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Brief Reports

Trihexyphenidyl for AcuteLife-Threatening Episodes Due toa Dystonic Movement Disorder in

Rett Syndrome

Artemis D. Gika, MD, MRCPCH, PhD,1*Elaine Hughes, BSc, MBBS, MRCP (UK), FRCPCH,1,2

Sushma Goyal, MBBS, MD, MRCPCH,3,4

Matthew Sparkes,4

and Jean-Pierre Lin, MB, ChB, MRCP (UK), PhD1,5

1Department of Paediatric Neurology, Evelina Children’sHospital, Guy’s and St Thomas’ NHS Foundation Trust,London, UK; 2Paediatric Epilepsy Service, EvelinaChildren’s Hospital and King’s College Hospital NHS

Foundation Trust, London, UK; 3Department ofNeurophysiology, Evelina Children’s Hospital, Guy’s and

St Thomas’ NHS Foundation Trust, London, UK;4Department of Neurophysiology, King’s College HospitalNHS Foundation Trust, London, UK; 5Complex Motor

Disorders Service, Evelina Children’s Hospital, Guy’s andSt Thomas’ NHS Foundation Trust, London, UK

Video

Abstract: In Rett syndrome (RS), acute life-threateningepisodes (ALTEs) are usually attributed to epilepsy or au-tonomic dysfunction but they can represent a movementdisorder (MD). We describe three girls with RS whoexperienced ALTEs from an early age. These were longconsidered epileptic until video-EEG in Patients 1 and 3revealed their non-epileptic nature. A primary dystonicmechanism was suspected and Patients 1 and 2 weretreated with Trihexyphenidyl with significantly reducedfrequency of the ALTEs. Patient 3 died before Trihexy-phenidyl was tried. Trihexyphenidyl in RS patients withsimilar presentations can modify the dystonia and preventALTEs. � 2010 Movement Disorder Society

Key words: Rett syndrome; dystonia; epilepsy; acute lifethreatening episodes; trihexyphenidyl

INTRODUCTION

Rett syndrome (RS) is a neurodevelopmental disor-

der which, in the majority of cases, is caused by muta-

tions in the MECP2 gene and mainly affects females.

The hallmark of the disease is the intense stereotypic

hand movements,1 which coincide with or even pre-

cede the loss of purposeful hand movements.2 Other

abnormal movements, including dystonia, are also

described but the whole spectrum of movement disor-

ders in RS is less well documented.3 Epilepsy, on the

other hand, is recognized as an important problem in

patients with RS, however, many events classified as

seizures in RS may be nonepileptic in origin. As auto-

nomic dysfunction along with patterns of abnormal

breathing in the awake state are also observed in RS,

many of the clinical ‘‘seizures’’ are considered to be a

manifestation of this dysfunction.4 However, episodes

accompanied by respiratory compromise or acute life-

threatening episodes (ALTEs) can also represent a dys-

tonic movement disorder.

We report three girls with RS and confirmed

MECP2 mutations who presented with longstanding

histories of ‘‘seizures’’ and ALTEs. We focus on the

description of their episodes and their treatment with

the aim to differentiate between the movement disorder

and other processes in patients with RS.

Case Histories

Patient 1, aged 13 years, started experiencing parox-

ysmal ALTEs, which were thought to be epileptic seiz-

ures at age 4 years. These were initially well controlled

on two antiepileptic drugs (AEDs) but recurred at age

7 years with increased severity despite addition of a

third AED. The episodes were characterized by gri-

macing, staring, tonic stiffening of arms, facial redness,

and jaw stiffening. As the episode progressed, cyanosis

occurred, but if posturing was recognized early, sooth-

ing with voice and touch could prevent progression. A

typical episode was captured during video-EEG telem-

etry (Video and Fig. 1) at 12 years. The episode was

not associated with any epileptiform activity on EEG

Additional supporting information may be found in the online ver-

sion of this article*Correspondence to: Artemis D Gika, Department of Paediatric

Neurology, Evelina Children’s Hospital, Westminster Bridge Road,London SE1 7EH, United Kingdom. E-mail: [email protected]

Potential conflict of interest: None to report.Received 24 August 2009; Accepted 2 November 2009Published online 8 January 2010 in Wiley InterScience (www.

interscience.wiley.com). DOI: 10.1002/mds.22926

385

Movement DisordersVol. 25, No. 3, 2010, pp. 385–404� 2010 Movement Disorder Society

thus demonstrating its nonepileptic nature. EEG attenu-

ation was noted during the event secondary to hypoxia

(Fig. 1) while the interictal EEG was abnormal

(Fig. 2). Further assessment of the patient revealed a

background dystonic movement disorder with bilat-

eral spontaneous extensor plantars (striatal toe),

which flexed on eliciting the Babinski manoeuvre.

Trihexyphenidyl (THP) was commenced, which led

to improvement of the movement disorder and

increased alertness while the patient stopped experi-

encing ALTEs.

Patient 2, aged 9 years, started having generalized

tonic-clonic seizures at age 2 years. At age 3 years,

different episodes were noted, described as staring,

tonic extension of arms followed by apnoea and cyano-

sis. Routine EEG at the time showed some interictal

parietal spikes but no episodes were captured. Over the

course of the next few years she received three AEDs

without effect. Her ALTEs were suspected to be dys-

tonic in nature and she was thus given THP which

resulted in cessation of the dystonic episodes and

increased alertness.

Patient 3, who died at the age of 20, started having

ALTEs at age 4 years. These were characterized by

staring associated with tonic extension and shaking of

head and limbs and were followed by apnoea and cya-

nosis. The episodes could be occasionally modified by

head positioning. Interictal EEG was abnormal and she

was treated with three different AEDs over the next

years without any effect. Although after some time,

her ALTEs were thought to be nonepileptic, they con-

tinued being managed with AEDs especially in emer-

FIG. 1. EEG/ECG/EMG recording on Patient 1 corresponding to Video. A: Arrow, onset of muscle artefact corresponding with onset of ALTE;double arrow, onset of secondary ECG changes (QRS amplitude reduction, relative bradycardia); (a) grimaces, tongue out; (b) leans forward,gasping noise; (c) head shaking, still gasping. B: arrow, onset of EEG attenuation secondary to hypoxia; (d) falls back onto bed; (e) arms raised;(f) still gasping. C: (g) doctor points to colour change (cyanosis).

386 A.D. GIKA ET AL.

Movement Disorders, Vol. 25, No. 3, 2010

gency situations. Video-EEG telemetry at the age of

16 years confirmed the nonepileptic nature of these

events. Additionally, she was noted to have a back-

ground dystonic movement disorder with scoliosis.

Different antidystonic drugs were used including baclo-

fen, tizanidine, gabapentin, and benzodiazepines with

only partial response of her dystonia but she unfortu-

nately died of respiratory complications before THP

was tried.

DISCUSSION

We have described three girls with RS who all had

ALTEs from an early age. The episodes were very

similar in all girls, consisting of dystonic posturing

with subsequent respiratory compromise. These had

been thought to represent epileptic seizures until pro-

longed Video-EEG confirmed their nonepileptic nature

in two of the three patients (Patients 1 and 3). Two of

the girls (Patients 1 and 2) responded well to treatment

with THP while Patient 3 unfortunately died before

treatment could be commenced.

Dystonia, although a common feature, is not always

well recognized in girls with RS. In the first analysis

of movement disorders in patients with RS, approxi-

mately 60% manifested some sort of dystonic move-

ments.3 Similar results were recently reported among

MECP2 positive patients and genotype–phenotype

correlation was attempted with dystonia being more

frequent in patients with truncating mutations.5 Fur-

thermore, other movement disorders, like bruxism and

oculogyric crises and importantly scoliosis, a common

feature of RS, are thought to represent forms of focal

dystonia. All our patients presented with episodes of

dystonic posturing from an early age. Their episodes

consisted of grimacing, tongue protrusion, staring, and

tonic stiffening of both arms followed by jaw stiffen-

ing, apnoea and cyanosis, most likely as a result of la-

ryngeal dystonia. Patients 1 and 3 also demonstrated a

background dystonic movement disorder. Although

dystonia in RS is believed to become more common

with age,3,6 dystonic movements have been reported

early in the course of the disease and even before

developmental regression occurs.2 A role for neuro-

transmitter disturbances in the pathogenesis of neuro-

logical symptoms such as the movement and sleep

disorders in RS has been postulated but results from CSF

studies have been contradictory.7 A reduction of dopa-

mine and norepinephrine metabolites in the substantia

nigra has, however, been shown in neuropathological

FIG. 2. Interictal EEG recording on Patient 1 demonstrating frontal spikes.

387DYSTONIC MOVEMENT DISORDER IN RETT SYNDROME


studies8 and is thought to possibly account for the appear-

ance of dystonia especially in older RS patients.

Involvement of the autonomic nervous system in RS

is suggested by clinical observations including the

frequent occurrence of cold and blue lower extremities,

chronic constipation, and dilated pupils and supported

by autonomic monitoring studies describing low cardi-

ovascular parasympathetic tone in patients with RS.9

Breathing dysrhythmia is indeed considered by most

authors as a sign of brainstem dysfunction and neuro-

transmitter dysregulation10; however, patients only

exhibit these breathing disorders when awake suggest-

ing involvement of higher centres4 and favoring the al-

ternative concept that they may be a type of stereo-

typy5 or a dystonia. Furthermore, it is well known that

all dystonias, tics and choreas are abolished by sleep.11

Our Video and simultaneous EEG/ECG/EMG monitor-

ing (Figure 1) on Patient 1 suggests that chronologi-

cally the episode begins with the occurrence of muscle

artefact on the EEG and with EMG changes, which

correspond with the onset of the ALTE on the Video

(grimace, tongue protrusion); secondary ECG changes

including reduction in QRS amplitude and relative

bradycardia follow thus pointing toward a primary dys-

tonic rather than autonomic onset. This is further sup-

ported by an excellent response of the ALTEs to treat-

ment with THP in Patients 1 and 2 as well as the back-

ground dystonic movement disorder observed in

Patients 1 and 3.

The events experienced by our patients were long

thought to be epileptic seizures. This was supported by

certain clinical characteristics of the events, including

the staring and stiffening with associated respiratory

compromise; it was also apparently supported by the

fact that they all had abnormal interictal EEGs.

