Movement Disorders Vol. 18, No. 5, 2003, pp.

539 550 2003 Movement Disorder Society

Executive Cognitive Decits in Primary Dystonia

Richard B. Scott, MSc, PhD,1,2* Ralph Gregory, FRCP,2 Joanna Wilson, BA,1 Sarah Banks, BA,1 Anna Turner, D Clin Psy,1,2 Simon Parkin, MRCP,2 Nir Giladi, MD,3 Carol Joint, RGN,2 and Tipu Aziz, MD, FRCS2
1 Russell-Cairns Unit, Radcliffe Inrmary, Oxford, United Kingdom Oxford Movement Disorder Group, Radcliffe Inrmary, Oxford, United Kingdom 3 Movement Disorders Unit, Department of Neurology, Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel 2

Abstract: Primary dystonia is a disorder of movement for which no consistent pathophysiology has been identied; in the absence of evidence to the contrary, it is assumed to be cognitively benign. We have studied a clinically heterogeneous group of 14 patients with primary dystonia on a battery of neuropsychological tests. Despite well-preserved speed of information processing, language, spatial, memory and general intellectual skills relative to normal controls, we have identied a constellation of attentional executive cognitive decits on the Cambridge Neuropsychological Test Automated Battery

(CANTAB). Specically, patients demonstrated signicant difculties negotiating the extra-dimensional set-shifting phase of the IED task. The implications of these ndings for the pathophysiology of primary dystonia are discussed. This is, to the best of our knowledge, the rst report of a signicant cognitive decit in patients with primary dystonia. 2003 Movement Disorder Society Key words: primary dystonia; neuropsychology; executive decits

Dystonia is a common, but clinically heterogeneous, disorder of involuntary movement characterised by sustained muscle contractions and an array of twisting, repetitive movements and/or abnormal posture. It may be classied according to age at onset, distribution (i.e., generalised, focal, or segmental) and aetiology (i.e., idiopathic/primary or symptomatic/secondary). Syndromes where dystonia is the sole phenotypic manifestation have been classied as primary rather than idiopathic; this group would therefore include dystonia with no known cause and those where a genetic abnormality has been identied.1 Fahn and colleagues1 also propose dystoniaplus and heredodegenerative classications, and a secondary classication to replace symptomatic, for dystonia that develops as a result of known or presumed environmental insult to the brain.

*Correspondence to: Dr. Richard B. Scott, Russell-Cairns Unit, Neurosciences Directorate, Radcliffe Inrmary, Oxford, OX2 6HE, United Kingdom. E-mail: rbs@neuropsyche.net Received 28 May 2002; Revised 23 September 2002; Accepted 14 October 2002

It is well established that cognitive sequelae are associated with heredodegenerative dystonia (i.e., Parkinsons disease, multiple system atrophy, progressive supranuclear palsy),2 and secondary dystonia (i.e., multiple sclerosis, Creutzfeldt-Jakob disease, head trauma). In the absence of any evidence to the contrary, however, it is widely held that neither general intellectual, nor more selective cognitive impairment, are characteristic features in early or advanced stages of primary dystonia. A review of the literature yields only one explicit investigation of the issue of cognitive impairment in, for example, spasmodic torticollis (ST),3 though other studies have had the opportunity to identify any impairment by virtue of pre-operative neuropsychological screening,4 or the investigation of medication effects.5,6 In addition, there have been reports of patients with ST or hereditary torsion dystonia, where below average intellectual ability was queried in patient subgroups.7,8 With an uncertain pathophysiological substrate, primary dystonia has been treated, with mixed success, in a variety of ways including botulinum toxin injections (to weaken the dystonic muscles), surgical denervation procedures, drug therapy (i.e., anticholinergics, benzodiazepines, L-dopa, and haloperidol), and behavioural ther-

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R.B. SCOTT ET AL. any temporal or causal relationship between the injuries and the onset of dystonic symptoms. Three cases were therefore classied as, potentially, secondary dystonia and excluded from the analysis reported here. In addition, one other case was excluded as her medical history included the previous placement, and then removal, of bilateral GPi stimulators, and we have previously observed cognitive sequelae after bilateral GPi lesions.13 Seven men and 7 women (mean age, 36.9 years) with a diagnosis of primary dystonia remained to be included in the analysis. All but 3 patients (with mixed/shifted dominance) were right-handed. Tables 1 and 2 include all 14 patients demographic and neurological details including age of symptom onset, distribution and aetiology as recommended by Fahn and colleagues.1 Patients IQs, psychological symptomatology, levels of pain and functional disability, treatment history and current medication for each case, are also presented. Assessment Protocols The neuropsychological assessment protocol is routinely employed in the Russell-Cairns Unit to clinically screen patients before functional neurosurgery. The core components of this protocol have been described in detail elsewhere,17 although the battery has evolved to shorten and rene the pencil and paper component of psychometric tests and to include additional computerised tests of attentional executive and spatial functions. The complete protocol includes a semi-structured clinical interview, and patientrated questionnaire measures of psychological symptomatology [Hospital Anxiety and Depression Scale (HADS)] and quality of life measures (Medical Outcomes Trust UK SF-36). Both patient and carer-rated questionnaires of functional disability are also obtained on the UK version [i.e., the Functional Limitations Prole (FLP)] of the Sickness Impact Prole (SIP).18 The primary psychometric assessment measures were ve subtests drawn from the CANTAB battery of computerised tests19 that is designed to examine attention, spatial and executive cognitive functions; before their administration, all patients successfully completed the motor screening subtest of CANTAB to conrm adequate motor function to perform the rest of the battery. Intra/extra-dimensional set-shifting. This task is a decomposition of the Wisconsin Card Sorting Test. Subjects learn a series of nine two-alternative, forced-choice discriminations using feedback provided automatically by the computer. Throughout the task participants are required to discover rules, initially through trial

