Brief Report

Dystonia in Wilson’s Disease

Marina Svetel, MD,1 Dusko Kozic, MD,2,* Elka Stefanova, MD,1 Robert Semnic, MD,2

Natasa Dragasˇevic, MD,1 and Vladimir S. Kosticˇ, MD1*

1Institute of Neurology CCS, Belgrade, Yugoslavia2MRI Center, Sremska Kamenica, Yugoslavia

Abstract: The frequency and type of dystonic movements, aswell as brain abnormalities, as depicted with magnetic reso-nance imaging (MRI), which might correlate with dystonia,were studied in 27 consecutive patients with a neurologic formof Wilson’s disease (WD) and optimized treatment. Dystoniawas found in 10 patients (37%), being generalized in half ofthem, while two patients had segmental, two patients multifocaldystonia, and one patient bilateral foot dystonia. Dystonia was

a presenting sign in four patients and developed later in thecourse of the disease in six patients, despite the administeredtherapy for WD. Putamen was the only structure significantlymore frequently lesioned in dystonic (80%) in comparison toWD patients without dystonia (24%), suggesting a relation be-tween abnormalities in this brain region and dystonic move-ments in WD. © 2001 Movement Disorder Society.

Key words: Wilson’s disease; dystonia; MRI; putamen

Symptoms indicative of central nervous system in-volvement are the presenting clinical feature in approxi-mately 40% to 50% of patients with Wilson’s disease(WD).1 It is a rare and treatable autosomal recessiveneurological disease that must be involved in the differ-ential diagnosis of all patients who develop dystonia be-fore the age of 40.2 Dystonia is a hallmark of the classic(dystonic) form of WD and, although rarely occurs inisolation,3 it was found at the first examination in asmuch as 65% of 31 patients presenting with neurologicform of the disease.4

The aim of this study was to investigate frequency andtype of dystonic movements in a group of consecutivepatients with the neurologic presentation of WD and op-timized treatment. Also, the purpose of the study was toidentify brain abnormalities, as depicted with magnetic

resonance imaging (MRI), which correlated with dysto-nia in this disease.

PATIENTS AND METHODSThe study comprised all patients with WD who were

admitted to the Department for Movement Disorders ofour institution between 1997 and 1999 (n4 27; 19males and eight females). The diagnosis of WD wasestablished by the following previously described crite-ria:5 (1) history; (2) physical examination; (3) serum ce-ruloplasmin and copper levels; (4) 24-hour urinary cop-per excretion; (5) liver biopsy; and (6) ophthalmologicexamination with a slit lamp. The data used in this studywere obtained in clinical and imaging examination dur-ing the last admission in the course of investigation.Clinical examinations were performed by two neurolo-gists (V.S.K., M.S.) and every symptom was scored (0,not present; 1, mild; 2, moderate; 3, severe). Agreementon the existence of dystonic movements (dystonic pos-tures, action dystonia, dystonic jerks) and the affectedpart(s) of the body, was reached by consensus. In pa-tients with dysarthria, special effort was made to differ-entiate those with dystonia of facial and bulbar muscles,

*Correspondence to: Vladimir S. Kostic, MD, PhD, Institute of Neu-rology CCS, ul. Dr Subotica 6, 11000 Belgrade, Yugoslavia. E-mail:kostic@imi.bg.ac.yu

Received 6 October 2000; Revised 8 January 2001; Accepted 22January 2001

Published online 15 June 2001; DOI 10.1002/mds.1118

Movement DisordersVol. 16, No. 4, 2001, pp. 719–723© 2001 Movement Disorder SocietyPublished by Wiley-Liss, Inc.

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including the examination for the previously describedfeatures:6 a range of the movements of the lips, ability towhistle, elevation of the soft palate, tongue movements,presence ofrisus sardonicus, presence of the prolonged,high-pitched or gargling inspiratory whine or cry, snoutreflex, jaw reflex, and contraction of facial muscles tostretch. All the patients gave informed and written con-sent for their participation in the study.