Patients 1 (Video) and 3 eventually had video-EEG te-

lemetry which clearly demonstrated the nonepileptic

nature of their events; hypoxia-induced EEG attenua-

tion was noted during the event in Patient 1. Epileptic

seizures occur in RS patients and AEDs are often pre-

scribed.1 Additionally, interictal EEG is almost invaria-

bly abnormal in patients with RS after 2 years of age

although there is no electroencephalographic pattern

considered pathognomonic for RS.4 Many events clas-

sified as seizures in patients with RS are nonepileptic

in origin and this has been confirmed by studies using

video-EEG monitoring.12 Moreover, a number of RS

patients are considered to have intractable seizures de-

spite AED polytherapy13 and this was indeed the case

with our patients for many years before the nonepilep-

tic nature of their events was confirmed. Video-EEG

recording for characterisation of clinical events in RS

is essential for accurate diagnosis of ALTEs and in

order to avoid unnecessary polytherapy.

THP is one of the few validated treatments and per-

haps the most commonly used medication for dysto-

nia.14 Children have long been known to respond more

favorably and with fewer adverse effects than adults to

treatment with THP.15 The mechanism of THP action

for treatment of dystonia is not known although it is

presumed to be associated with central anticholinergic

effects. The use of THP for treatment of dystonia and

specifically for ALTEs in patients with RS has not, to

our knowledge, been previously reported. Other drugs,

such as the serotonin agonist buspirone, have been sug-

gested for treatment of ‘‘apneusis’’ in RS but their use

is not widespread.16

In conclusion, episodes of posturing followed by re-

spiratory compromise can be mistaken as seizures or

autonomic dysfunction in RS leading to increased mor-

bidity and mortality if untreated. The clinical presenta-

tion, video-EEG findings and response to THP support

a primary dystonic mechanism. A trial of THP in RS

patients with similar presentations can modify the dys-

tonia leading to reduction in unnecessary use of AEDs,

improve quality of life, and prevent respiratory crises

presenting as ALTEs.

LEGEND TO THE VIDEO

The video demonstrates Patient 1 having an acute

life-threatening episode (ALTE). The recording corre-

sponds with the EEG/ECG/EMG recording on Figure 1

and was taken during video-EEG telemetry.

Author Roles: Artemis D Gika involved in writing

of the first draft, patient assessment, and follow up.

Elaine Hughes involved in review and critique, patient

assessment, and follow up. Sushma Goyal involved in

review and critique, EEG analysis. Matthew Sparkes

involved in review and critique, EEG analysis. Jean-

Pierre Lin involved in review and critique, patient

assessment, and follow up.

Financial Disclosure: None.

REFERENCES

1. Hagberg B, Hanefeld F, Percy A, Skjeldal O. An update on clini-cally applicable diagnostic criteria in Rett syndrome. Comments toRett Syndrome Clinical Criteria Consensus Panel Satellite to Euro-pean Paediatric Neurology Society Meeting Baden Baden, Ger-many, 11 September 2001. Eur J Paediatr Neurol 2002;6:293–297.

2. Temudo T, Maciel P, Sequeiros J. Abnormal movements in Rettsyndrome are present before the regression period: a case study.Mov Dis 2007;22:2285–2287.

388 A.D. GIKA ET AL.


3. FitzGerald PM, Jankovic J, Percy AK. Rett syndrome and associ-ated movement disorders. Mov Dis 1990;5:195–202.

4. Glaze DG. Neurophysiology of Rett syndrome. J Child Neurol2005;20: 740–746.

5. Temudo T, Ramos E, Dias K, et al. Movement disorders in Rettsyndrome: an analysis of 60 patients with detected MECP2mutation and correlation with mutation type. Mov Dis 2008;23:1384–1390.

6. Roze E, Cochen V, Sangla S, et al. Rett syndrome: an over-looked diagnosis in women with stereotypic hand movements,psychomotor retardation, parkinsonism and dystonia? Mov Dis2007;22:387–433.

7. Temudo T, Rios M, Prior C, et al. Evaluation of CSF neurotrans-mitters and folate in 25 patients with Rett disorder and effects oftreatment. Brain Dev 2009;31:46–51.

8. Wenk GL, Naidu S, Moser H. Altered neurochemical markers inRett syndrome. Ann Neurol 1989;26:467.

9. Julu POO, Witt-Engerstrom I. Assessment of the maturity-relatedbrainstem functions reveals the heterogeneous phenotypes andfacilitates clinical management of Rett syndrome. Brain Dev2005;27:S43–S53.

10. Julu POO, Kerr AM, Apartopoulos F, et al. Characterisation ofbreathing and associated central autonomic dysfunction in theRett disorder. Arch Dis Child 2001;85:29–37.

11. Fish DR, Sawyers D, Allen PJ, Blackkie JD, Lees AJ, Mars-den CD. The effect of sleep on the dyskinetic movements ofParkinson’e disease, Gilles de la Tourettes syndrome, Hunting-ton’s disease and torsion dystonia. Arch Neurol 1991;48:210–214.

12. Moser SJ, Weber P, Lutschg J. Rett syndrome: clinical and elec-trophysiological aspects. Pediatr Neurol 2007;36:95–100.

13. Huppke P, Kohler K, Brockmann K, Stettner GM, Gartner J.Treatment of epilepsy in Rett syndrome. Eur J Paediatr Neurol2007;11;10–16.

14. Balash Y, Giladi N. Efficacy of pharmacological treatment of dystonia:evidence-based review including meta-analysis of the effect of botuli-num toxin and other cure options. Eur J Neurol 2004;11:361–370.

15. Fahn S. High dosage anticholinergic therapy in dystonia. Neurol-ogy 1983;33:1255–1261.

16. Julu POO, Witt-Engerstrom I, Hansen S, et al. Cardiorespiratorychallenges in Rett’s syndrome. Lancet 2008;371;1–2.

Failure of Cathodal Direct CurrentStimulation to Improve FineMotor Control in Musician’s

Dystonia

Franziska Buttkus, MSc,1 Matthias Weidenmuller, MD,2

Sabine Schneider, PhD,1 Hans-Christian Jabusch, MD,3

Michael A. Nitsche, MD,2 Walter Paulus, MD,2

and Eckart Altenmuller, MD1*

1Institute of Music Physiology and Musicians’ Medicine,University of Music and Drama, Hanover, Germany;

2Department of Clinical Neurophysiology, Georg-AugustUniversity, Goettingen, Germany; 3Institute of Musicians’Medicine, University of Music Carl Maria von Weber,

Dresden, Germany

Abstract: Musician’s dystonia (MD) is a task-specificmovement disorder with a loss of voluntary motor controlin highly trained movements. Defective inhibition on dif-ferent levels of the central nervous system is involved inits pathophysiology. Cathodal transcranial direct currentstimulation (ctDCS) diminishes excitability of the motorcortex and improves performance in overlearned tasks inhealthy subjects. The aim of this study was to investigatewhether ctDCS improves fine motor control in MD. Pro-fessional guitarists (n 5 10) with MD played exercisesbefore, directly after ctDCS, and 60 min after ctDCS.ctDCS (2 mA, 20 min) was applied on the primary motorcortex contralateral to the affected hand. Guitar exerciseswere video-documented and symptoms were evaluated bythree independent experts. No beneficial effect of ctDCSon fine motor control was found for the entire group.However, motor control of one guitarist improved afterstimulation. This patient suffered from arm dystonia,whereas the other guitarists suffered from hand dys-tonia. � 2010 Movement Disorder Society

Key words: focal dystonia; musician’s cramp; transcranialdirect current stimulation; neuroplasticity

Focal dystonia in musicians (MD) is a task-specific

movement disorder, which presents itself as a loss of

voluntary motor control of extensively trained move-

ments while playing a musical instrument.1 Deficient

inhibition at different levels of the CNS is involved in

its pathophysiology.2 Transcranial direct current stimu-

*Correspondence to: Dr. Eckart Altenmuller, Institute of MusicPhysiology and Musicians’ Medicine, University of Music andDrama Hohenzollernstrasse 47, 30161 Hannover, Germany.E-mail: [email protected]

Potential conflict of interest: Nothing to report.Received 2 September 2009; Accepted 9 November 2009Published online 8 January 2010 in Wiley InterScience (www.


389CATHODAL tDCS AS A TREATMENT FOR FOCAL DYSTONIA?


lation (tDCS) modulates cortical excitability of the

motor cortex.3 Cathodal (c)tDCS decreases cortical

excitability and hereby may facilitate fine motor con-

trol considering the specific pathophysiology of

reduced cortical inhibition in MD. Moreover, ctDCS

applied over V5 was reported to improve performance

in overlearned visuomotor tracking tasks in healthy

subjects, probably due to an enhanced signal-to-noise

ratio.4

The aim of this placebo-controlled and double-

blinded study was to investigate whether single-session

ctDCS of the primary motor cortex facilitates fine

motor control in a group of professional guitarists with

MD via reducing motor cortex excitability.

METHODS

Participants

A group of 10 professional guitarists (all men) suf-

fering from MD participated in the study (mean age:

48.8 6 6.4 years). Task-related dystonia was diagnosed

in our out-patient clinic and presented itself in the typi-

cal manner as painless cramping of one or more fingers

of the right hand while playing the guitar. One guitarist

suffered also from cramping of the right forearm with

stiffening of the wrist. Mean duration of MD was 8.7

years (range: 6 months–26 years), severity varied

between patients. Patients were not pharmacologically

treated for MD during the time of the study. Six guita-

rists had received botulinum toxin in their past history

of MD. One patient received a botulinum toxin injec-

tion 5 weeks before participating; however, the effect

concerning weakness and motor improvement had

completely worn off at the time of the experiments. In

all other cases, there was at least a time interval of 8

weeks between injection and experiments of the study.

Patients were informed about all aspects of the experi-

ment and signed an informed consent form. The study

was approved by local ethics committee, and we con-

form to the Declaration of Helsinki.

Stimulation

Cathodal direct current stimulation was induced

through water-soaked sponge electrodes (surface 35

cm2) and delivered by a battery-driven, constant cur-

rent stimulator (eldith GmbH, Ilmenau, Germany). The

stimulating electrode was placed over the left primary

motor cortex (C3 according to the international 10–20

system), and the reference electrode was placed over

the right supraorbital area. As the study was placebo-

controlled and double-blinded, tDCS was operated

by an independent assistant. Current strength was 2

mA (20 min) for the active condition and 0.2 mA

for the placebo condition (20 seconds). Both sessions

were separated by at least 1 week. Active condition

and placebo condition were conducted in balanced

order.