apy (where there were thought to be psychogenic factors). More recently, a renaissance in functional neurosurgery for the treatment of Parkinsons disease (PD), and developments in the understanding of basal ganglia circuitry thought to be implicated,9 have led to a reexamination of the efcacy of pallidotomy,10,11 and pallidal stimulation12 in the treatment of dystonia. Though these procedures have been associated with improvements in dystonic movements and motor function for up to 3 months, there have been no reports in the literature of outcome measures that include a cognitive audit, despite evidence that bilateral pallidotomy in PD causes a selective and reliable decit in attentional executive cognitive function,13 and other reports of more or less severe dysexecutive syndromes after bilateral pallidal stimulation for PD.14 16 We began a prospective clinical investigation of outcomes from bilateral Globus Pallidus interna (GPi) stimulation in a consecutive series of patients with dystonia. This case series has included a routine audit of neurological, neuropsychological, psychiatric and quality of life domains at pre-operative baseline and 6 months post-operatively. In the course of this audit, a comprehensive assay of cognitive domains showed an unanticipated baseline neuropsychological prole, which will be reported here. PATIENTS AND METHODS Patient Series We initially studied 8 men and 10 women with various presentations of dystonia and a mean age of 36 years. The clinical presentation and medical histories of each patient were reviewed by the referring neurologists to conrm the most appropriate classication of dystonia. There was no evidence to suggest any cases of dystoniaplus or heredodegenerative dystonia, but the question of whether a number of patients were suffering from secondary dystonia was apposite. For example, one had an episode of slurred speech and sensory disturbance 10 years before she presented with ST; magnetic resonance imaging (MRI) brain scanning identied scattered white matter lesions consistent with a diagnosis of multiple sclerosis, although the potential relationship between the two diagnoses was uncertain. In a second case the dystonia had progressed rapidly over 3 years and MRI showed diffuse small white matter lesions of uncertain signicance. Three cases had medical histories including whiplash and concussion, although in 2 of these (Cases 12, 13; see Table 2) there was no suggestion of

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TABLE 1. Neurological and quality of life proles on Patients 110 who failed ed-shift on the CANTAB IED task (Group 1)
Patient no. 1 36 91 21 No Yes Yes No Yes Yes Yes Yes Id. Gen. N.T. M.D. M.D. (9)a None Diaz Mirtazapine, Madopar, Clonaz Migraine Baclofen, BT, Diaz None Benzhexol, Baclofen Clonaz, Sinemet Benzhexol, Tetraben Yes Yes Tort. No Yes Yes No Yes Id. Gen. N.T. 24.8 44.4 No Yes Yes Yes Yes Yes Yes Yes DYT1 Gen. DYT1 38.9 44.4 (19)a (8)a Amantine, Benzhexol, Clonaz None Tetraben, Fluoxetine, Mirtazepine None BT, Sulpiride, Pergolide, Sinemet CR/; Baclofen, Benhexol Tetraben, Clonaz No No Lat. Scoliosis DP DP No No Id. Gen. Negative 10.7 66.7 Yes Yes Yes Yes Yes Yes Yes Yes DYT1 Gen. DYT1 33.3 100 No No Yes No No No No No Id. Focal Negative 11 22.2 (9)a Yes No Yes Yes Yes Yes Yes Yes Id. Gen. Negative M.D. M.D. 52 128 34 30 100 15 28 98 2 20 112 7 47 111 42 39 113 36 34 91 30 Yes No Yes Yes Yes Yes Yes Yes Id. Gen. Negative 37.1 25 2 3 4 5 6 7 8 9 41 105 19 Yes Yes Yes No Yes Yes Yes Yes DYT1 Gen. DYT1 16.4 66.7 10

23 73 16

Age (yr) SPM IQ Onset age (yr) Symptom Mouth Speech-swallow Neck Trunk R arm L arm R leg L leg Aetiology Distribution DYT1 status FLP Total SF-36 Pain HADS Anxiety HADS Depression Current medication Amitrip BT