Patients underwent brain 1.5-T MRI (MagnetomSiemens SP4000; Siemens AG, Erlangen, Germany) andthe following pulse sequences were used: (1) sagittalgradient echo (GE) T1-weighted (repetition time [TR]/echo time [TE]/flip angle–266/6/80, one acquisition,5-mm slice thickness with 0.1 interslice gap, 250-mmfield of view [FOV], and 192 × 256 matrix); (2) axialturbo spin echo (TSE) T2-weighted (TR/TE–3,000/13-93; one acquisition, 6-mm slice thickness with 0.1 inter-

slice gap, 230-mm FOV, and 192 × 256 matrix; (3) axialGE T2-weighted (800/26/20, one acquisition, 6-mm slicethickness, 250-mm FOV, and 256 × 256 matrix). Thepresence or absence of atrophy, as well as the presence ofincreased signal on T2/proton density (PD)-weighted se-quence and low/absent signal on GE T2-weighted se-quence in the subcortical white matter, putamen, caudate,globus pallidus, thalamus, midbrain, tectum, pons, andcerebellum were recorded. The MRI were independentlyanalyzed by two neuroradiologists (D.K., R.S.), whowere blinded to the results of clinical examinations. Ab-normal gray matter nuclei were localized by tracing thenuclei on the PD-weighted MR images.

RESULTSThe study comprised 27 patients diagnosed with WD.

Their clinical features are presented in Table 1. All thepatients were treated with D-penicillamine (18 patients),zinc (eight patients) or trientine (one patient), with thecopper reduced to a subtoxic threshold (nonceruloplas-min plasma copper < 25mg/dl; 24-hour urinary copper#500 mg) and a reduction toward normal liver-derivedserum enzymes if these were elevated.5 Dystonia was apart of clinical presentation in 10 (37%) patients, whilein 17 (63%), it was not present either at rest or duringactivation. Interestingly enough, in none of the patientsin whom clinical parameters were suggestive of pre-dominantly dystonic dysarthria was there an isolatedfinding of dystonia; i.e., dystonia always affected someother part of the body as well (five patients). Groups ofpatients with and without dystonia did not differ in theirdemographic or clinical features (Table 1).

Table 2 illustrates types of dystonia, clinical features,and morphological changes verified on MRI. Half ofdystonic patients had generalized dystonia (n4 5),two had segmental dystonia, two patients multifocal dys-tonia (in one of them with prominent writer’s cramp),and in one patient bilateral foot dystonia. All the patients

TABLE 1. Demographic and clinical characteristics ofpatients with Wilson’s disease (WD) with and

without dystonia

WD patientswith dystonia

WD patientswithout dystonia

Number of patients 10 17Gender (male/female

ratio)# 7/3 12/5Age (years)* 36.7 ± 7.9 (22–45) 35.6 ± 7.8 (24–56)Age at disease onset

(years)* 28.3 ± 9.1 (12–41) 29.4 ± 6.5 (17–40)Duration of WD

(years)* 8.4 ± 5.5 (1–17) 6.7 ± 4.7 (1–19)Treatment&,#

Penicillamine 6/10 12/17Zinc 2/10 6/17Trientine 1/10 0/17

Duration of treatment(years)* 6.6 ± 4.4 (1–16) 5.0 ± 3.7 (1–13)

Familial history&,# 1/10 3/17

*Values expressed as means ± S.D. (min-max);#number with spe-cific feature/total number of patients;&more than one feature may bepresent at the same time.

