthycontrols

Scott,2003

89Case

series

14Primarydystonia(7

men,

7wom

en)priorto

undergoing

GPideepbrain

stimulationsurgery

Baselineimpairm

entwith

extradimensionalsetshifting

(priorto

DBSsurgery),partof

CANT

ABbattery

CANT

AB,NA

RT,Raven,

SDMT,

Stroop,TM

,BN

T,JLO,

SCOLP,

RMT,

AMIPB,

DS,CF

Notclearifthisimpairm

entis

functionally

significant

orifit

improves

with

GPisurgery;

studynotcontrolledformood,

pain,medications

Balas,2006

44Case–control


ofDY

T1Symptom

aticpatientsperform

edbetteron

semantic

verbal

fluency

test,worse

onverbal

learning

test

Raven,

RAVLT,

RCF,

PVF,

SVF,

TMA/B,

Stroop,CA

NTAB

,WAIS-III,JLO,

PP

Nodifferencebetween

nonsym

ptom

aticcarriers

and

controls;statisticallyaccounted

formedications,anxietylevels

8Nonm

anifestingcarriers

ofDY

T128

Matched

controls

Pillon,

2006

52Longitudinalcohort

22Primarygeneralized

dystoniaundergoing

DBS

surgery

Nopresurgicalcognitivedecline

inexecutivefunction;

GPiD

BSmildlybutsignificantly

improved

executivefunction

Raven,

WAIS-R,

GBT,

WCS

T,VFT,

TMA/B

Improvem

enteither

relatedto

DBSor

reductionin

anticholinergicdrugs20

of22

patientson

medications

prior

tosurgery



TABLE3.(Continued)

Author,year

Studytype

Sample

size

Findings

Neuropsychologicaltests

Comments

Allam,2007

51Case–control

9Primarycranialdystonia

(blepharospasm

)Sustainedattentiondeficits

prior

toBotoxinjections;following

injections,no

significant

differenceinsustained

attentioncomparedwith

controls

RAVLT,

TPT,

DSub,DS

Y,SC

WT

Executivedysfunctionmay

berelatedto

disruptingeffectsof

symptom

s9Healthycontrols

Bugalho,

2008

45Case–control

45Idiopathicfocal/segmental

dystonia

Moreset-shiftingdeficits

indystoniagroup,

also

had

significantlymoreobsessive

compulsivesymptom

s

WCS

T,SC

WT,

BAT,

BVRT

Nopatientson

anticholinergic

medication

27Healthycontrols

Carbon,2008

16Case–control

6Nonm

anifestingcarriers

ofDY

T1NM

Cpatientsperform

edat

controllevelsduringsequence

learning

TSEQ

,CCW

NMCpatientsoveractivated

lateralcerebellum,right

inferotemporalcortex,

underactivated

prefrontal

regions

6Healthycontrols

Alem

an,2009

43Case–control

20Blepharospasm

BLpatientsshow

edimpairm

ent

ofcomplex

movem

ent

planning,motor

dexterity,

visuospatialw

orking

mem

ory,

andtactile

object

recognition

WAIS-III,FDT,

Raven,

LT,

LOW

I/II,SL,WCS

T,PP,

OMT,

DR,TD

,Tap

Groups

matched

forseverityof

depression

andeducationlevel

17Healthycontrols

AC,anticholinergic;BC,BlockCountingItem

from

Stanford-B

inetIntelligenceTe

st;AMIPB,AdultMemory

andInform

ationProcessingBattery;BAT,

BlockAssembly

TestofWAIS;BL,blepharospasm;BNT,

Boston

NamingTe

st;BSRT,

BuschkeSelectiveRemindingTe

st;BVRT,

BentonVisualRetentionTe

st;CALT,ConditionalAssociativeLearningTe

st;CANTAB,CambridgeNeuropsychologicalTe

stAutomatedBattery;CBTT,

Corsi’s

BlockTa

ppingTe

st;CCW,matchedmotorbaselinetask;CF,

MedicalCollegeofGeorgia

ComplexFigures;CLT

R,ConsistentLong-Term

Memory;DR,DigitalRecognition;DRT,

DelayedRecognitionSpan

Test;