Assessment of Fine Motor Control

Patients played 14 guitar-specific exercises before,

directly after ctDCS, and 60 min after tDCS. The exer-

cises contained scales, arpeggios, and chords. Move-

ments of the affected hand were recorded with a video

camera. Video segments were arranged randomly with

respect to condition and time. Three independent

experts evaluated symptoms of MD in a standardized

video rating procedure. One of the experts was neurol-

ogist and expert in musician’s movement disorders,

and the others were guitar teachers.

Evaluation of symptoms was based on the following

criteria: Overall impression, temporal evenness, con-

stancy in loudness, sound quality, abnormal gross

movements, and one scale of the Arm Dystonia Dis-

TABLE 1. Intraclass correlations (ICC) for each evaluation criterion, time, and condition

Evaluation criterion

ICC

Before tDCS 1 min after tDCS 60 min after tDCS

ctDCS Placebo ctDCS Placebo ctDCS Placebo

Overall impression 0.97 0.76 0.76 0.90 0.90 0.81Temporal evenness 0.94 0.94 0.74 0.89 0.92 0.96Constancy in loudness 0.86 0.79 0.56 0.92 0.88 0.79Quality of sound 0.86 0.93 0.74 0.78 0.87 0.85ADDS 0.91 0.87 0.85 0.86 0.91 0.92Abnormal gross motor movements 0.96 0.96 0.93 0.96 0.97 0.97FAM: dystonic flexions 0.90 0.88 0.95 0.71 0.94 0.93FAM: compensatory extensions 0.88 0.88 0.81 0.82 0.67 0.90


390 F. BUTTKUS ET AL.

ability Scale5 (ADDS). The experts also filled in the

Frequency of Abnormal Movements Scale6 (FAM)

counting flexions and compensatory finger movements.

This scale was originally developed for pianists and

was slightly modified. Except for the FAM scale, all

criteria were evaluated with Likert scales (with a range

of 0–3 similar to the ADDS: 0 5 no difficulty, 1 5mild difficulties, 2 5 moderate difficulties, and 3 5marked difficulties). The experts received a careful

coaching of the rating process by the authors. Addi-

tionally, guitarists gave a self-report of their perceived

motor abilities in percent for each exercise before and

after ctDCS.

Statistical Analysis

Mean values of expert ratings were calculated for

the 14 exercises played at each time point for every

guitarist and each criterion. All criteria were assessed

for inter-rater reliability using intraclass correlation

coefficients. As inter-rater reliabilities for all categories

were good (Table 1), mean values of the expert ratings

were used for further analysis of each criterion.7

Two-factor analyses of variance (general linear

model) with repeated measurements for experimental

condition and for time were performed on each evalua-

tion criterion. The experimental condition factor con-

sisted of two levels: ctDCS and placebo-tDCS. The

factor of time consisted of three levels: guitar playing

before, directly after tDCS, and 60 min after tDCS.

The alpha level was set at 0.05. Data analysis was

performed with SPSS 16 (SPSS, Chicago, IL). Addi-

tionally, to group statistics, data were analyzed on a

single-patient level.

RESULTS

Inter-rater reliability of the video rating process was

tested with intraclass correlations for each criterion at

each time point of measurement (Table 1). The highest

inter-rater reliability was calculated for the criterion

‘‘overall impression’’ (ICC 5 0.97), and the lowest

was calculated for ‘‘constancy in loudness’’ (ICC 50.56).

Results of two-factor analyses of variance with

regard to the factors time, condition, and interaction

factors are given in Table 2. Expert rating before

active condition and before placebo condition did not

differ between conditions. There was no statistically

significant main effect of both factors for any criterion.

No statistically significant interaction between condi-

tion and time was found. These results indicate a stable

standard of playing during the experiment for the

group of guitarists. Expert rating of the ‘‘overall

impression’’ is exemplified in Figure 1A. In none of

the seven criteria, expert rating showed a tendency for

improvement or deterioration after ctDCS.

However, on the single-patient level, one guitarist

was evaluated to have lesser symptoms after real stim-

ulation but not after placebo-tDCS (Fig. 1B). No other

guitarist benefited from real stimulation in contrast to

placebo stimulation; on the contrary, in a few patients,

there was deterioration in motor control after real

ctDCS (Fig. 1B, participants 3, 6, and 8).

Analysis of self-reports by the guitarists did not

reveal improved perceived motor control after ctDCS

for the entire group. However, the same guitarist bene-

fiting from ctDCS according to the expert rating also

reported a better perceived motor control after both

ctDCS and placebo-tDCS.

DISCUSSION

No beneficial effect of single-session ctDCS on fine

motor control in guitarists with MD was found in this

study. There was no tendency toward improvement of

symptoms in any of seven criteria evaluated by three

experts or in self-reports of the guitarists, although

TABLE 2. F values (df 5 2,9), P values, and effect size estimates (g2) on each evaluation criterion for factor 1 (condition) andfactor 2 (time) and the interaction of both factors

Evaluation criterion

Factor 1: condition Factor 2: time Interaction: condition*time

P F h2 P F h2 P F h2

Overall impression 0.86 0.03 0.004 0.77 0.26 0.03 0.94 0.06 0.01Temporal evenness 0.43 0.71 0.09 0.50 0.73 0.09 0.62 0.50 0.07Constancy in loudness 0.93 0.009 0.002 0.35 1.16 0.19 0.37 1.1 0.18Quality of sound 0.87 0.03 0.006 0.57 0.58 0.10 0.34 1.2 0.19ADDS 0.42 0.75 0.11 0.33 1.2 0.17 0.55 0.62 0.09Gross motor movements 0.24 1.63 0.19 0.15 2.22 0.24 0.21 1.8 0.20FAM: dystonic flexions 0.96 0.003 0.001 0.47 0.86 0.22 0.46 0.87 0.23FAM: compensatory extensions 0.96 0.003 0.001 0.35 1.26 0.29 0.79 0.23 0.07



we used a high stimulation intensity of 2 mA. This

might be due to several reasons. First, the most plau-

sible conclusion is that neurophysiological improve-

ment of dystonia as it is now established with deep

brain stimulation needs time. As was recently shown,

SICI and LTP like plasticity changes improve only

over months after implantation in patients with dysto-

nia.8 This may eventually lead to the consequence

that also transcranial stimulation methods have to be

applied possibly daily over months to obtain a benefi-

cial effect. The positive aspect of this addresses

safety. If single session of ctDCS would have a dra-

matic beneficial effect, maladaptive plasticity mecha-

nisms might also lead to a dramatic worsening. Sec-

ond, stimulation of M1 only might not be sufficient

to change the neuronal pathways underlying dystonic

symptoms. Guitar playing is a complex motor task,

which requires a high level of movement preparation

and precise movement execution. Thus, additional

stimulation of premotor areas, the supplemental motor

cortex, or even V5 might have beneficial effects on

motor control in guitarists with MD. There is also the

possibility that ctDCS was not capable to decrease

cortical excitability because of the special pathology

of MD. When ctDCS was applied on patients with

another type of focal dystonia, writer’s cramp, the

normal inhibitory effect of ctDCS on corticospinal

excitability was absent.9

FIG. 1. Results of single-session ctDCS on fine motor control in guitarists with musician’s dystonia. A: Bars show expert rating of motor per-formance on a four-point Likert scale. High values indicate poor motor control and vice versa. Active tDCS condition is displayed as gray bars,and placebo tDCS is displayed as open bars. Error bars depict standard deviations of expert ratings. B: Bars show expert rating of motor perform-ance on a single-patient level. High values indicate poor motor control and vice versa.

392 F. BUTTKUS ET AL.


Although group results revealed no beneficial effect

of ctDCS on motor control, voluntary motor control

of one patient was improved by ctDCS. In contrast to

the other patients, he suffered from an atypical arm

dystonia. Typical symptoms of MD are cramping of

one or more fingers while playing the musical instru-

ment but without segmental dystonia-like symptoms,

such as cramping of the arm. This result suggests that

ctDCS of the primary motor cortex should be investi-

gated in musicians with nontypical, less focal types

of MD.

In summary, we can conclude that single-session

ctDCS does not improve fine motor control in MD in

this study. Nevertheless, this result helps to gain new

insight into the pathophysiology of MD. Further

research applying other stimulation parameters, such as

changing electrode positions or using other stimulation

patterns (repetitive stimulation, random noise stimula-

tion), is needed to extend knowledge about effects of

electrical stimulation. Physiological changes during

and after electrical stimulation should be additionally

measured with transcranial magnetic stimulation. It

should also be noted that there is a marked interpatient

phenotypic variability in dystonia, which may lead to

the consequence of heterogenous stimulation techni-

ques as possible treatment approaches. However, the

outcome of this study also suggests that other thera-

peutical strategies for MD should be investigated with

increased effort. Pedagogical retraining, botulinum

toxin, and trihexyphenidyl are reported to show good

results treating MD, but further research is needed to

improve the currently available therapies.10

Financial Disclosures: F. Buttkus, MSc, receives a schol-arship ‘‘Georg-Christoph-Lichtenberg’’ of lower Saxony,Germany, as a PhD student. She won the ‘‘Ernst-August-Schrader-Preis’’ at the University of Music and Drama, Han-over, Germany, in the category ‘‘Science’’. M. Weidenmuller,MD, receives no grants for research. Dr. Schneider hasreceived support from the German Research Foundation(Deutsche Forschungsgemeinschaft, DFG) and the GermanFederal Ministry of Education and Research (Bundesministe-rium fur Bildung und Forschung, BMBF). Dr. Jabusch ischair and full professor paid by the University of Music, CarlMaria von Weber, Dresden, Germany. He is coinvestigator ofa research project funded by the Dystonia Medical ResearchFoundation, USA. He participated in a CME course fundedby Pharm-Allergan GmbH, Germany. Dr. Nitsche hasreceived support from the German Research Foundation(Deutsche Forschungsgemeinschaft, DFG) and the GermanFederal Ministry of Education and Research (Bundesministe-rium fur Bildung und Forschung, BMBF). Dr. Paulus isdirector of the department of Clinical Neurophysiology paidby the University Medicine of Gottingen, Germany. He hasreceived support from the German Research Foundation(Deutsche Forschungsgemeinschaft, DFG), the German Fed-

eral Ministry of Education and Research (Bundesministeriumfur Bildung und Forschung, BMBF), the European Union, theVolkswagen Foundation, the Rose Foundation, and that hehas served as an advisor for several companies working onthe development of stimulating apparatus of tDCS and TMS.Dr. Altenmuller is chair and full professor paid by the Uni-versity of Music and Drama, Hannover, Germany. He servesin the Editorial board of following Journals: Journal of Inter-disciplinary Music Studies, Medical Problems of PerformingArtists, Musicae Scientiae, Music and Medicine. He receivesgrants from the German Research Foundation (Al 269/5-3,Al 269/7-3) and the Dystonia Medical Research Foundation,USA. He receives royalties from the publication in the book‘‘Music, Brain and Motor Control,’’ which appeared atOxford University press, 2006.