TABLE 2. Type of dystonia, clinical characteristics and magnetic resonance imaging (MRI) findings in patients with dystonia(n = 10)

Patient SexAge(yrs)

Duration of thedisease (yrs) Type of dystonia Lesions on MRI*

1 m 40 5 Multifocal NC, GP, SN, dorsal mesencephalon2 f 35 8 Multifocal Pu, GP, NR, pons, cerebellar hemispheres3 m 17 13 Generalized Pu, GP, SN, Th4 m 24 3 Generalized Pu, NC, cerebellar hemispheres5 m 42 5 Generalized GP, SN, claustrum, frontal white matter6 m 43 17 Generalized Pu, GP, claustrum, dorsal mesencephalon7 m 22 10 Segmental Pu, Th, pons, frontal white matter8 f 36 6 Segmental Pu, subthalamic tegmental region, claustrum9 m 37 1 Bilateral foot dystonia Pu, GP, SN, Th

10 f 42 16 Generalized Pu, subthalamic tegmental region, frontal white matter, cerebellar hemispheres

*Bilateral; NC, caudatus; Pu, putamen; GP, globus pallidus; SN, substantia nigra; NR, nucleus ruber; Th, thalamus; m, male; f, female.

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with generalized and segmental, as well as one patientwith multifocal dystonia, had prominent facial grimacing(six patients), tongue dyskinesia (four patients), andblepharospasm (three patients). A fixed, “sardonic”smile was found in only two patients. Dystonia increasedwith ambulation in 6 patients and, in one patient wasonly evident on ambulation. Severe, sustained dystonic

contractions of the limb and axial muscles were seen intwo and only one patient, respectively.

The relative frequencies of the MRI detected lesionsamong WD patients with and without dystonia are shownin Table 3. Putamen was the only structure significantlymore frequently lesioned in dystonic (80%) in compari-son to WD patients without dystonia (24%;P < 0.05; Fig.1). The frequencies of damages of the thalamus, frontal,and cerebellar hemispheres’ white matter were alsohigher but did not reach the level of statistical signifi-cance (Table 3).

DISCUSSION

Patients with WD and neurological abnormalities usu-ally present in the second or third decade as: (1) anakinetic-rigid syndrome resembling parkinsonism; (2)postural and intention tremor with ataxia, titubation anddysarthria (“pseudosclerosis”); or (3) a generalized dys-tonic syndrome. Dystonia was present in 37% of ourtreated patients with neurological manifestation of WD.Our findings are mainly within the range of referential.Grimm et al.8 found 27 out of 48 patients with WD tohave at least one of five extrapyramidal signs (dysarthria,tremor, ataxia, rigidity/bradykinesia, and chorea/dystonia), with chorea/dystonia present in 33% of them.In another study, dystonia was present in 42.3% of 71patients with WD at the time of diagnosis.9 In the studyof van Wassenaer-van Hall et al.,7 16 of the 28 symp-tomatic patients had neurologic symptoms, 18% of

TABLE 3. Frequency of magnetic resonance imaging (MRI)cranial lesions in patients with Wilson’s disease with (n =

10) and without dystonia (n = 17)

Structure

Patients withdystonia(n 4 10)

Patients withoutdystonia(n 4 17) P value

Gray matterGlobus pallidus 6/10 (60%) 7/17 (41%) n.s.Putamen 8/10 (80%) 4/17 (24%) P < 0.05Nucleus caudatus 1/10 (10%) 3/17 (18%) n.s.Thalamus 3/10 (30%) 2/17 (12%) n.s.Nucleus ruber 1/10 (10%) 1/17 (6%) n.s.Substantia nigra 4/10 (40%) 6/17 (35%) n.s.Subthalamic tegmental

region 2/10 (20%) 4/17 (24%) n.s.Claustrum region 3/10 (30%) 5/17 (29%) n.s.

White matterFrontal 3/10 (30%) 2/17 (12%) n.s.Parietal and temporal 0/10 (0%) 1/17 (6%) n.s.Dorsal mesencephalon 1/10 (10%) 3/17 (18%) n.s.Central mesencephalon 0/10 (0%) 0/17 (0%) n.s.Pons 1/10 (10%) 3/17 (18%) n.s.Cerebellar hemispheres 3/10 (30%) 2/17 (12%) n.s.

n.s., not significant.

FIG. 1. Proton density (a) and correspondent T2-weighted (b) axial magentic resonance (MR) image of a 35-year-old female patient with multifocaldystonia at the level of basal ganglia demonstrates linear high signal intensity in lateral aspect of putamen (so-called “peripheral putamen sign”)andin globus pallidus bilaterally.