DS,digit

span;DSub,Digit

SubtestofWechslerMemory

Scale-R

;DSY,Digit

Symbolsubtestofthe

WechslerIntelligence

Scale-R

;DTP,

dualtaskperform

ance;FDT,

Five

DigitsTe

st;

GBT,

Groberand

Buschke

test;

HC,healthy

controls;HRDT,

Hebb’s

Recurring

Digits

Test;

IFD,idiopathic

focaldystonia;IG

D,idiopathic

generalized

dystonia;JLO,judgmentofline

orientation;LNNB,Luria-N

ebraska

neuropsychologicalbattery;LOW

I/II,ListofWordsIand

II;LP,

LogicalPassages;LT,Luriatask;MC,manifesting

carriers;MDT,

missing

digittest;

ME,motorexecution;MSW,motorsequencelearning;MW,

Mehrfachwahl-Worschatztest;

NART,

NationalAdultReadingTe

st;NMC,nonmanifestingcarriers;OMT,

OralMakingTrails;PET,

positronemissiontomography;PMC,premotorcortex;PP,

Purduepegboard;PVF,

phonemic

verbalfluency;PVSAT,

Paced

VisualSerialAddition

Test;

RAN,reaction

time/m

otorperform

ance;Raven,Raven’s

Matrices;RAVLT,Reyauditory

verballearning

test;

RCF,

Reycomplexfigure;RMT,

RecognitionMemory

Test;RNG,random

numbergeneration;SCOLP,

SpeedandCapacityofLanguageProcessingtest;SCWT,

StroopColour-Word

Test;SDMT,

Sim

ple

DigitModalitiesTe

st;SEQ

–motorlearning

task;SL-SpatialLocation;SMA-supplementary

motorarea;SORNS-S

elf-O

rderedRandom

NumberSequences;SVF-semanticverbalfluency;Ta

p,Ta

ppingTe

st;TD,Ta

ctile

Denomination;TMA/B

,Trail-makingA

and

B;TPT,

Toulouse-P

ieron

Test;

TSEQ,trial-and-error-guided

motorsequence

learning

task;TT,

TowerofTo

ronto

Test;

VFT,

VerbalFluencyTe

st;

VR,VisualReproduction;VVCAL,Visual-VisualConditional

AssociativeLearning;VSL,visualsequencelearning;VST,

visuospatialtesting;WAIS-R

,WechslerAdultIntelligenceScale-revised;WAIS-III,WechslerAdultIntelligenceScale–III;WCST,

Wisconsin

Card

Sorting

Test;WFT,

word

fluencytest;



abnormal or reduced REM sleep,58–60 and changes inspindle activity.58,60,61 In a study of 10 patients withblepharospasm and oromandibular dystonia, impairedsleep efficiency and decreased REM sleep were found,both of which correlated with the severity of dystoniaand EMG abnormalities.59 In contrast, a larger studyof 24 patients with focal or generalized torsion dysto-nia (14 primary, 10 secondary) showed that sleeparchitecture and organization did not vary significantlyfrom control patients.62

Much like other nonmotor symptoms in dystonia,the etiology of sleep abnormalities may include pri-mary effects of dystonia on sleep as well as secondaryeffects of pain and medications. Some of the patientsin the aforementioned studies were on benzodiaze-pines, known to change sleep architecture and spindleactivity.57 Anticholinergic medications may alsoaccount for some of the sleepiness seen in patients withhigh ESS scores.57 There is conflicting evidence aboutwhether the severity of dystonia is associated with theoccurrence of sleep disorders. Although impaired sleepefficiency, decreased REM sleep, and sleep qualityhave all been linked to severity of motor symptoms infocal or cervical dystonia,59,63 excessive daytime sleepi-ness was not correlated with scores on the TorontoWestern Spasmodic Torticollis Rating Scale (TWSTRS)or its subscores in another study.57 There is evidencethat at least certain forms of dystonia, including ble-pharospasm and Meige’s syndrome, may persist duringsleep, although its frequency and severity aredecreased.64 Whether this may affect sleep quality isunknown. Restless legs–like symptoms were found in 6of 34 patients with DYT5 dystonia prior to the initia-tion of levodopa in a detailed clinical evaluation.65