No Yes Yes Yes Yes Yes Yes Yes Id. Gen. N.T. 25.4 22.2 (10)a

BT, benzhexol, Sinemet

Medical history BT, L-dopa, Propan, Primidone, Clonaz

None

None

None Benzhexol

None Benzhexol, Tetraben, Madopar

EXECUTIVE COGNITIVE DEFICITS IN PRIMARY DYSTONIA

Treatment history

Baclofen, Tetraben

Writers cramp as a child BT

Baclofen, Benzhexol, Clonaz, BT, Dantrolene, Diaz Gastrostom y, feeding tube Vigabatrin

Caseness SPM IQ, Standard Progressive Matrices Intelligence Quotient; Tort., torticollis; Lat., laterocollis; Id., idiopathic; Gen., generalised; N.T., not tested; FLP Total, % Functional Limitations Prole, Total % Disability Score; M.D., missing data; HADS, Hospital Anxiety and Depression Scale; D.P., dystonic posturing; BT, Botulinum Toxin; Amitrip, Amitriptyline; Clonaz, Clonazepam; Diaz, Diazepam; Tetraben, Tetrabenazine; Propan, Proanolol.

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TABLE 2. Neurological and quality oife proles of Patients 1114 who passed the ed-shift stage of the CANTAB IED task (Group 2)

Patient no. Age (yr) SPM IQ Onset age (yr) Symptoms Mouth Speech-swallow Neck Trunk R arm L arm R leg L leg Aetiology Distribution DYT1 status FLP Total SF-36 Pain HADS Anx HADS Dep Medication Medical history 38 115 12 No No Yes No Yes Yes No No Id. Segmental N.T. 6.7 66.7 None

11 44 130 36 No No Yes No No No No No Id. Focal N.T. 13.8 22.2

12 48 130 15 Yes No Yes Yes Yes Yes Yes Yes Id. Gen. Negative 16.5 44.4 Aspirin, BT

13 31 100 7 No No Yes No Yes Yes Yes No Id. Gen. Negative 7.5 44.4 (11)a (8)a BT None

14

Alcohol abuse

(8)a Carbamaz, Amitrip, Caitalopram, Dihyd Depression, alcohol abuse, whiplash injury several years before dystonia Benzhexol, BT, Amtrip Baclofen, Analgesics

Treatment history

Madopar, Sulpiride, Chlord, Clonaz, Benzhexol, BT

Ulcerative colitis, ileorectal anastomosis, DVT, anticardiolipin antibodies, concussion. L-dopa, Benzhexol, Baclofen, Olanzepine

Artane, Tetraben, Sinemet, Baclofen Carbamaz, Clonaz

Caseness SPM IQ, Standard Progressive Matrices Intelligence Quotient; Id., idiopathic; Gen., generalised; N.T., not tested; FLP Total, % Functional Limitations Prole, Total % Disability Score; HADS, Hospital Anxiety and Depression Scale; Carbamaz, Carbamazapine; Amitrip, Amitriptyline; Dihyd, Dihydrocodeine; BT, Botulinum Toxin; Chlord, Chlordiazepoxide; Clonaz, Clonazepam; Tetraben, Tetrabenazine.

and error. For example, the rst stage of the test requires the participant to make a simple visual discrimination between two abstract stimuli. Touching the correct stimulus is rewarded whereas if the participant touches the wrong stimulus they are informed that their selection was incorrect. Once the rule is achieved on six consecutive occasions the computer establishes a new rule. At each stage of the test two sets of visual stimuli are displayed. Two critical shifts occur during the test, one at the sixth rule change when subjects must shift to new exemplars of the most recent dimension (i.e., intradimensional shift) and a second at the eighth rule change where subjects must shift to a second dimension (i.e., extradimensional shift equivalent to a shift of set in the Wisconsin Card Sorting Test). Due to the graded nature of this task the most obviously useful metric is the number of categories achieved by the subject. A second outcome metric that has proven popular with users of the CANTAB system is the total number of occasions upon which the subject fails to select the correct stimulus. Because subjects who fail to complete the test do not have the opportunity to make as many errors as those that do, however, an adjustment is made to the total error score

based on the total number of possible errors that can be made at levels not reached, less a correction for trials correct by chance. Reaction time. This a relatively brief (i.e., nine trials) test of reaction time in which the subject must release a home button and then touch whichever of ve target stimuli has been indicated on the touch-screen. Metrics traditionally examined on such tasks may, for example, include 1) speed of response (latency); and 2) errors, either of omission (e.g., failures to respond) or commission (anticipations and decision errors). Before beginning the trial phase of this task, participants are given practice trials in which they rst master simple release of the home button, progressing to full versions of the task in which the home button is released to record RT and then the screen is touched to record movement time. All trials for which a correct response was recorded were included in the calculation of individual mean performance. The measures reported here were mean simple and ve choice, reaction, and movement latencies.