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whom had predominantly dystonic symptoms. Neverthe-less, Starosta-Rubinstein et al.4 reported the highest fre-quency of dystonia in their clinical assessment of 31patients with WD, where dystonia, after dysarthria (pre-sent in 97% of patients), was the most common neuro-logic finding (65%).

Dystonia was among initial clinical signs in four pa-tients and developed later in the course of the disease insix patients, despite the administered therapy for WD.Also, we were not able to confirm retrospectively fromthe medical charts any substantial improvement of dys-tonic movements ($ 2 points) during the treatment. Thisis in accordance with the statement that an improvementin virtually all facets of clinical dysfunction in WD mayoccur with appropriate treatment, although tremor andcerebellar signs seem to improve more readily than dys-tonia, while the fixed smile and dysarthria may show noimprovement.10 However, at no time in the course of thedisease the presence of specific neurologic symptomswas a guide to the status of anti-copper therapy.5

The distribution of dystonia in our patients is differentfrom the distribution in 20 dystonic patients with WDdescribed by Starosta-Rubinstein et al.4 These authorsfound multifocal dystonia in 64% of patients in compari-son to 20% in our series, followed by generalized dys-tonia, which affected half of our patients.

Putamen was the only brain region in our study thatwas significantly more frequently lesioned in dystonic(80%) in comparison to WD patients without dystonia(24%;P < 0.05; Table 3). In different studies, an abnor-mal lentiform nucleus was found in 36% to 72% of pa-tients with WD.4,7,11 Recently, King et al.12 interpretedbasal ganglia to be abnormal in 19 of 25 (76%) patientswith WD, with the involvement of putamen in all of themand with abnormalities in the globus pallidus, caudate,and thalami occurring in about half of these cases. OnMR images, abnormal signal intensity was described inthe outer rim of the putamen immediately adjacent to theextreme capsule and claustrum.11,12Correlation betweenthe presence of abnormal neuroimaging findings andpresence of neurological symptoms has been establishedin some studies11,13,14but not in others.15,16Resolutionof MRI lesions after continuing chelating therapy (D-penicillamine, trien), long-term oral zinc therapy, or fol-lowing liver transplantation has been reported,11,12,17,18

frequently associated with clinical improvement. Twogroups of patients in this investigation (dystonic andnondystonic ones) were similarly treated and had similarduration of treatment (6.6 and 5.0 years, respectively).As in our study (Table 3), several reports suggested arelation between abnormalities in the putamen and dys-tonia in WD.4,8,11,19For instance, in their clinical assess-

ment of 31 patients with WD, Starosta-Rubinstein et al.4

found that dystonia and bradykinesia correlated with pu-taminal lesions and dysarthria correlated with both pu-taminal and caudate lesions.

The role of the basal ganglia damage in dystonia hasbeen firmly established. Putaminal lesions are the mostfrequent cause of hemidystonia or, less frequently, limbdystonia.20–22Even some patients with idiopathic dysto-nia have a T2 signal alteration in the putamen in high-field MRI.23 However, in some cases it is difficult andoversimplified to establish the most relevant lesion, sincedescriptions of cranial dystonia associated with putam-inal lesions have also been reported.24,25 Similarly tosymptomatic dystonia related to focal brain lesions, ourresults may suggest that the structural basis of dystoniain WD mainly lies in the basal ganglia-thalamocorticalmotor circuits. For instance, in dystonia, basal gangliadysfunction may result in an inability to target inhibitionto opposite sets of cortical neurons, thus producing ex-cessive motor output, particularly during movement.26

In conclusion, dystonia was a frequent finding (37%)in a group of patients with WD and optimized, chronictreatment. The distribution of dystonia was generalizedin half of our patients. Putamen was more frequentlylesioned on MRI in dystonic in comparison to WD pa-tients without dystonia, suggesting relation between ab-normalities in this brain region and dystonic movementsin WD. Finally, we are in favor of suggesting that MRIabnormalities are obligatory in neurological form of WDand allow interesting anatomoclinical correlations.11

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