Author Roles: F. Buttkus: Organization and Execution ofResearch project; Design, Execution, and Review andCritique of Statistical Analysis; Writing of the first draftand Review and Critique of Manuscript. M. Weidenmuller:Conception, Organization, and Execution of Researchproject; Review and Critique of Manuscript. S. Schneider, E.Altenmuller: Conception and Organization of Researchproject; Review and Critique of Statistical Analysis; Reviewand Critique of Manuscript. H.-C. Jabusch, M.A. Nitsche, W.Paulus: Conception of Research project; Review andCritique of Statistical Analysis; Review and Critique ofManuscript.

REFERENCES

1. Altenmuller E. Focal dystonia: advances in brain imaging andunderstanding of fine motor control in musicians. Hand Clin2003;19:523–538.

2. Hallett M. Pathophysiology of dystonia. J Neural Transm Suppl2006;70:485–488.

3. Nitsche MA, Paulus W. Excitability changes induced in thehuman motor cortex by weak transcranial direct current stimula-tion. J Physiol 2000;527:633–639.

4. Antal A, Nitsche MA, Kruse W, et al. Direct current stimulationover V5 enhances visuomotor coordination by improving motionperception in humans. J Cogn Neurosci 2004;16:521–527.

5. Fahn S. Assessment of primary dystonias. In: Munsat TL, editor.Quantification of neurologic deficit. Boston: Butterworths; 1989.p 241–270.

6. Spector JT, Brandfonbrener AG. A new method for quantificationof musician’s dystonia: the frequency of abnormal movementscale. Med Probl Perform Art 2005;20:157–162.

7. Bortz J, Doring N. Forschungsmethoden und Evaluation. Berlin:Springer-Verlag; 2002. p 184.

8. Ruge D, Tisch S, Limousin P, et al. Longitudinal effects of deepbrain stimulation in the globus pallidus on intracortical GABAer-gic inhibition and LTP-like plasticity in dystonia. Mov Disord2009;24 (Suppl 1):105–106.

9. Quartarone A, Rizzo V, Bagnato S, et al. Homeostatic-like plas-ticity of the primary motor hand area is impaired in focal handdystonia. Brain 2005;128:1943–1950.

10. Jabusch HC, Altenmuller E. Focal dystonia in musicians:from phenomenology to therapy. Adv Cogn Psychol 2006;2:207–220.



Table Tennis Dystonia

Anne Le Floch, MD,1 Marie Vidailhet, MD,2,3,4

Constance Flamand-Rouviere, ST,5

David Grabli, MD, PhD,2,3,4 Jean-Michel Mayer, MD,2

Michel Gonce, MD,6

Emmanuel Broussolle, MD, PhD,7,8

and Emmanuel Roze, MD, PhD2,3,9*

1Service de Neurologie, Hopital Nımes, Nımes, France; ;2Federation des Maladies du Syteme Nerveux, Hopital Pitie-Salpetriere, Paris, France; 3Universite Pierre et Marie

Curie-Paris6, INSERM, UMRS 975, CNRS UMR 7225, Paris,France; 4INSERM, UMR_S679, Neurology and ExperimentalTherapeutics, Paris, France; 5Service de Neurologie, Hopital

de Bicetre, Le Kremlin Bicetre, France; 6ServiceUniversitaire de Neurologie, CHR de la Citadelle et Servicede Neurologie Reparatrice, Clinique Le Peri, Liege, Belgique;

7Universite Lyon I; Hospices Civils de Lyon, HopitalNeurologique Pierre Wertheimer, Service de Neurologie C,Lyon, France; 8CNRS, UMR 5229, Centre de NeurosciencesCognitives, Lyon, France; 9Centre d’Investigation Clinique

9503, INSERM, AP-HP, Paris, France

Video ;;

Abstract: Focal task-specific dystonia (FTSD) occurs exclu-sively during a specific activity that usually involves a highlyskilled movement. Classical FTSD dystonias include writer’scramp and musician’s dystonia. Few cases of sport-relateddystonia have been reported. We describe the first four casesof FTSD related to table tennis (TT), two involving professio-nal international competitors. We also systematically analyzedthe literature for reports of sport-related dystonia includingdetailed clinical descriptions. We collected a total of 13 casesof sport-related dystonia, including our four TT players.Before onset, all the patients had trained for many years, fora large number of hours per week. Practice time had fre-quently increased significantly in the year preceding onset. AsTT is characterized by highly skilled hand/forearm move-ments acquired through repetitive exercises, it may carry ahigher risk of FTSD than other sports. Intensive training mayresult in maladaptive responses and overwhelm homeostaticmechanisms that regulate cortical plasticity in vulnerableindividuals. Our findings support the importance of environ-mental risk factors in sport-related FTSD, as also suggested inclassical FTSD, and have important implications for clinicalpractice. � 2010 Movement Disorder Society

Key words: task-specific dystonia; risk factor; plasticity;pathophysiology; sport

INTRODUCTION

Focal task-specific dystonia (FTSD) occurs exclu-

sively during a specific activity that usually requires

highly skilled movements. Classical forms of FTSD

include writer’s cramp, typist’s dystonia, and musi-

cian’s dystonia. Sport-related dystonia has occasionally

been reported among persons engaging in golf,1,2 trap

shooting,3 pistol shooting,4 tennis,5 running,6,7 petan-

que,8 billiards, darts, snooker, and cricket.4

Intensive motor training in highly skilled movements

may be crucial in FTSD onset.9 Table tennis (TT) is a

sport that requires time-constrained goal-directed move-

ments with high-level hand-eye coordination and per-

ception-action coupling. At a competitive level, TT

training is partly based on high-frequency repetition of

stereotyped upper-limb movements, including robot

training. Surprisingly, FTSD has never been reported in

TT players. We report four cases of FTSD in TT players

and analyze previous reports of sport-related dystonia.

PATIENTS AND METHODS

Four patients with TT-related dystonia were referred

to our movement disorders clinics for clinical evalua-

tion and management. In addition to a comprehensive

neurological examination, the patients had a detailed

history-taking and were questioned on their TT prac-

tice. The dystonia was analyzed after video recording

of a normal TT training session. All the patients gave

their written informed consent to participate in the

study and to be filmed.

We also analyzed the literature on sport-related dys-

tonia. The NIH Pubmed, SUDOC, and PASCAL

BIOMED (Paris V University) databases were scanned

up to 2009 for reports including the key words ‘‘sport’’

and ‘‘dystonia.’’ The reference lists of the reports thus

retrieved were also scrutinized. We enrolled cases meet-

ing all the following criteria: (1) typical clinical features

of FTSD, (2) FTSD triggered electively by sporting

practice, and (3) no other obvious cause of dystonia.

Only reports including a detailed clinical description

were considered for analysis. Cases of Golfer with

‘‘yips’’ were excluded as we considered that the cause of

this disorder is controversial and the reported golf player

patients with yips probably include both patients with a

psychological cause and patients with dystonia.10,11

RESULTS

Illustrative Case Report

A 29-year-old right-handed professional TT player

(Patient 1 in Table 1) complained of stiffness and

*Correspondence to: Dr. Emmanuel Roze, Federation de Maladiesdu Systeme Nerveux, Groupe Hospitalier, Pitie-Salpetriere, 47-83Boulevard de l’Hopital, 75651 Paris Cedex 13, France.E-mail: [email protected]

Potential conflict of interest: Nothing to report.Received 28 September 2009; Revised 11 November 2009;

Accepted 19 November 2009Published online 27 January 2010 in Wiley InterScience (www.


394 A. LE FLOCH ET AL.


abnormal movements of his right upper arm, electively

triggered when playing TT and affecting his perform-

ance. He began to play TT at age 5 years, playing for

5 to 15 hours per week between age 6 and 12 years,

and for about 35 hours per week between age 12 and

28 years. At this latter age, following a period of more

intensive training, he began to experience involuntary

abnormal elbow flexion when serving. Owing to the

resulting decline in his performance, he increased his

training load and paid special attention to serving. The

abnormal movements gradually became more severe

over the following 6 months. After 3 months of highly

intensive training (6–7 hours daily), he developed addi-

tional abnormal movements that interfered with

‘‘normal’’ forehand movements. Finally, he reported

that the involuntary movement occasionally occurred

during daily-life movements requiring elbow flexion,

such as bringing a mobile phone to the ear. He stopped

training after a further marked decline in performance.

When examined while playing TT, he was seen to

have a dystonic movement characterized by elbow flex-

ion associated with elevation and adduction of the

shoulder that occurred almost each time he served or

made a forehand stroke (see Video). The interfering

movement only occurred when hitting a ball with a

racket: the movement was fluid when performed with-

out a racket and ball. He was able to attenuate the

abnormal movement (1) by using a sensory trick,

namely touching the right arm with a left finger and (2)

by including a whirling movement before the normal

forehand movement. When he played with the left

hand, there was no abnormal movement of the left upper

limb and no mirror dystonia of the right upper limb.

Abnormal posture and movements were absent at rest,

and other voluntary movements did not trigger dystonia.

Neurological findings were otherwise normal. There was

no pain or joint limitation. Routine laboratory tests, brain

and cervical MRI and neurophysiological investigations,

including nerve conduction velocity studies, were normal.