Finally, Wetterberg (1978) found decreased amplitudeof melatonin fluctuations in a patient with ‘‘hereditarydystonia’’; however, this was not replicable in a largerseries of 19 patients.66

Sleep impairment and its secondary symptoms areparticularly burdensome for patients with dystonia.Studies using the Cervical Dystonia Impact Scale, arating scale for measuring the health impact of cervi-cal dystonia based on patient perceptions,67 haveshown that a large percentage of patients with dysto-nia report sleep affecting their QOL. Subjective ratingsof both energy and tiredness are associated with QOL,even when controlling for depression. In fact, the tiredsubscore of the Visual Analogue Mood Scale wasfound to be the most strongly correlated with overallQOL in our recent study.4

Additional research analyzing polysomnograms inpatients off antidystonic medications would help toclarify if changes in sleep structure are a primary orsecondary effect in dystonia. Also, studies assessingwhether treatment of motor symptoms alone improvesobjective sleep measures are needed. Finally, althoughfatigue plays a significant role in QOL in dystonia, no

studies to date have assessed the symptom as a mani-festation of dystonia.

Pain (n 5 12)

Pain is one of the most common and disabling com-plaints in many patients with dystonia. Studies suggestthat the prevalence of pain in patients with cervicaldystonia ranges from 67% to 75%.68–70 In cervicaldystonia, pain is often experienced in the head andneck and down the ipsilateral arm on the side towhich the head is rotated.69 The sternocleidomastoidand trapezius are the most frequently involvedmuscles.71 Although it may seem obvious that dys-tonic muscles would be painful, not all patients withsimilar degrees of dystonia report equal amounts ofpain. Although degree of head deviation and subjec-tive muscle tension may correlate with pain level,somewhat surprisingly, the objective severity of neuro-logic signs has not.69

One potential reason that pain is so prevalent indystonia is that the threshold for experiencing painmay be reduced. In a small study of 9 patients with id-iopathic cervical dystonia, pain-pressure thresholdswere about 2 times lower in the dystonia group versusa group of age- and sex-matched controls.72 Patientswith dystonia may also have alterations in pain proc-essing, even in body parts without dystonic involve-ment. For example, in the same study, the nonaffectedmasseter muscles of patients with idiopathic cervicaldystonia also showed reduced pain-pressure thresholdscompared with the control group.72 Another potentialmechanism for excessive pain includes alterations inthe somatosensory system that have been documentedin patients with focal or generalized dystonia. Theseinclude changes in excitability on neurophysiologicaltesting, abnormal representation in S1 of dystonicbody parts, and changes in somatosensory cortical ac-tivity during movement.73 Ongoing depression, com-mon in this population, correlates with symptoms ofpain. Last, sleep itself may mitigate against pain, ascervical spinal pain intensity and unpleasantness werereduced by about 50% overnight in 1 study ofpatients with idiopathic cervical dystonia.74

To our knowledge, no recent studies have evaluatedany other pharmacologic agents to specifically treat ei-ther primary or secondary dystonic pain symptoms.Double-blind, randomized controlled trials assessingwhether analgesic agents could lead to objective meas-ures of additional decreased pain in dystonia patientsare needed, particularly in patients refractory to botu-linum toxin. Whether the type and location of dysto-nia correlate with pain level is also not known.