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EXECUTIVE COGNITIVE DEFICITS IN PRIMARY DYSTONIA Spatial working memory. This task measures ability to remember locations (distributed on the touch-screen) previously visited, and devise a self-ordered search strategy. Participants are rst shown an array of three boxes and are told that in one of these boxes they will nd a token reward. They are also informed that once they have found a token, it will not be found again at the same location and they will have to search other boxes in the array to nd the remaining tokens. The task progresses in difculty from three boxes, up to the most difcult stage of eight boxes. Within each trial, the number of occasions upon which the subject revisited a box in which a reward token had already been found on that particular trial (between errors) is recorded. A strategy score is measured by recording the number of occasions a subject begins a trial at the same location as previous searches on the current trial, as this approach is thought to reect an efcient organisational strategy for optimal performance. Spatial span. In this test of non-verbal working memory, analogous to the Corsi block-tapping test, subjects are required to monitor and recall a sequence of blocks. The test begins by testing immediate recall of a sequence of two spatial locations. Success at this and subsequent stages allows subjects to progress to later levels of the test, up to a maximum sequence of nine spatial locations. Subjects are permitted a maximum of three attempts at each level of the test. The outcome metric recorded for this test is the maximum sequence length correctly recalledthe subjects maximum span. Stockings of Cambridge. This is a modied version of the Tower of London spatial planning task that allows for the measurement of both speed and accuracy. Participants are shown a split screen with a set of three stockings displayed at the top of the screen and again in the bottom half of the screen. The top half of the screen shows the location of coloured balls within the stocking array in a goal state. The bottom half of the screen contains the same number of coloured balls in a start state. Participants are instructed to make the bottom half of the screen look like the top half of the screen, in as few moves as possible, by moving coloured balls from one stocking to another. A variety of outcome measures from this test have been evaluated by different authors, including time taken to make the rst move of the sequence (initial thinking time), time taken to make remaining moves in the sequence (subsequent

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thinking time) and the number of occasions upon which the subject completes the problem in the minimum number of moves (minimum move solutions). We selected the third of these measures for our evaluation as we wished to measure the efciency with which our subjects completed trials on this test. Rapid Visual Information Processing Test. A continuous performance test of vigilance. We selected two summary measures for this test. A is the signal detection measure of sensitivity to the target, regardless of response tendency; in essence a measure of how good the subject is at detecting the target sequences using the probability of a hit and probability of a false alarm. B is the signal detection measure of the strength of trace required to elicit a response; the tendency to respond regardless of whether the target sequence is present (and also using the probability of a hit and probability of a false alarm). In addition to CANTAB, other psychometric tests were administered to obtain measures of premorbid and non-verbal IQ and screen other cognitive domains (i.e., language and spatial functions, auditory attention, praxis, speed of information processing and memory/new learning ability). These tests included the National Adult Reading Test (NART), Ravens Standard Progressive Matrices (RSPM), the Symbol Digit Modalities Test (SDMT), the Stroop Test, the Trailmaking test (TM), tests of categorical and phonemic verbal uency, the Boston Naming Test (BNT), the Judgement of Line Orientation test (JOLO), the Speed of Comprehension subtest taken from the Speed and Capacity of Language Processing test (SCOLP), the Recognition Memory Test (RMT), the story recall subtest from the Adult Memory and Information Processing Battery (AMIPB), the Digit Span (DS) subtest taken from the Wechsler Scales, and both copy and recall administrations of the Medical College of Georgia Complex Figures (CF); all tests are described and referenced in standard compendia and the literature.20 28 All psychometric tests were administered to patients in the same sequence and according to standardized manuals and protocols. The scores presented in Table 3 include raw scores for verbal uency, JOLO, CF and BNT, standard scores for SCOLP, RMT, DS (mean 10; SD 3) and RSPM and NART IQs (mean, 100; SD, 15); all other scores are Z-scores. Control data were obtained from the appropriate manuals and references. In the case of CANTAB, raw scores were transformed into Z-scores with reference to the most closely matched sample (minimum N 30) in terms of age, NART IQ and gender,

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TABLE 3. Differences between patients who achieved (Group 2), and failed (Group 1) ed-shift
Whole group n Age (yr) FLP Total functional disability (%) FLP alertness category (%) CFLP Total functional disability (%) CFLP alertness category (%) HADS anxiety (raw) HADS depression (raw) SF-36 Pain (%) 14 36.9 20.1 20.0 19.3 8.7 7.7 5.6 49.5 Group 2 (ed-shift attainment) 4 40.5 11.1 5.9 14.0 9.3 7.2 5.7 44.4 Group 1 (ed-shift failure) 10 35.4 24.7 20.0 21.6 8.7 8.6 5.6 52.4

Values are expressed as mean scores. SF-36 norms based upon the Oxford Healthy Life Survey 19911992, Oxford, UK. N 7245 with no GP consultation in the last 2 weeks.