We diagnosed TT-related primary task-specific focal dys-

tonia. After 5 months without training, the dystonia

improved somewhat, but it again worsened as soon as

normal training sessions were resumed. Finally, we

advised the patient to drastically reduce his total practice

load and to exclude all repetitive movements. His condi-

tion had improved significantly 2 years after onset. He

returned to the competitive circuit but did not regain his

previous level. The dystonia persisted.

Table 1 shows the main characteristics of our four

patients and on another nine cases of sport-related dys-

tonia collected from the literature.

None of our four patients had family history of dys-

tonia, Parkinson’s disease, tremor, tics, or scoliosis and

there was no mention of such history in the nine

patients of the literature except for Patient #12 who

had a sister with dystonia. There was no psychiatric or

cognitive comorbidity in our four patients and there

was no mention of such comorbidity in the nine

patients of the literature except for Patient #6 who had

a diagnosis of social phobia. None of the 13 patients

had a previous history of neuroleptics use.

DISCUSSION

We describe the first four cases of FTSD in TT

players, including two international professionals, and

TABLE 1. Characteristics of our four patients with table tennis dystonia and nine published cases with othersport-related dystonia

PatientGender/

handedness Sport

Age (yr) atonset/at

examination

Cumulativeyears oftraining

before onset

Trainingintensity(hr/wk)

Increasedtraining the yearbefore onset

Prior head* orperipheral injury

1 (This study) M/R Table tennis 27/29 22 30 Yes No2 (This study) F/L Table tennis 19/28 12 25 Yes No3 (This study) M/R Table tennis 67/69 6 10 No Head trauma4 (This study) M/L Table tennis 17/20 4 8 No No5 (Ref. 5) M/L Tennis 16/34 10 NA NA No6 (Ref. 8) M/R Petanque 48/52 25 (break 3 yr) NA Yes NA7 (Ref. 8) M/R Petanque NA/56 >20 NA Yes NA8 (Ref. 1) M/R Golf 37/45 2 28 NA No9 (Ref. 6) F/L Ld running 37/40 NA NA NA Superficial knees injury10 (Ref. 6) F/R Ld running 40/49 NA NA NA Knee injury then surgery11 (Ref. 4) M/R Pistol shooting 36/64 7 14 NA No12 (Ref. 7) F/NA Ld running 55/57 NA NA NA NA13 (Ref. 7) M/NA Ld running 30/40 NA NA NA NA

*Only head trauma with loss of consciousness was considered.M, male; F, female; R, right handedness; L, left handedness; Ld running, long-distance running; NA, not available.


395TABLE TENNIS DYSTONIA

also analyze nine previously reported cases of sport-

related dystonia. We found the following common fea-

tures: (1) a large amount of time spent training each

week (8–30 hours), (2) a long period of continuous

training before onset (2–22 years), (3) a frequent

increase in practice intensity in the year preceding

onset, (4) no family history of dystonia (except for one

patient), and (5) no cause of symptomatic dystonia.

TT training is characterized by highly skilled and

highly repetitive hand movements, characteristics that

may be associated with a higher risk of FTSD than in

other sports. The two professional TT players

described here improved significantly, albeit only par-

tially, when they reduced their training intensity and

abandoned exercises requiring repetitive movements.

As FTSD may be diagnosed very late in TT players

and others sportspersons, leading to unnecessary

concerns and investigations, neurologists, sports

physicians, and competitive sportspersons should be

aware of this disorder. Erroneous psychiatric diagnoses

have been reported in sportspersons with dystonia5,8;

this was the case of our Patient #2, who suffered

severe social, familial, and psychological consequen-

ces. The improvement noted in Patients #1 and #2

when their training strategy was adapted suggests that

the disorder is at least partially reversible.

Our findings support the importance of environmen-

tal risk factors in the development of sport-related

FTSD, as previously suggested in classical forms of

FTSD. TT players’ training consists partly of high-fre-

quency repetition of specific movements that are likely

to favor the onset of dystonia, as in a primate model

of focal dystonia induced by intensive motor training.12

In a case–control study of 104 consecutive patients

with writer’s cramp and matched controls, we identi-

fied a dose-effect relationship with the amount of daily

handwriting, an additional trigger being an unusual

increase in the time spent writing in the year before

onset.9 We found such a recent increase in practice

time in the two professional TT players studied here

(Patients 1 and 2), as previously reported in other

sportspersons6,8 and in professional musicians.13,14 The

total time spent practicing, and a recent unusual

increase in the quantity or nature of training, may

reflect the same disruptive phenomenon. Patients with

focal dystonia have been found to have excessive sen-

sorimotor cortex plasticity and an impaired homeostatic

response.15,16 Pushing motor training to extremes can

result in maladaptive responses to highly skilled move-

ments. Homeostatic mechanisms that regulate cortical

plasticity may thereby be overwhelmed in susceptible

subjects, resulting in consolidation of abnormal motor

programs with altered muscle activation patterns.

Although probably underestimated, FTSD is likely to

be less frequent in sportspersons than in musicians.

The particular processing of the auditory feedback to

monitor online the movements pattern may implies

higher adaptive requirements in musicians.

Taking into account the low frequency of FTSD

among regular practitioners of highly skilled activities,

FTSD might involve a ‘‘double hint’’ model in which a

preexisting disorder makes some individuals vulnerable

to an FTSD triggering event. This particular suscepti-

bility of some subjects to dystonia may reflect an endo-

phenotype of the disease that could be either acquired

or genetically influenced.15,16 We found only one case

with dystonia in a relative.7 In contrast, a recent study

based on systematic examination of family members

found dystonic signs in a considerable number of rela-

tives of index patients with FTSD.18 This points to a

genetic component in FTSD vulnerability, in addition

to environmental factors.

Our study population is too small to speculate on a

possible link between sport-related dystonia and head

or other focal body trauma. Only 1 of the 13 patients

had a history of head trauma. Head trauma may facili-

tate the onset of dystonia by inducing subtle brain

damage or transient cortical dysfunction. We and

others have found that head trauma is a risk factor for

adult-onset focal dystonia, but other studies focusing

on cranial dystonia showed no such association.9,18

Two of the 13 patients in this study reported a history

of local body injury, but sportspersons may be more

exposed than the general population to peripheral

trauma. Peripheral injury might facilitate the onset of

dystonia by altering sensory inputs and leading to cort-

ical reorganization. Various primary adult-onset focal

dystonias have been linked to peripheral trauma.9,14

In conclusion, this study supports the crucial role of

environmental factors as FTSD triggers and has impor-

tant implications for clinical practice. Not only neurol-

ogists, but also sports physicians, trainers, and compet-

itors should be aware of this disorder, in order (1) to

adopt preventive strategies, (2) to detect FTSD rapidly,

(3) to offer adequate emotional support and therapy,

and (4) to adapt training accordingly.

LEGEND TO THE VIDEO

Patient 1 has an abnormal flexion of the elbow with

adduction and elevation of the shoulder when he

makes a forehand stroke. As a consequence, note that

the racquet is very close to his forehead at the end of

the movement. He attenuates the abnormal movement

396 A. LE FLOCH ET AL.


by touching the right arm with a left finger, and then

by including a whirling movement before the normal

forehand movement. Patient 2 has an abnormal brisk

cubital flexion of the wrist immediately before she

makes a forehand topspin.

Financial Disclosures: The authors have no financial dis-closures.

Author Roles: Anne Le Floch: Research project: execu-tion; manuscript: writing of the first draft. Marie Vidailhet:Research project: execution; manuscript: review and critique.Constance Flamand-Rouviere: Research project: conceptionand organization; manuscript: review and critique. DavidGrabli: Manuscript: writing of the first draft and review andcritique. Jean-Michel Mayer: Research project: execution.Michel Gonce: Research project: organization and execution;manuscript: review and critique. Emmanuel Broussolle:Research project: organization and execution; manuscript:review and critique. Emmanuel Roze: Research project: con-ception, organization, and execution; manuscript: writing ofthe first draft and review and critique.

REFERENCES

1. Tanaka M, Ohyagi Y, Kawajiri M, et al. [A patient with focal dysto-nia induced by golf and presenting a decrease in activity of cerebralmotor cortex on task]. Rinsho Shinkeigaku 2005;45:304–307.

2. Adler CH, Crews D, Hentz JG, Smith AM, Caviness JN. Abnor-mal co-contraction in yips-affected but not unaffected golfers:evidence for focal dystonia. Neurology 2005;64:1813–1814.

3. Ajax ET. Trapshooter’s cramp. Archiv Neurol 1982;39:131–132.

4. Sitburana O, Ondo WG. Task-specific focal hand dystonia in aprofessional pistol-shooter. Clin Neurol Neurosurg 2008;110:423–424.

5. Mayer F, Topka H, Boose A, Horstmann T, Dickhuth HH. Bilat-eral segmental dystonia in a professional tennis player. Med SciSports Exerc 1999;31:1085–1087.

6. Wu LJ, Jankovic J. Runner’s dystonia. J Neurol Sci 2006;251:73–76.

7. Leveille LA, Clement DB. Case report: action-induced focal dys-tonia in long distance runners. Clin J Sport Med 2008;18:467–468.

8. Lagueny A, Burbaud P, Dubos JL, et al. Freezing of shoulderflexion impeding boule throwing: a form of task-specific focaldystonia in petanque players. Mov Disord 2002;17:1092–1095.

9. Roze E, Soumare A, Pironneau I, et al. Case-control study ofwriter’s cramp. Brain 2009;132 (Pt 3):756–764.

10. Smith AM, Adler CH, Crews D, et al. The ‘yips’ in golf: a con-tinuum between a focal dystonia and choking. Sports Med 2003;33:13–31.

11. Stinear CM, Coxon JP, Fleming MK, Lim VK, Prapavessis H,Byblow WD. The yips in golf: multimodal evidence for two sub-types. Med Sci Sports Exerc 2006;38:1980–1989.

12. Byl NN, Merzenich MM, Jenkins WM. A primate genesis model offocal dystonia and repetitive strain injury. I. Learning-induced dedif-ferentiation of the representation of the hand in the primary somato-sensory cortex in adult monkeys. Neurology 1996;47:508–520.

13. Conti AM, Pullman S, Frucht SJ. The hand that has forgotten itscunning—lessons from musicians’ hand dystonia. Mov Disord2008;23:1398–1406.