Autonomic Symptoms (n 5 2)

Patients receiving botulinum toxin, especially typeB, may experience autonomic symptoms including dry



mouth, blurred vision, reduced sweating, constipation,and urinary retention.75 Anticholinergic medicationsmay also cause similar symptoms. Autonomic symp-toms have rarely been reported outside the context ofthese medical treatments or secondary dystonia (com-plex regional pain syndrome and brain injury). Tipleet al (2008) found that patients with cervical dystoniahad mild subclinical changes in some measures ofheart rate variability and baroreflex sensitivity thatwere present before receiving botulinum toxin injec-tions.76 Aside from this, no reports of erectile, sexual,urinary, or bowel dysfunction were found. Futureresearch should attempt to further clarify whether au-tonomic symptoms are seen outside known side effectsof treatment.

Conclusions

In addition to there being the more visually appa-rent and well-defined motor symptoms of dystonia,there is emerging evidence for the presence of nonmo-tor symptoms in primary and other genetic forms ofdystonia. The available evidence can at times be con-flicting, and the question remains: are these nonmotorsymptoms secondary to motor causes and medications,or do they reflect a primary defect in neuronal proc-essing or neurochemistry? Given that nonaffected fam-ily members with dystonia biomarkers can be affectedand that symptoms can be seen prior to the onset ofmotor symptoms, it seems likely that the primaryeffects of the disease are at least partly to blame.Although the pathophysiology and neuroanatomy ofthese effects have not been clearly elucidated, theunderlying defects in dystonia may provide a substratefor nonmotor symptoms to develop, particularly whencombined with motor features of the disease and/orside effects of treatment.Further studies are clearly indicated. First, by inves-

tigating the specific cortical and subcortical networksinvolved in dystonia, the genesis of the disease andthe development of nonmotor symptoms might bebetter understood. Defining the neuroanatomy andpathways involved in these symptoms by using func-tional imaging studies may yield new treatment strat-egies. Using such studies to image nonmanifestingcarriers of dystonia genes may shed light on a ‘‘pre-motor’’ phase of dystonia, akin to what is describedin PD. We also recommend a formal presurgical psy-chiatric evaluation for DBS candidates to screen spe-cifically for mood disorders, given their prevalence indystonia. This should include an assessment from apsychiatrist as well as a standardized measure ofdepression. Development of carefully designed preva-lence studies of all nonmotor symptoms, controllingfor secondary effects of motor symptoms and sideeffects of medicine, are needed.

Much has been learned about the manifestations ofdystonia including both motor and nonmotor symp-toms over the past 2 decades. We must understandthat nonmotor manifestations will likely widely varyamong dystonia subtypes. Only when the entire phe-notype of dystonia is fully understood will we be ableto provide appropriate, comprehensive care and meas-urable improvements in QOL for these patients.

Acknowledgments: We thank Leah Lleras for her help in the preparationof this manuscript. We would also acknowledge the support of Tyler’sHope for a Dystonia Cure.

References1. Anderson KE, Marshall FJ. Behavioral symptoms associated with

Huntington’s disease. Adv Neurol 2005;96:197–208.

2. Simuni T, Sethi K. Nonmotor manifestations of Parkinson’s dis-ease. Ann Neurol 2008;64(Suppl 2):S65–S80.

3. Miller KM, Okun MS, Fernandez HF, et al. Depression symptomsin movement disorders: Comparing Parkinson’s disease, dystonia,and essential tremor. Mov Disord 2007;22:666–672.

4. Soeder A, Kluger BM, Okun MS, et al. Mood and energy determi-nants of quality of life in dystonia. J Neurol 2009;256:996–1001.

5. Geyer HL, Bressman SB. The diagnosis of dystonia. Lancet Neurol2006;5:780–790.

6. Lauterbach EC, Freeman A, Vogel RL. Differential DSM-III psy-chiatric disorder prevalence profiles in dystonia and Parkinso’s dis-ease. J Neuropsychiatry Clin Neurosci 2004;16:29–36.