drawn from a pool of over 700 normal subjects (175 for RVIP). Statistical Analysis Data were entered into SPSS v. 10 (SPSS Inc., Chicago, IL) for analysis. A one-sample t test was employed to test the null hypothesis of no difference between obtained test scores and the control means for each test. Contingency tables were prepared and Pearsons 2 analysis was employed to compare percentage e-shift failure rates, on the IED task, between clinical groups and controls. An independent samples t test was employed to examine the equality of means in patient subgroups (Group 1 and Group 2); Levenes test for equality of variances identied those instances where equal variances could not be assumed. Subsequent analyses included Pearson and Spearman correlation coefcients to examine covariance between parametric and non-parametric variables, respectively. A Bonferroni correction (0.00151) was applied to the data. Given the relatively limited sample size, the exploratory nature of the study, and our concern to avoid making a type 2 error, a relatively conservative of 0.01 is illustrated in Table 4. RESULTS Patient Series: Pain, Functional Disability, and Psychological Symptoms Tables 1, 2, and 3 illustrate that relative to normative control data (with an approximate mean of 4% FLP Total functional disability), our rened sample of 14 patients with primary dystonia registered relatively high levels of self (20.1%; range, 6.738.9, 0 100 where 0 good health) and relative-rated (19.3%; range, 3.750.3) total functional disability. Mean self-rated pain was also high (SF-36 Pain subscale 49.5, 0 100 where 100 equals good health) relative to over 7,000 normal controls who had no GP consultation in the previous 2 weeks in the

19911992 Oxford Healthy Life Survey (mean SD, self-rated pain 84.6 18.8); there was also a considerable range of individual scores. Group mean questionnaire (HADS) rated symptoms of anxiety and depression were below caseness (i.e., scores 8 10), though 4 individuals were at caseness for anxiety (raw scores 10 19), and 4 were at caseness for depression (raw scores 8 9). Mean verbal and non-verbal IQs were average. Patient Series: Cognitive Proles Table 4 illustrates the detailed neuropsychological prole of the 14 cases with primary dystonia. Group mean scores on all pencil and paper tests sensitive to cognitive domains including verbal and non-verbal IQ (RSPM and NART), memory/new learning ability (RMT, AMIPB paragraph recall and complex gure recalls), speech and language (verbal uencies, BNT and SCOLP), spatial skills (CF copy and JOLO), and auditory attention span (digit span) were in the average range. Group scores on tests of visual selective attention/speed (Stroop) and speed of information processing (SDMT) were in the low-average range. Although a number of group mean scores on these tests were up to approximately 1 SD below the control mean, none was signicantly impaired. Within this context of preserved general intellectual skills, and applying an of 0.01, the 14 selected patients scored signicantly below the control mean on the following measures: IED stages reached, IED total adjusted errors, IED total adjusted trials, ed-shift errors, the SWM strategy score, simple RT movement latency, and the written administration of the SDMT. It was of particular interest that 10 of the 14 patients failed specically at the ed-shift stage of the IED test; a 10/14 binomial probability at a failure rate for normal controls of 0.12, yields P 0.000000019. Having applied a Bonferroni correc-

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TABLE 4. Neuropsychological proles of patients with primary dystonia relative to control means
Cognitive domains N IQ SPM (ss) NART (ss) Speech-language Verbal uency, phonemic (rs) Verbal uency, categorical Boston naming, number correct (rs) Scolp, speed of comprehension (ss) Attention, executive Digit span (ss) SDMT, oral/written Stroop Trailmaking, A/B RVIP A/B CANTAB soc min move solutions CANTAB IED, % (ed-shift achieved) CANTAB IED total trials (adjusted) CANTAB IED total adjusted errors CANTAB errors (up to ed-shift) CANTAB errors (ed-shift) CANTAB simple/ve-choice movement time CANTAB simple/ve-choice reaction time Memory RMT, faces (ss) RMT, words (ss) Amipb story, IR/DR Complex gure, IR/DR (rs) Spatial Jolo (rs) Complex gure, copy (rs) Cantab spatial span Cantab swm (between errors) Cantab swm (strategy) All patients 14 106.9 96.1 37.4 19.5 37 8.8 9.5 0.9/1.6a 1.2 0.4/0.4b 0.7/0.6 0.5 28.6a 1.3b 1.3b 0.1 1.6a 1.2a/1.1 0.9/0.2 8.2 10.9 0.5/0.6 21.9/21.3 24.6 33.1 0.5 0.6 0.7b Group 1 (ed-shift failure) 10 102 91.6 33.1 17.3 35.4 7.7 8.0 0.9/1.7a 1.3 0.3/.3b 1.0/1.0 0.8 0 1.8a 1.9a 0.2 2.4a 1.6a/1.0 1.3/0.4 8.6 11.5 0.6/0.8 23.1/21.7 23.3 34.7 0.9 1.1 0.9b Group 2 (ed-shift pass) 4 118a 106 49 25 40.5a 10.7 13.2 0.4/1.6 0.8 0.6/0.5 0.6/0.1 0.2 100 0.5 0.3 0.1 0.3 0.43/1.3 0.2/0.2 7.7 9.7 0.3/0.3 19.7/20.6 27.7 29.9 0.2 0.3 0.2 100 15 100 15 36/33/43 (nart predicted) 17.3 5 35.4 4.4 10 3 10 3 01 01 01 01 01 12% 01 01 01 01 01 01 10 3 10 3 01 NA 25.6 3436 01 01 01 Population

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Values are expressed as mean Z scores, unless otherwise stated. a P 0.001; bP 0.01. RS, raw score; SS, standard score (mean 100, SD 15); SS, scaled score (mean 10, SD 3); NA, not available.