14. Defazio G, Berardelli A, Hallett M. Do primary adult-onset focaldystonias share aetiological factors? Brain 2007;130 (Pt 5):1183–1193.

15. Quartarone A, Siebner HR, Rothwell JC. Task-specific hand dys-tonia: can too much plasticity be bad for you? Trends Neurosci2006;29:192–199.

16. Quartarone A, Morgante F, Sant’angelo A, et al. Abnormal plas-ticity of sensorimotor circuits extends beyond the affected bodypart in focal dystonia. J Neurol Neurosurg Psychiatry 2008;79:985–990.

17. Schmidt A, Jabusch HC, Altenmuller E, et al. Etiology of musi-cian’s dystonia: familial or environmental? Neurology 2009;72:1248–1254.

18. Defazio G, Berardelli A, Abbruzzese G, et al. Possible risk fac-tors for primary adult onset dystonia: a case-control investigationby the Italian Movement Disorders Study Group. J Neurol Neu-rosurg Psychiatry 1998;64:25–32.

Prolonged Vastus LateralisDenervation After Botulinum

Toxin Type A Injection

John W Dunne, MBBS (Hons), FRACP,1,2

Barbara J Singer, PT, MSc, PhD,2*Peter L Silbert, MBBS (Hons), FRACP,1,2

and Kevin P Singer, PT, MSc, PhD2

1Department of Neurology, Royal Perth Hospital,Perth, Australia; 2Centre for Musculoskeletal Studies,School of Surgery, The University of Western Australia,

Perth, Australia

Abstract: Intramuscular injection of botulinum toxin(BoNT) produces reversible blockade of neuromusculartransmission. In animal experimental models, recoverybegins within four weeks and is usually complete bytwelve weeks. We present evidence of prolonged denerva-tion following BoNT injection of the vastus lateralis (VL)muscle to correct quadriceps muscle imbalance in patientswith chronic anterior knee pain. Needle electromyographydata were obtained from 10 subjects who had received asingle BoNT treatment 5 to 19 months earlier as part of aclinical trial. Insertional and spontaneous activity, recruit-ment, and motor unit action potentials were examined.Clear differences between the injected and non-injectedVL muscles, which correlated with the time since injec-

*Correspondence to: Barbara J Singer, School of Surgery, TheUniversity of Western Australia, Level 2 Medical Research Founda-tion Bldg, Royal Perth Hospital, Perth WA 6000, Western Australia.E-mail: [email protected]

Potential conflict of interest: Product (Dysport1) for the clinicaltrial from which these data are derived, was provided by Ipsen Aus-tralia to Royal Perth hospital at no cost. Drs. Kevin and BarbaraSinger report having received travel support from Allergan, Inc andIpsen, Ltd. Dr. Peter Silbert and Dr. John Dunne report no potentialconflicts of interest.

Received 30 June 2009; Revised 18 September 2009; Accepted 25September 2009

Published online 27 January 2010 in Wiley InterScience (www.


397PROLONGED VL DENERVATION AFTER BONT INJECTION


tion, were identified in all subjects. All 10 subjects studiedwith needle EMG showed evidence of persistingdenervation in the BoNT-A injected VL muscle beyondthe period of neuromotor recovery expected from animalexperimental studies. � 2010 Movement Disorder Society

Key words: botulinum A toxin; muscle denervation;electromyography; neuromuscular blockade

Botulinum neurotoxin (BoNT) is produced by

Clostridium botulinum. Seven serotypes have been

identified, all of which inhibit acetylcholine release

from nerve terminals.1 Botulinum toxin type A (BoNT-

A) is the most commonly used serotype. In animal

models, initial recovery of neuromuscular transmission

commences within 4 weeks because of nerve terminal

sprouting at the neuromuscular junction.2–4 The parent

terminal remains nonfunctioning until approximately 8

weeks, at which time there is a return of vesicle turn-

over and the new sprouts begin to regress, with full

recovery of the parent terminal apparent by three

months post injection.2–4

However, consistent clinical benefit has been demon-

strated from BoNT-A injections in focal muscle over-

activity, with some patients having improvements last-

ing greater than 3 months after a single treatment.5–7

Few data exist documenting the duration of neurophys-

iological effects following a single BoNT-A interven-

tion; although a recent investigation in normal volun-

teers has described neurogenic muscle atrophy, which

was still present at 12 months.8

This report presents evidence of prolonged denerva-

tion following BoNT-A injection to the distal third of

the vastus lateralis (VL) muscle for chronic anterior

knee pain associated with quadriceps muscle imbal-

ance.9 Clinical results have been published else-

where.10 Improvements in functional mobility, knee

extensor torques and activity induced knee pain were

maintained at study follow up 12 months post-injec-

tion10; however, many subjects had persistent focal at-

rophy of the injected area of VL muscle.


Subjects

This study was approved by the institutional ethics

review committee. Subjects who had participated in

previous clinical investigations of a single BoNT

injection for chronic anterior knee pain10,11 were

approached to undergo needle EMG assessment to

examine the extent of any residual BoNT-A effect. All

subjects had received a standard dose of 500 units

Dysport (Ipsen) diluted with 4 ml of normal saline into

the distal third of the VL muscle, 5 to 19 months

earlier.

Electromyography

Concentric bipolar needle electromyography (Viking

IV EMG, Nicolet) was performed by an independent

electromyographer who was blinded to the side and

timing of BoNT-A injections. Subjects did not commu-

nicate information about which limb had been previ-

ously treated. Qualitative and quantitative EMG was

performed on both limbs in random order. Recordings

were made from two or three sites within the previ-

ously injected area (distal third of the VL muscle).

Qualitative EMG assessment employed a bandpass of

20 Hz–20 KHz, a sweep speed of 10 msec/division, and

sensitivities of 50 lV/division for insertional and sponta-neous activity and 200 lV/division for recruitment and

motor unit action potential (MUP) assessment.

Quantitative multi-MUP analysis of at least

16 MUPs was recorded from each muscle using auto-

matic template matching software, a bandpass of 2

Hz–10 kHz, a sweep speed of 5 msec/division and sen-

sitivity of 100 lV–200 lV/division. MUPs were

sampled from different depths using slight to moderate

contraction, and mean amplitude and duration were

derived. MUP parameters were considered abnormal if

the mean MUP value or at least three individual MUPs

were outside the reference range.11,12

Needle electromyography interference pattern analy-

sis in mild-moderate isometric muscle contraction was

also performed, but without quantitation of the force of

muscle contraction. A bandpass of 20 Hz –10 kHz and

sensitivity of 1 mV/division were used, with the Nico-

let system calculating from a 5 second EMG epoch.

Peak-to-peak amplitude, mean rectified voltage, the

root mean square (RMS) voltage, and turns per second

(the number of peaks in the waveform exceeding a

level of 100 lV) were calculated.

Subsequent to data analysis the data were coded

according to treated side. MUP parameters from unin-

jected and injected limbs were compared utilising the

paired t-test. A least squares linear regression was used

to examine effects between limbs and time since

injection. A probability of P < 0.05 was used as the

criterion for determining meaningful differences

between sides.

RESULTS

This study investigated a sample of convenience of

subjects enrolled in clinical trials investigating the

398 DUNNE ET AL


TABLE

1.Qua

litative

andqu

antitative

needle

EMG

exam

inationfin

ding

sof

BT-A

(Dyspo

rt1)injected

andcontroldistal

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in10

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Subject

Tim

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MUP

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MRV

(lV)

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(lV)

1.(BT-A

)5

21

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4*

833

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32

1.(control)

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NL

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1272

8.1

3.2

1083

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49

2.(BT-A

)5

012

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507

6.7*

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1041

20

49

2.(control)

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823

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41500

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83

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)7.5

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7.9#

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833

626

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151

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)8

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69

4.(control)

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775

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96

5.(BT-A

)8

11

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22

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361

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––

–5.(control)

0NL

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970

12.5

3.6

6000

135

297

6.(BT-A

)8.5

11

21

22

12

375

7.6#

2.6

1541

93

141

6.(control)

0NL

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767

12.2

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2250

91

153

7.(BT-A

)9

11

21

22

12

229#

6.8*

6.6*

916

43

64

7.(control)

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708

11.6

3.8

5666

217

358

8.(BT-A

)11

11

NL

12

12

852

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#1708

70

110

8.(control)

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NL

NL

1186

12.1

2.5

6000

187

383

9.(BT-A

)12

21

11

22

22

403

8.0

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85

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934

11.3

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3500

154

248

10.(BT-A

)19

011

12

11

984

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4.3*

4791

88

198

10.(control)

0NL

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NL

916

15.1

2.8

8000

105

258

Spontaneousfibrillationgradings:

11

forpersistentfibrillationsandin

atleasttwoareasofthemuscle.21

formoderatenumbersofpersistentfibrillationsin

‡3areas.

MUPduration

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plitudeabnorm

alities:1formildand2formoderate,

‘‘2’’decreaseand‘‘1’’increase

*meanvalues

outsidereference

rangeandat

leastthreeindividual

MUPsoutsidereference

range.

#at

leastthreeindividual

MUPsoutsidereference

range.



effect of BoNT injection, to the distal portion of the

VL muscle, for refractory anterior knee pain.10 Ten of

25 subjects contacted agreed to participate in the nee-

dle EMG investigation. Nine were women (mean age

27; range 16–56) and all were physically active. All 10

subjects reported ongoing relief of symptoms at the

time of this investigation; however, two subsequently

underwent surgery for exacerbation of knee related dis-

ability at 12 and 20 months, respectively, post BoNT

injection.

The data are summarised in Table 1. Clear interlimb

differences were evident for the VL muscle in all

10 subjects. No EMG qualitative or quantitative abnor-

mality was found in the uninjected VL muscles.

Qualitative EMG showed abnormalities in the

injected VL muscle in all subjects. These findings

included: increased insertional activity with spontane-

ous fibrillations in 8 subjects, reduced MUP amplitudes

in all subjects and altered MUP duration in 8 subjects.

Increased MUP turns/phases were present in 9 of 10

subjects. MUP recruitment was reduced in 2 subjects

at 5 months postinjection and increased in 5 subjects at

longer durations postinjection (Table 1).