7. Naber D, Weinberger DR, Bullinger M, et al. Personality variables,neurological and psychopathological symptoms in patients suffer-ing from spasmodic torticollis. Compr Psychiatry 1988;29:182–187.

8. Cannito MP. Emotional considerations in spasmodic dysphonia:psychometric quantification. J Commun Disord 1991;24:313–329.

9. Gundel H, Wolf A, Xidara V, et al. Social phobia in spasmodictorticollis. J Neurol Neurosurg Psychiatry 2001;71:499–504.

10. Heiman GA, Ottman R, Saunders-Pullman RJ, et al. Increased riskfor recurrent major depression in DYT1 dystonia mutation car-riers. Neurology 2004;63:631–637.

11. Murry T, Cannito MP, Woodson GE. Spasmodic dysphonia. Emo-tional status and botulinum toxin treatment. Arch OtolaryngolHead Neck Surg 1994;120:310–316.

12. Jahanshahi M, Marsden CD. Personality in torticollis: a controlledstudy. Psychol Med 1988;18:375–387.

13. Gundel H, Wolf A, Xidara V, et al. High psychiatric comorbidityin spasmodic torticollis: a controlled study. J Nerv Ment Dis 2003;191:465–473.

14. Jahanshahi M, Marsden CD. A longitudinal follow-up study ofdepression, disability, and body concept in torticollis. Behav Neu-rol 1990;3:233–246.

15. Moraru E, Schnider P, Wimmer A, et al. Relation between depres-sion and anxiety in dystonic patients: implications for clinical man-agement. Depress Anxiety 2002;16:100–103.

16. Carbon M, Ghilardi MF, Argyelan M, et al. Increased cerebellaractivation during sequence learning in DYT1 carriers: an equiper-formance study. Brain 2008;131:146–154.

17. Ceballos-Baumann AO, Passingham RE, Warner T, et al. Overac-tive prefrontal and underactive motor cortical areas in idiopathicdystonia. Ann Neurol 1995;37:363–372.

18. Ghilardi MF, Carbon M, Silvestri G, et al. Impaired sequencelearning in carriers of the DYT1 dystonia mutation. Ann Neurol2003;54:102–109.

19. Asanuma K, Ma Y, Okulski J, et al. Decreased striatal D2 receptorbinding in non-manifesting carriers of the DYT1 dystonia muta-tion. Neurology 2005;64:347–349.

20. Carbon M, Su S, Dhawan V, et al. Regional metabolism in pri-mary torsion dystonia. Neurology 2004;62:384–1390.



21. Van Hove JLK, Steyaert J, Matthijs G, et al. Expanded motor andpsychiatric phenotype in autosomal dominant Segawa syndromedue to GTP cyclohydrolase deficiency. J Neurol Neurosurg Psychi-atry 2006;77:18–23.

22. Lewis L, Butler A, Jahanshahi M. Depression in focal, segmentaland generalized dystonia. J Neurol 2008;255:1750–1755.

23. Scheidt CE, Heinen F, Nickel T, et al. Spasmodic torticollis—amulticentre study on behavioural aspects IV: psychopathology.Behav Neurol 1996;9:97.

24. Grafman J, Cohen LG, Hallett M. Is focal hand dystonia associ-ated with psychopathology? Mov Disord 1991;6:29–35.

25. Jahanshahi M. Behavioural and psychiatric manifestations indystonia. In: Anderson K,Weiner W, Lang A, eds. BehaviouralNeurology of Movement Disorders. 2nd ed. Philadelphia, PA: Lip-pincott, Williams & Wilkins; 2005:291–319.

26. Halbig TD, Gruber D, Kopp UA, et al. Pallidal stimulation in dys-tonia: effects on cognition, mood, and quality of life. J NeurolNeurosurg Psychiatry 2005;76:1713–1716.