tion (0.00151), only the written administration of the SDMT, IED stages reached, and ed-shift errors achieved statistical signicance. SF-36 and FLP questionnaire ratings of physical disability or pain did not signicantly co-vary with performance on any cognitive measure. Written SDMT and movement latency in RT are those measures within the battery with the highest loading on grapho-motor skills (and speeded dexterity more generally), and therefore, decits in these domains were likely to be accounted for by the physical disability of some of the patients. Eleven patients had dystonic symptoms or posturing in the dominant hand, and 3 had shifted functional dominance as a result of their impaired dexterity. The CANTAB IED and SWM tests where patients also demonstrated signicant difculties, however, do not require speeded dexterity for an adequate performance, and no signicant correlation was found between simple RT movement latency,

the written administration of the SDMT, SWM strategy and IED scores. Furthermore, there was no signicant correlation between the SWM scores and IED scores (i.e., that might suggest some commonality in the cognitive decits identied). DISCUSSION The detailed neuropsychological assessment of this group of 14 clinically heterogeneous patients with primary dystonia, has showed a selective prole of attentional executive cognitive impairment on the IED, and possibly also the SWM, tasks taken from the CANTAB battery. It is of particular interest that over 71% of the patient series failed at the extra-dimensional set-shifting (ed-shift) phase on the IED task compared to a 12% failure rate on rst administration in a normal control population (N 200).29 More selectively, normal controls within the age range 24 to 39 years with NART IQs

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TABLE 5. Distribution of CANTAB decits by disease
Parkinsons disease Unmed.* Mild med.**
a

Severe med.***
a

MSA
a

PSP
a a a a

FTD

PFL
a

HD

Primary dystonia

Primary dystonia ed-shift failure

a

SS SWM SOC IED

()
a

a a

a a a a a

*Mean disease duration 1.5 years, mean H&Y 1.93. **Mean disease duration 7.07 years, mean H&Y 1.8. ***Mean disease duration 10.2 years, mean H&Y 3.43, FTD mild. a Decit of same measure as reported here. Med, medicated; MSA, multi-system atrophy (mean disease duration 6 years); PSP, progressive supranuclear palsy; FTD, fronto-temporal dementia; PFL, pre-frontal lesions; HD, asymptomatic but genetically at risk Huntingtons Chorea; SS, spatial span; SWM, spatial working memory strategy score; SOC, stockings of Cambridge minimum move solutions; IED, ed-shift adjusted error rate or ed-shift failure rate; , decits on CANTAB subtest measures other than those specied here.

of 105 demonstrate an 11% failure rate, whereas those with IQs in the 110 to 120 range have only a 4% failure rate. All 10 patients who failed to achieve ed-shift, negotiated the preceding stages 1 to 7 (including the intradimensional set-shifting phase) without difculty and had a comfortably average error rate until encountering the ed-shift, where their error rate became signicantly impaired. Although patients performance on the strategic search measure from SWM was not signicantly discrepant from normal controls when a Bonferroni correction was applied, there was a trend toward impairment on this measure, suggesting that patients failed to devise or employ an efcient organisational strategy in their searches. Unlike the other essentially continuous psychometric measures in the test battery, the attainment of ed-shift (within pre-dened trial constraints) represents a conceptually critical marker of ability. Therefore, in addition to the neuropsychological proles of the whole case series, Table 4 also presents the neuropsychological proles of the 4 patients who achieved edshift (Group 2) and the 10 who failed (Group 1). Patients in Group 2 had a higher mean IQ, though the difference did not achieve statistical signicance. Further, there was 1 patient with an RSPM IQ in the superior range, and 3 patients with IQs in the high-average range in Group 1, and 1 patient in Group 2 with an average IQ (see Tables 1 and 2). Nevertheless, the trend across a range of tests, for scores to be better in Group 2 than Group 1, may reect higher IQs in the former group. There were no signicant differences between the test scores of Groups 1 and 2 in any domain other than IED test measures. The case series also performed poorly on those tests in the battery selectively sensitive to dominant hand dexterity and speed of movement, though these decits were not correlated with the IED and SWM decits. Further,

the cognitive component of each of the measures implicated, was not impaired. Namely, although simple RT movement time was impaired (i.e., time from lifting hand to touching screen stimulus) simple and complex RTs were not signicantly different from the control population. Similarly, patients were impaired on the written but not the oral version of the SDMT. It is unclear, and outside the scope of this paper to determine whether these decits in speeded dexterity reect bradykinesia in primary dystonia,9 arm reaching more specically,30 or more general functional disability. However, nearly 78% of the case series had dystonic symptoms or posturing in the preferred hand, and there were three instances of shifted hand-preference secondary to disability. There is now an extensive literature detailing the sensitivity of the CANTAB neuropsychological test battery to disorders involving the basal ganglia and frontostriatal circuitry. The battery has for example been used to fractionate executive decits associated with PD, frontotemporal dementia (FTD), Huntingtons disease (HD), progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and following neurosurgical lesions to prefrontal cortex (PFC).2,3135 Variation in the available CANTAB subtest measures utilized, clinical populations, design and methodology between these various studies precludes the detailed comparison of neuropsychological proles, but some general patterns are discernible (Table 5). Impairments in performance on the IED task have been identied in patients with both mild (un-medicated), mild (medicated) and advanced PD, MSA, PSP, HD, and PFL; additional decits in the strategy score of SWM have been seen in PFL and PSP. Although there is some evidence to suggest that there may be qualitatively different reasons for ed-shift failure between clinical groups and some may also demonstrate difculties with earlier conceptual phases of the task,36