Quantitative MUP analysis revealed reduction in

MUP amplitude, MUP duration or both in seven of the

10 subjects. Mean MUP phases were increased in 9 of

10 subjects. All 10 subjects showed significant quanti-

tative differences in the injected compared with the

control limb including: a mean MUP amplitude reduc-

tion of 452 lV or 49% (range 0–79%) (P 5 0.0005), a

mean MUP duration reduction of 4.4 msec or 36%

(range 0–58%) (P 5 0.0003), and MUPs with a mean

of two more phases (P 5 0.03) (Table 1). Interference

pattern analysis of the injected VL compared with the

other side showed a mean peak to peak amplitude

reduction of 2227 lV or 49% (range 17–84%) (P 50.007), mean rectified voltage reduction of 53 lV or

47% (range 0–84%) (P 5 0.03) and RMS reduction of

112 lV or 48% (range 8–83%) (P 5 0.02). Turns per

second did not reveal consistent side to side differen-

ces (see Table 1).

Linear regression showed an association between

degree of MUP amplitude reduction and time since

BoNT-A treatment (P 5 0.02; Fig. 1), with a mean

return to the untreated limb MUP amplitudes at 19

months (lower 95% confidence band of 14 months).

DISCUSSION

We have found both qualitative and quantitative nee-

dle EMG evidence of prolonged denervation in all 10

subjects injected with BoNT-A between 5 and 19

months previously. Blinded qualitative EMG was as

sensitive and specific as quantitative EMG in identify-

ing the injected limb in all subjects. The extent of the

identified abnormalities correlated with time since

injection.

Increased insertional activity with spontaneous fibril-

lations was found in 8 subjects. Fibrillations are the

spontaneous action potentials of single muscle fibres,

and arise in functionally denervated muscle fibres.13

The loss of functioning muscle fibres in a motor unit

causes a reduction in MUP amplitude and duration,

with an increase in turns and phases because of ran-

dom fibre loss and desynchronisation amongst remain-

ing muscle fibres. As we have found in this study,

MUP recruitment may be influenced variably by neuro-

muscular blockade, with reduced recruitment seen in

2 subjects who were 5 months postinjection and

increased recruitment in four subjects at longer dura-

tions post-injection. Functional blockade of random

muscle fibres within a motor unit may increase recruit-

ment, since more motor units are required to compen-

sate for a smaller force generated per motor unit. Con-

versely, functional blockade of whole motor units may

reduce recruitment. It is important to note that there

was no clinical evidence of a neurogenic disorder in

any of the subjects studied. The EMG changes

observed are characteristic of BoNT effect on neuro-

muscular transmission. In contrast, in a chronic

neurogenic process, EMG examination reveals high

amplitude and long duration motor unit potentials with

reduced recruitment.

FIG. 1. Bivariate scattergram with linear regression and 95% confi-dence bands for the mean MUP amplitude in BoNT-A injected andcontrol muscles in 10 subjects.

400 DUNNE ET AL


Electrophysiological changes in the VL muscle

were evident after this single BoNT-A treatment

beyond the period of recovery of the neuromuscular

junction expected from previously reported animal

studies.2–4 Despite this, at the time of investigation,

most subjects reported significantly improved symp-

toms compared with preinjection status. We consider

this to represent a lasting improvement in balance

between the medial and lateral components of the

quadriceps muscle.10 Very few studies have examined

the persistence of neurophysiological effects from a

single BoNT injection. A recent investigation in nor-

mal volunteers reported reduction in the cross sec-

tional area of the injected lateral head of gastrocne-

mius muscle, as well as histopathological evidence of

neurogenic atrophy at 12 months post injection of

BoNT-A.8 These changes were not associated with

functional impairment. It is possible that the persistent

change observed in these individuals, and in our

cohort, is the rule, not the exception. Findings of this

study may also reflect a dose-dependent effect.14 The

dose was selected empirically based on the size of

the VL muscle and our prior clinical experience. The

duration of BoNT-A effect may also be muscle and

condition specific. Further investigation is required to

establish the duration of muscle denervation in addi-

tion to clinical benefit.

CONCLUSIONS

All 10 subjects studied with needle EMG showed

evidence of persisting denervation in the BoNT-A

injected muscle beyond the period of neuromotor

recovery expected from animal experimental studies.

Author Roles: John Dunne: Conception, design and exe-cution of research project, statistical analysis, manuscriptreview and critique. Barbara Singer: Conception and designof research project, writing first draft of manuscript. PeterSilbert: Execution of research project, manuscript review andcritique. Kevin P Singer: Conception and design of researchproject, manuscript review and critique.

Financial disclosure: Product (Dysport1) for the clinicaltrial from which these data are derived, was provided byIpsen Australia to Royal Perth hospital at no cost. Data werecollected and analyzed independently by authors. Ipsen Aus-tralia had no role in data management. One author (BJS)received partial salary support (2005–6) for the clinical trialfrom which these data are derived from the Raine MedicalResearch Foundation, at The University of Western Australia.This body places no restriction on data collection, analysis orreporting. All authors have full-time university or clinicalpractice employment contracts. There are no other sources offinancial support or funding for the preceding twelve months

for Dr John Dunne, Dr Peter Silbert, Dr Kevin Singer. DrBarbara Singer has a full-time academic appointment and hasalso received funding support in 2008-9. The effect ofrepeated passive dorsiflexion on reducing calf muscle stiff-ness following acquired brain injury. Neurotrauma ResearchProgram, Western Australia ($116,000). Move Again Project’(MAP)—establishing an exercise network to improve func-tional, physical, mental and social health in the neurologi-cally impaired’. Neurotrauma Research Program, WesternAustralia ($100,000). The impact of a NMES based bilateraltraining program on left neglect, anosognosia and arm func-tion after stroke. Neurotrauma Research Program, WesternAustralia.

REFERENCES

1. Dressler D, Hallett M. Immunological aspects of Botox, Dys-port and Myobloc/NeuroBloc. Eur J Neurol 2006;13(Suppl 1):11–5.

2. Comella JX, Molgo J, Faille L. Sprouting of mammalian motornerve terminals induced by in vivo injection of botulinum type-Dtoxin and the functional recovery of paralysed neuromuscularjunctions. Neurosci Lett 1993;153:61–64

3. de Paiva A, Meunier FA, Molgo J, Aoki KR, Dolly JO. Func-tional repair of motor endplates after botulinum neurotoxin typeA poisoning: biphasic switch of synaptic activity between nervesprouts and their parent terminals. Proc Natl Acad Sci USA1999;96:3200–3205

4. Juzans P, Comella JX, Molgo J, Faille L, Angaut-Petit D.Nerve terminal sprouting in botulinum type-A treated mouselevator auris longus muscle. Neuromuscul Disord 1996;6:177–185.

5. Dunne JW, Heye N, Dunne SL. Treatment of chronic limb spas-ticity with botulinum toxin A. J Neurol Neurosurg Psychiatry1995;58:232–235.

6. Chiu MJ, Chang YC, Hsiao TY. Prolonged effect of botulinumtoxin injection in the treatment of cricopharyngeal dysphagia:case report and literature review. Dysphagia 2004;19:52–57.

7. Benecke R, Dressler D. Botulinum toxin treatment of axial andcervical dystonia. Disabil Rehabil 2007;29:1769–1777

8. Schroeder AS, Ertl-Wagner B, Britsch S, Schroder JM, NikolinS, Weis J, Muller-Felber W, Koerte I, Stehr M, Berweck S,Borggraefe I, Heinen F. Muscle biopsy substantiates long-termMRI alterations one year after a single dose of botulinum toxininjected into the lateral gastrocnemius muscle of healthy volun-teers. Mov Disord. 2009;24:1494–1503.

9. Malone T, Davies G, Walsh WM. Muscular control of thepatella. Clin Sports Med 2002;21:349–362.

10. Singer BJ, Silbert PL, Dunne JW, Song S, Singer KP. An openlabel pilot investigation of the efficacy of Botulinum toxin typeA (Dysport) injection in the rehabilitation of chronic anteriorknee pain. Disabil Rehabil 2006;28:707–713

11. Bischoff C, Stalberg E, Falck B, Eeg-Olofsson KE. Referencevalues of motor unit action potentials obtained with multi-MUAPanalysis. Muscle Nerve 1994;17:842–851.

12. Stalberg E, Bischoff C, Falck B. Outliers, a way to detect abnor-mality in quantitative EMG. Muscle Nerve 1994;17:392–399.

13. Kimura J. Nerve conduction and needle electromyography. In:Dyck PJ, Thomas PK, editors. Peripheral neuropathy, Vol. 1.Elsevier Saunders, Philadelphia 2005. p 937–969.

14. Dresseler D, Rothwell JC. Electromyographic quantification of theparalyzing effect of botulinum toxin. Eur Neurol 2000:43:13–16.



The Montreal CognitiveAssessment as a Screening Toolfor Cognitive Dysfunction in

Huntington’s Disease

Aleksandar Videnovic, MD, MSc,1*Bryan Bernard, PhD,2 Wenqing Fan, MS,2

Jeana Jaglin, RN,2 Sue Leurgans, PhD,2

and Kathleen M. Shannon, MD2

1Department of Neurology, Northwestern University FeinbergSchool of Medicine, Chicago, Illinois, USA; 2Department

of Neurological Sciences, Rush UniversityMedical Center, Chicago, Illinois, USA

Abstract: Cognitive dysfunction is one of the hallmarks ofHuntington’s disease (HD) and may precede the onset ofmotor symptoms. The Montreal Cognitive Assessment(MoCA), a brief cognitive screening instrument with highspecificity and sensitivity for detecting early cognitiveimpairments, has not been studied in the HD population.In this study, we compare the MoCA with the mini-men-tal state examination (MMSE) as a screening tool for cog-nitive dysfunction among 53 patients with HD. The meanMMSE score was 26 6 2.4, and mean MoCA score was21 6 4.4. Twenty-one patients (81%) of those who scored‡26 on the MMSE had the MoCA score <26. Thirty-twopatients (78%) of those who scored ‡24 on the MMSEhad the MoCA score <24. The MoCA may be a moresensitive screening tool for cognitive impairments in HDrelative to the MMSE. � 2010 Movement Disorder Society

Key words: Huntington’s disease; MoCA; MMSE;cognition

Huntington’s disease (HD) is an autosomal dominant

neurodegenerative disorder characterized by abnormal

movements, cognitive impairment, and behavioral

symptoms. Early cognitive deficits in HD are changes

in visuospatial abilities, visual-motor skills, executive

function, and facial expression recognition.1 These

changes may emerge before the onset of frank motor

signs in some individuals carrying the HD mutation.