27. Kupsch A, Benecke R, Muller J, et al. Pallidal deep-brain stimula-tion in primary generalized or segmental dystonia. N Engl J Med2006;355:1978–1990.

28. Valldeoriola F, Regidor I, Minguez-Castellanos A, et al. Efficacyand safety of pallidal stimulation in primary dystonia: results ofthe Spanish multicentric study. J Neurol Neurosurg Psychiatry2010;81:65–69.

29. Vidailhet M, Vercueil L, Houeto JL, et al. Bilateral, pallidal, deep-brain stimulation in primary generalized dystonia: a prospective 3year follow-up study. Lancet Neurol 2007;6:223–29.

30. Burkhard PR, Vingerhoets FJG, Berney A, et al. Suicide after suc-cessful deep brain stimulation for movement disorders. Neurology2004;63:2170–2172.

31. Foncke EMJ, Schuurman PR, Speelman JD. Suicide after deepbrain stimulation of the internal globus pallidus for dystonia. Neu-rology 2006;66:142–143.

32. Jahanshahi M, Marsden CD. Body concept, disability and depres-sion in torticollis. Behav Neurol 1990;3:117–131.

33. Muller J, Kemmler G, Wissel J, et al. The impact of blepharospasmand cervical dystonia on health-related quality of life and depres-sion. J Neurol 2002;249:842–846.

34. Whurr R, Nye C, Lorch M. Meta-analysis of botulinum toxintreatment of spasmodic dysphonia: a review of 22 studies. Int JLang Commun Disord 1998;33(Suppl):327–329.

35. Heller W, Koven NS, Miller GA. Regional brain activity in anxietyand depression, cognition/emotion interaction, and emotion regula-tion. In:Hugdahl K,Davidson RJ, eds. The Asymmetrical Brain.Cambridge, MA: The MIT Press;2003:533–564.

36. McNamara P, Stavitsky K, Harris E, et al. Mood, side of motorsymptom onset and pain complaints in Parkinson’s disease. Int JGeriatr Psychiatry 2010;25:519–524.

37. Cavallaro R, Galardi G, Cavallini MC, et al. Obsessive compulsivedisorder among idiopathic focal dystonia patients: an epidemiologi-cal and family study. Biol Psychiatry 2002;52:356–361.

38. Saunders-Pullman R, Shriberg J, Heiman G, et al. Myoclonus dys-tonia: possible association with obsessive-compulsive disorder andalcohol dependence. Neurology 2002;58:242–245.

39. Wenzel T, Schnider P, Wimmer A, et al. Psychiatric comorbidity inpatients with spasmodic torticollis. J Psychosom Res 1998;44:687–690.

40. Heiman GA, Ottman R, Saunders-Pullman RJ, et al. Obsessive-compulsive disorder is not a clinical manifestation of the DYT1dystonia gene. Am J Med Genet B Neuropsychiatr Genet 2007;144B:361–364.

41. Hess CW, Raymond D, Aguiar Pde C, et al. Myoclonus-dystonia,obsessive-compulsive disorder, and alcohol dependence in SGCEmutation carriers. Neurology 2007;68:522–524.

42. Doheny DO, Brin MF, Morrison CE, et al. Phenotypic features of myo-clonus-dystonia in three kindreds. Neurology 2002;59:1187–1196.

43. Aleman GG, de Erausquin GA, Micheli F. Cognitive disturbancesin primary blepharospasm. Mov Disord 2009;24:2112–2120.

44. Balas M, Peretz C, Badarny S, et al. Neuropsychological profile ofDYT1 dystonia. Mov Disord 2006;21:2073–2077.

45. Bugalho P, Correa B, Guimaraes J, et al. Set-shifting and behav-ioral dysfunction in primary focal dystonia. Mov Disord 2008;23:200–206.

46. Jahanshahi M, Rowe J, Fuller R. Cognitive executive function indystonia. Mov Disord 2003;18:1470–1481.

47. Fahn S, Burke R, Stern Y. Antimuscarinic drugs in the treatmentof movement disorders. Prog Brain Res 1990;84:389–397.