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EXECUTIVE COGNITIVE DEFICITS IN PRIMARY DYSTONIA the percentage ed-shift failure rate is a relatively straightforward metric that enables some cross-group comparisons. Thus, a 38% failure rate in patients with PD37 compares with failure rates of 40% in patients with MSA38 and 50% in patients with PFC lesions.34 More recently, we have found that bilateral surgical lesions to GPi in patients with advanced PD universally and selectively extinguished their ability to negotiate the ed-shift phase of the IED task that had been successfully demonstrated before surgery. In the same study, a 47% edshift failure rate was reported in 37 patients with a carefully conrmed diagnosis of advanced PD studied pre-operatively. Further, neither unilateral GPi lesions, nor either unilateral or bilateral STN lesions or stimulation were found to be reliably associated with ed-shift failure.13 In the light of these ndings, and a failure rate in normal controls of only 11 to 12%, the 71.4% ed-shift failure rate identied in this series of 14 patients with primary dystonia is surprisingly high. Perusal of the neurology, disability, demography, and psychological symptomatology of individual patients that comprised Groups 1 and 2 (in Tables 1 and 2) does not suggest any consistent characteristics to differentiate ed-shift success (i.e., Group 2) from failure (i.e., Group 1). Individual cases of both average and above average IQs were well represented in both groups, and all individual CANTAB Z-scores were referenced to robust control groups matched for age, gender, and IQ. Table 3 illustrates that there were also no signicant differences between Groups 1 and 2 in terms of age, questionnaire measures of functional disability, alertness, psychological symptoms or pain; though, there was a trend toward more functional disability in Group 1, and more selfreported cognitive difculties (i.e., the FLP alertness sub-category). The small numbers of those passing edshift, however, makes it likely that there was insufcient power to show any real differences between these two groups on these measures. Although probably inadequate to explain elevated ed-shift failure rates, other differences between the groups included the following: all 3 conrmed cases of DYT1 deletion fell in Group 1, but there were 4 that were negative and 3 who had not been genetically screened; in Group 2 there were 2 who had not been screened and 2 who tested negative. Potentially psychoactive medications were distributed throughout the case series. No consistent anatomical pathology has been identied for primary dystonia, but it is now well established that most lesions responsible for secondary dystonia involve the basal ganglia or thalamus. Indeed in a meta-analysis of 240 patients with basal ganglia lesions and movement disorders, 36% were found to

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have dystonic symptoms, with the putamen and globus pallidus the most frequently affected sites in these cases.39 A range of cognitive and behavioural decits were also seen in this series, and there have been a number of other reports of either naturally occurring, or surgical lesions of the basal ganglia being associated with cognitive and behavioural sequelae, particularly of the dysexecutive type.15,16,39 42 As far as possible, the series of 14 patients reported here excluded any potential cases of secondary dystonia, where ed-shift failure might be explained by the index brain insult. Nevertheless, of the 3 cases with suspected secondary dystonia, 1 failed and 2 passed edshift; the 1 additional case where there had been previous placement of GPi stimulators also failed edshift. Therefore in an undifferentiated group of 18 patients initially presenting with dystonic symptoms, 66% who were initially screened neuropsychologically, failed to achieve ed-shift In the absence of any evidence in the literature to suggest the contrary, patients with primary dystonia have previously been assumed to be cognitively intact; indeed they have effectively been used as cognitively normal control subjects in studies of the effects of medication.6 In a detailed neuropsychological study, Taylor and colleagues6 evaluated a group of 20 cognitively intact patients with dystonia on a battery of psychometric tests of explicit memory, procedural learning, visuo-spatial and executive functions. Relative to an age- and IQ-matched normal control group, there were no signicant differences on any of 20 neuropsychological measures (before the administration of anti-cholinergic medication). In the one study we have been able to identify that explicitly investigated the cognitive status of patients with ST, the neuropsychological focus was primarily upon visuo-spatial functions.3 The possibility that decits identied might be secondary to, or associated with, other cognitive decits or psychological/physical problems was not evaluated, and could not therefore be entirely ruled out. Nevertheless, this study concluded that the patients performance on various visuo-spatial tasks was signicantly inferior relative to an age-matched control population. Interestingly, the authors went on to consider, and then dismiss, the possibility that visuo-spatial decits might be secondary to mental set-shifting, and note reports of similar visuo-spatial decits in patients with PD and HD suggestive of basal ganglia or frontostriatal dysfunction. In a recent review of the pathophysiology of primary dystonia, Berardelli and colleagues9 conclude that avail-