There is, therefore, a need for screening and detection

of these early cognitive changes in the HD population.

As the disease progresses, it is important to have a sen-

sitive tool to measure the rate of cognitive decline.

The mini-mental state examination (MMSE) is a

widely used screening instrument for detecting cogni-

tive deficits.2 Although it may be completed quickly

and user friendly, the MMSE may not capture cogni-

tive domains affected across a wide spectrum of de-

mentia syndromes, and it lacks adequate sensitivity for

detection of mild cognitive impairment.3,4 Neuropsy-

chological testing, although the gold standard for meas-

uring cognitive performance, is lengthy and requires

expertise for its administration and interpretation.

The Montreal Cognitive Assessment (MoCA) is a

brief cognitive screening tool with high specificity and

sensitivity for detecting mild cognitive impairment.5

Executive function, language abilities, and visuospatial

processing are assessed more rigorously with the

MoCA relative to the MMSE. As the MoCA has not

been studied as a measure of cognitive performance in

the HD population, we conducted this study to com-

pare MoCA with MMSE as a screening tool for cogni-

tive dysfunction in HD.


Consecutive patients with HD presenting for a rou-

tine follow-up assessment, were recruited from the HD

clinic at Rush University Movement Disorders Center

over a 5-month period. All study participants signed

informed consent. The study protocol was approved by

the Institutional Review Board of Rush University.

Standardized evaluations used were the Unified Hun-

tington’s Disease Rating Scale (UHDRS)6 and the

Total Functional Capacity Scale (TFC).6 The demo-

graphics, education level, and disease duration of the

patients were ascertained as well.

Study instruments included the MMSE and MoCA,

and were administered on the same day in alternating

order. Participants completed both scales in their origi-

nal format. Cut off scores of <26 and <24 were used

as values indicative of cognitive impairment. These cut

off scores were chosen based on the cut off values in

studies assessing cognitive performance.2,5,7

Associations of MoCA and MMSE scores with dis-

ease severity, UHDRS, and TFC were evaluated via

Spearman rank correlations, with a significance level

of P < 0.05. Frequencies and percents were calculated

for categorical variables. Mean and standard deviations

were calculated for continuous variables.

RESULTS

Fifty-three patients (27 M, 26 F) participated in this

study. The mean age of the study cohort was 53 6

*Correspondence to: Dr. Aleksandar Videnovic, Department ofNeurology, Feinberg School of Medicine, Northwestern University,710 N Lake Shore Drive #1106, Chicago, IL 60611, USA.E-mail: [email protected]

Potential conflict of interest: Nothing to report.Received 6 March 2009; Revised 16 July 2009; Accepted 19 July

2009Published online 27 January 2010 in Wiley InterScience (www.


402 A. VIDENOVIC ET AL.


11.4 years, and mean duration of symptoms was 8 65.9 years. The diagnosis was confirmed genetically in

47 participants. For the remaining six participants, the

diagnosis was based on the clinical features of HD and

positive family history. Forty-nine participants (93%)

completed high school. The mean motor UHDRS score

was 33 6 16.7 and mean TFC was 7 6 3.4.

The mean MMSE score was 26 6 2.4 and mean

MoCA score was 21 6 4.4 (Fig. 1). The MMSE score

correlated with TFC (r 5 0.3, P 5 0.03). The MoCA

score correlated with TFC (r 5 0.5, P 5 0.0001) and

motor UHDRS (r 5 20.5, P 5 0.0001).

The range of scores on the MMSE was 17–30 and

on the MoCA 11–30 (Fig. 2). The ceiling effect was

mild, and maximal scores on the MMSE and MoCA

were obtained in one participant. Twenty-seven

patients (51%) scored <26 on the MMSE, and 48

patients (91%) scored <26 on the MoCA. The MMSE

scores were <24 in 12 patients (23%), and MoCA

scores were <24 in 43 patients (81%). Twenty-one

patients (81%) of those who scored ‡26 on the MMSE

had the MoCA score <26. Thirty-two patients (78%)

of those who scored ‡24 on the MMSE had the MoCA

score <24. None of the subjects who scored >24 or

>26 on the MoCA had MMSE scores <24 or <26,

respectively.

DISCUSSION

Standardized cognitive batteries, such as the MMSE

and the Cambridge Mental Disorders of Elderly Exam-

ination,8 have been developed to streamline screening

for cognitive impairment and decline. Ceiling effects

and lack of adequate sampling of various cognitive

domains in testing paradigms limit the sensitivity of

these instruments for detecting cognitive impairment.

High MMSE scores have been reported in individuals

with well-ascertained dementia.9

This is, to our knowledge, the first report of the

MoCA as a screening instrument for cognitive impair-

ment in the HD population. The MoCA scores were

less than the MMSE scores in our cohort. Using the

cut off scores of 24 and 26, more patients with HD

were identified as having cognitive impairment on the

MoCA relative to the MMSE. No significant ceiling

effect was observed on the MoCA. We therefore

believe that the MoCA may be a more sensitive

screening instrument for cognitive impairment in HD

relative to the MMSE.

The MoCA was designed to be more sensitive to

abnormal performance in memory, language, and exec-

utive function domains in mildly impaired individuals.5

We therefore speculate that differences in performance

on the MMSE and MoCA in our cohort may be

explained by the better ability of the MoCA to capture

memory, high-level language abilities, executive cogni-

tive function, and visuospatial processing in HD

patients.

Although the MoCA has not been systematically

studied in the HD population, several reports assessed

the utility of the instrument as a screening tool for cog-

nitive impairment in Parkinson’s disease (PD).10,11

These reports suggest that the MoCA may provide

more insight into the cognitive status of patients with

PD, relative to the widely used MMSE. In PD, the

MoCA demonstrated good test–retest and inter-rater

reliability, as well as good convergent validity with a

neuropsychological battery.10

We recognize several important limitations of our

study. The study cohort is relatively small. We did not

conduct a neuropsychological testing that is a gold

standard for the assessment of cognitive performance.

We used cutoff scores of 24 and 26 as indicators ofFIG. 1. Mean mini-mental state examination (MMSE) and MontrealCognitive Assessment (MoCA) scores 6 standard deviations.

FIG. 2. Frequency of scores on the mini-mental sate examination(MMSE) and Montreal Cognitive Assessment (MoCA).

403MoCA IN HD


cognitive impairment. It is, however, not known if

these values are a good representative of cognitive

impairments in the HD population. Further studies that

will use neuropsychological evaluations will better

define cutoff scores in the HD population.

Despite these limitations, our findings suggest that

the MoCA may be a more sensitive screening instru-

ment relative to the MMSE for detecting cognitive

impairment in the HD population. Longitudinal valida-

tion studies of the MoCA against neuropsychological

batteries in larger cohorts of patients with HD are

needed to establish the role of the MoCA as a cogni-

tive screening tool in the HD population.

Financial Disclosures: A. Videnovic: American Academyof Neurology Foundation, Parkinson Disease Foundation; B.Bernard, W. Fan, J. Jaglin: None; S. Leurgans: National Insti-tute of Aging (NIA), Michael J. Fox Foundation; K. Shannon:National Institute of Neurological Disorders and Stroke(NINDS), Parkinson Study Group, Huntington Study Group.

Author Roles: A. Videnovic: Research project: Concep-tion, organization, execution; Statistical analysis: Design,review and critique; Manuscript: Writing of the first draft. B.Bernard: Research project: Conception, execution. W. Fan:Research project: Execution; Statistical analysis: Design, exe-cution, review and critique; Manuscript: Review and critique.J. Jaglin: Research project: Organization, execution. S. Leur-gans: Statistical analysis: Design, execution. K. Shannon:Research project: Conception, execution; Statistical analysis:Review and critique; Manuscript: Review and critique.

REFERENCES

1. Verny C, Allain P, Prudean A, et al. Cognitive changes inasymptomatic carriers of the Huntington disease mutation gene.Eur J Neurol 2007;14:1344–1350.

2. Folstein MF, Folstein SE, McHugh PR. ‘‘Mini-mental state.’’ Apractical method for grading the cognitive state of patients forthe clinician. J Psychiatr Res 1975;12:189–198.

3. Tombaugh TN, McIntyre NJ. The mini-mental state examination:a comprehensive review. J Am Geriatr Soc 1992;40:922–935.

4. Wind AW, Schellevis FG, Van Staveren G, Scholten RP, JonkerC, van Eijk JT. Limitations of the mini-mental state examinationin diagnosing dementia in general practice. Int J Geriatr Psychia-try 1997;12:101–108.

5. Nasreddine ZS, Phillips NA, Bedirian V, et al. The MontrealCognitive Assessment, MoCA: a brief screening tool for mildcognitive impairment. J Am Geriatr Soc 2005;53:695–699.

6. Huntington Study Group. Unified Huntington’s Disease RatingScale: reliability and consistency. Mov Disord 1996;11:136–142.

7. Anthony JC, LeResche L, Niaz U, von Korff MR, Folstein MF.Limits of the ‘Mini-mental state’ as a screening test for dementiaand delirium among hospital patients. Psychol Med 1982;12:397–408.

8. Randhawa S, Walterfang M, Miller K, Scholes A, Mocellin R,Velakoulis D. The development and validation of a carer ques-tionnaire to assess cognitive function in neuropsychiatric patients.J Psychosom Res 2007;63:93–98.

9. Shiroky JS, Schipper HM, Bergman H, Chertkow H. Can youhave dementia with an MMSE score of 30? Am J AlzheimersDis Other Dement 2007;22:406–415.

10. Gill DJ, Freshman A, Blender JA, Ravina B. The Montreal cog-nitive assessment as a screening tool for cognitive impairment inParkinson’s disease. Mov Disord 2008;23:1043–1046.

11. Zadikoff C, Fox SH, Tang-Wai DF, et al. A comparison of themini mental state exam to the Montreal cognitive assessment inidentifying cognitive deficits in Parkinson’s disease. Mov Disord2008;23:297–299.


404 A. VIDENOVIC ET AL.

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