48. Taylor AE, Lang AE, Saint-Cyr JA, et al. Cognitive processes inidiopathic dystonia treated with high-dose anticholinergic therapy:implications for treatment strategies. Clin Neuropharmacol 1991;14:62–77.

49. Marsden CD, Marion MH, Quinn N. The treatment of severe dys-tonia in children and adults. J Neurol Neurosurg Psychiatry 1984;47:1166–1173.

50. Greisberg S, McKay D. Neuropsychology of obsessive-compulsivedisorder: a review and treatment implications. Clin Psychol Rev2003;23:95–117.

51. Allam N, Frank JE, Pereira C, Tomaz C. Sustained attention incranial dystonia patients treated with botulinum toxin. Acta Neu-rol Scand 2007;116:196–200.

52. Pillon B, Ardouin C, Dujardin K, et al. Preservation of cognitivefunction in dystonia treated by pallidal stimulation. Neurology2006;66(10):1556–1558.

53. Ghilardi MF, Ghez C, Eidelberg D. Visuo-spatial learning may beimpaired in non-manifesting carriers of the DYT1 dystonia muta-tion. Neurology 1999;52(Supp l2):A516.

54. Lou JS, Kearns G, Benice T, et al. Levodopa improves physicalfatigue in Parkinson’s disease: a doubleblind, placebo-controlled,crossover study. Mov Disord 2003;18:1108–1114.

55. Ancelin ML, Artero S, Portet F, et al. Non-degenerative mild cog-nitive impairment in elderly people and use of anticholinergicdrugs: longitudinal cohort study. BMJ 2006;332:455–459.

56. Buysse DJ, Reynolds CF, Monk TH, et al. The Pittsburgh SleepQuality Index: a new instrument for psychiatric practice andresearch. Psychiatry Res 1989;28:193–213.

57. Trotti LM, Esper CD, Feustel PJ, Bliwise DL, Factor SA. Excessivedaytime sleepiness in cervical dystonia. Parkinsonism Relat Disord2009;15:784–786.

58. Jankel WR, Allen RP, Niedermeyer E, Kalsher MJ. Polysomno-graphic findings in dystonia musculorum deformans. Sleep 1983;6:281–285.

59. Sforza E, Montagna P, Defazio G, Lugaresi E. Sleep and cranialdystonia. Electroencephalogr Clin Neurophysiol 1991;79:166–169.

60. Wein A, Golubev V. Polygraphic analysis of sleep in dystonia mus-culorum deformans. Waking Sleeping 1979;3:41–50.

61. Jankel WR, Niedermeyer E, Graf M, Kalsher M. Polysomnographyof torsion dystonia. Arch Neurol 1984;41:1081–1083.

62. Fish DR, Allen PJ, Sawyers D, Marsden CD. Sleep spindles in tor-sion dystonia. Arch Neurol 1990;47:216–218.

63. Avanzino L, Martino D, Marchese R, et al. Quality of sleep in primaryfocal dystonia: a case-control study. Eur J Neurol 2010;17:576–581.

64. Silvestri R, De Domenico P, Di Rosa AE, Bramanti P, Serra S, DiPerri R. The effect of nocturnal physiological sleep on variousmovement disorders. Mov Disord 1990;5:8–14.

65. Trender-Gerhard I, Sweeney MG, Schwingenschuh P, et al. Auto-somal-dominant GTPCH1-deficient DRD: clinical characteristicsand long-term outcome of 34 patients. J Neurol Neurosurg Psychi-atry 2009;80:839–845.

66. Menkes JH, Wetterberg L, Ross SB, Yuwiler A. Catecholaminergicactivity in idiopathic torsion dystonia. Neurology 1987;37:779–783.

67. Cano SJ, Warner TT, Linacre JM, et al. Capturing the true burdenof dystonia on patients: the Cervical Dystonia Impact Profile(CDIP-58). Neurology 2004;63:1629–1633.