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R.B. SCOTT ET AL. extent PET scanning, might limit the subgroups of patients that could be studied to more focal and hypokinetic clinical presentations. In this respect, given the similar regional patterns of metabolic abnormality (i.e., increased activity in the lentiform nuclei, cerebellum and supplementary motor cortex) that have been identied in movement-free DYT1 carriers with and without clinical manifestations,46 if asymptomatic DYT1 carriers were also found to have abnormally high ed-shift failure rates, then they would represent an ideal cohort for further investigation of the neurophysiological substrate of extradimensional set-shifting ability with fMRI or PET scanning. Such a study might also inform the question of percentage DYT1 penetrance from a neuropsychological perspective. The ndings reported here may prove to be of further clinical signicance when complete data are available on outcome after bilateral GPi stimulation. Seven of the 14 patients in this series have been re-examined on the CANTAB battery. Three of these 7 passed ed-shift pre-operatively, and all but 1 passed again after post-operative clinical optimisation of stimulation parameters. Interestingly, the 1 patient who failed ed-shift after surgery (having previously passed), had a very poor clinical outcome and there was evidence to suggest that he had, against advice to the contrary, increased the rate of stimulation to exceptionally high levels. Of the 4 other patients who failed ed-shift pre-operatively, 2 passed and 2 failed (again) after surgery. The numbers here (particularly of those who failed ed-shift pre-operatively) are too small to offer any denitive conclusions, but further investigations are underway to determine whether edshift failure predicts clinical outcome, and whether GPi stimulation improves the performance of patients with primary dystonia on the IED task. The signicance of difculties negotiating the IED task for activities of daily living has not been established in the extensive CANTAB literature. The fact that patients with primary dystonia have not subjectively reported, or been observed clinically, to manifest cognitive difculties with sufcient consistency or regularity to prompt a detailed study of this issue to date, suggests that the decit is subtle and perhaps not signicantly disabling in everyday life, at least not to an extent more functionally salient than the disorder of movement. Nevertheless, with the possible exception of mild unmedicated PD, the inability to pass ed-shift has invariably been seen in neurological conditions where there are well-established cognitive, and sometimes personality, sequelae with a signicant impact on everyday life. One hypothesis would be that in a

able evidence suggests it is associated with a functional, rather than structural, disturbance of the basal ganglia, and that there is an emergent common theme in disparate research of reduced inhibition at different levels of the motor system. For example, interpreted within the anatomical model of information ow in parallel segregated neuronal circuitry in cortico-striatal-pallidal-thalamocortical loops43 a common nding in animal44 and human models of dystonia is underactive (inhibitory) GPi output. For example, intraoperative recordings of neuronal activity in the GPi of patients with primary dystonia have also suggested that there is a reduction and irregularity in ring rates and a widening of sensory receptive elds.45 Given our previous observation that bilateral GPi lesions in patients with PD invariably leads to a selective loss of extra-dimensional set-shifting ability on the IED task,13 the ndings reported here of an abnormally high, selective, 71.4% ed-shift failure rate in primary dystonia lends neuropsychological support to the hypothesis that a bilateral reduction (or less specic disturbances) in GPi output are associated with clinically heterogeneous presentations (i.e., focal or generalised) of primary dystonia. Given the relatively small sample and the fact that difculties on the IED task may also be associated with, for example, psychiatric conditions, a cautionary note must be sounded, however, until our ndings have been replicated on larger groups of patients with primary dystonia. It would be oversimplistic to equate failure of inhibition within the neurophysiological substrate of the motor system, with the kind of dysexecutive failure of inhibition that can underlie a poor performance on set-shifting cognitive tasks. As we noted previously in relation to our observation of an association between the loss of extra-dimensional set-shifting ability and bilateral ablation of the motor circuit in GPi,13 an elevated ed-shift failure rate in patients with (what was previously thought to be) a pure movement disorder, raises intriguing questions about the presumed dissociation between movement and cognition at the neuronal and functional levels. Without further studies to evaluate the performance on CANTAB of much larger subgroups of patients with primary dystonia (i.e., manifesting vs. unaffected carriers of the DYT1 gene; focal vs. generalised), it would be premature to overemphasise the signicance of difculties negotiating the ed-shift phase of the IED task as a common or differential marker for primary dystonia. Functional and metabolic studies would also be indicated to explore the pathophysiological signicance of this decit in primary dystonia, although anticipated difculties with movement artefact in fMRI, and to a lesser

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EXECUTIVE COGNITIVE DEFICITS IN PRIMARY DYSTONIA substantial proportion of patients with primary dystonia (i.e., those with DYT1 deletions), the cognitive skill expressed by extradimensional set-shifting ability on IED might never be reliably acquired, so there would be no subjective awareness of change.
Acknowledgments: We thank M.N. Scott sine qua non, A. Mehmet of Maracis Solutions, Ltd., for assistance with data management and analysis, P.E. McKnight for help in formatting, Cambridge Cognition for technical support, and Dr. A. Lloyd of MEDTAP for statistical advice. CANTAB is available from Cambridge Cognition, Vision Park, Histon, Cambridge.

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