68. Jankovic J, Leder S, Warner D, Schwartz K. Cervical dystonia:clinical findings and associated movement disorders. Neurology1991;41:1088–1091.

69. Kutvonen O, Dastidar P, Nurmikko T. Pain in spasmodic torticol-lis. Pain 1997;69:279–286.

70. Lowenstein DH, Aminoff MJ. The clinical course of spasmodictorticollis. Neurology 1988;38:530–532.

71. Duane DD.Spasmodic torticollis. In:Jankovic J,Tolosa E, eds.Advances in Neurology. New York:Raven Press; 1988:135–150.

72. Lobbezoo F, Tanguay R, Thon MT, Lavigne GJ. Pain. perceptionin idiopathic cervical dystonia (spasmodic torticollis). Pain 1996;67:483–491.



73. Tinazzi M, Rosso T, Fiaschi A. Role of the somatosensory systemin primary dystonia. Mov Disord 2003;18:605–622.

74. Lobbezoo F, Thu Thon M, Remillard G, et al. Relationshipbetween sleep, neck muscle activity, and pain in cervical dystonia.Can J Neurol Sci 1996;23:285–290.

75. Dressler D, Benecke R. Autonomic side effects of botulinum toxintype B treatment of cervical dystonia and hyperhidrosis. Eur Neu-rol 2003;49:34–38.

76. Tiple D, Strano S, Colosimo C, et al. Autonomic cardiovascularfunction and baroreflex sensitivity in patients with cervical dysto-nia receiving treatment with botulinum toxin type A. J Neurol2008;255:843–847.

77. Aronson AE, Brown JR, Litin EM, et al. Spastic dysphonia. I.Voice, neurologic, and psychiatric aspects. J Speech Hear Disord1968;33:203–218.

78. Van Hoof JJ, Horstink MW, Berger HJ, et al. Spasmodic torticol-lis: the problem of pathophysiology and assessment. J Neurol1987;234:322–327.

79. Harrington RC, Wieck A, Marks IM, et al. Writer’s cramp: notassociated with anxiety. Mov Disord 1988;3:195–200.

80. Jahanshahi M, Marsden CD. Depression in torticollis: a controlledstudy. Psychol Med 1988;18:925–933.

81. Jahanshahi M, Marsden CD. Conversion ‘‘V’’ profiles in torticollis.Behav Neurol 1989;2:219–225.

82. Meares R. Obsessionality, the Sandler-Hazari scale and spasmodictorticollis. Br J Med Psychol 1971;44:181–182.

83. Bindman E, Tibbetts RW. Writer’s cramp—a rational approach totreatment?Br J Psychiatry 1977;131:143–148.

84. Bihari K, Hill JL, Murphy DL. Obsessive-compulsive characteris-tics in patients with idiopathic spasmodic torticollis. Psychiatry Res1992;42:267–272.

85. Broocks A, Thiel A, Angerstein D, et al. Higher prevalence ofobsessive-compulsive symptoms in patients with blepharospasmthan in patients with hemifacial spasm. Am J Psychiatry 1998;155:555–557.

86. Kubota Y, Murai T, Okada T, et al. Obsessive-compulsive charac-teristics in patients with writer’s cramp. J Neurol Neurosurg Psy-chiatry 2001;71:413–414.

87. Eldridge R, Harlan A, Cooper IS, et al. Superior intelligence inrecessively inherited torsion dystonia. Lancet 1970;1:65–67.

88. Hinse P, Leplow B, Humbert T, et al. Impairment of visuospatial func-tion in idiopathic spasmodic torticollis. J Neurol 1996;243:29–33.

89. Scott R, Gregory R, Wilson J, et al. Executive cognitive deficits inprimary dystonia. Mov Disord 2003;18:539–550.



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Nonmotor manifestations of dystonia: A systematic review