Bilateral, pallidal, deep-brain stimulation in primary generalised dystonia: a prospective 3 year follow-up study

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1 Bilateral, pallidal, deep-brain stimulation in primary generalised dystonia: a prospective 3 year follow-up study Marie Vidailhet, Laurent Vercueil, Jean-Luc Houeto, Pierre Krystkowiak, Christelle Lagrange, Jerôme Yelnik, Eric Bardinet, Alim-Louis Benabid, Soledad Navarro, Didier Dormont, Sylvie Grand, Serge Blond, Claire Ardouin, Bernard Pillon, Katy Dujardin, Valérie Hahn-Barma, Yves Agid, Alain Destée, Pierre Pollak, and The French SPIDY Study Group* Summary Background We have previously reported the efficacy and safety of bilateral pallidal stimulation for primary generalised dystonia in a prospective, controlled, multicentre study with 1 year of follow-up. Although long-term results have been reported by other groups, no controlled assessment of motor and non-motor results is available. In this prospective multicentre 3 year follow-up study, involving the same patients as those enrolled in the 1 year follow-up study, we assessed the effect of bilateral pallidal stimulation on motor impairment, disability, quality of life, cognitive performance, and mood. Methods We studied 22 patients with primary generalised dystonia after 3 years of bilateral pallidal stimulation. We compared outcome at 3 years with their status preoperatively and after 1 year of treatment. Standardised video recordings were scored by an independent expert. Data were analysed on an intention-to-treat basis. Findings Motor improvement observed at 1 year (51%) was maintained at 3 years (58%). The improvement in quality of life (SF-36 questionnaire) was similar to that observed at 1 year. Relative to baseline and to the 1 year assessment, cognition and mood were unchanged 3 years after, but slight improvements were noted in concept formation, reasoning, and executive functions. Pallidal stimulation was stopped bilaterally in three patients because of lack of improvement, technical dysfunction, and infection, and unilaterally in two patients because of electrode breakage and stimulation-induced contracture. No permanent adverse effects were observed. Interpretation Bilateral pallidal stimulation provides sustained motor benefit after 3 years. Mild long-term improvements in quality of life and attention were also observed. Introduction Severe forms of primary dystonia causing marked motor and social impairments in patients with normal cognitive functions respond poorly to medical treatment. Bilateral pallidal neurostimulation has been shown, in both controlled 1,2 and open-label studies, 3 7 to improve motor symptoms, motor disability, and quality of life without cognitive or affective adverse effects. 8,9 A sustained benefit of pallidal stimulation has been reported in small groups of patients with primary generalised dystonia 10,11 or cervical dystonia, 10,12,13 and also in a large open-label study, 3,6 but long-term efficacy and safety remains to be ascertained. The aim of this prospective multicentre study was to assess the effect of bilateral pallidal stimulation on motor impairment, functional disability, quality of life, cognitive performance, and mood 3 years after in patients with primary generalised dystonia. We also prospectively recorded adverse effects and health-care consumption. Methods Participants 22 patients with primary generalised dystonia treated by means of bilateral pallidal stimulation were monitored for 3 years in this prospective multicentre study. The same patients had already been assessed, with similar methods, both before and 1 year postoperatively. 1 The patients were analysed preoperatively (baseline) and at 1 year and 3 years postoperatively, and were compared at these three different time points. During neurostimulation they were assessed while taking their usual treatments. Procedures The movement and disability subscores of the Burke- Fahn-Marsden dystonia scale 14 were used to assess the effects of neurostimulation. Patients were videotaped according to a standard protocol 1 and the recordings were scored by an independent expert using the movement subscale of the Burke-Fahn-Marsden dystonia scale. Results were analysed on an intention-to-treat basis. The total number of hospital visits over the 3 year study period was recorded (patients were advised to return to the hospital when needed, but only the visits at 1 year and 3 years were part of the protocol). Cognitive function was assessed with the mini-mental status examination (MMS), 15 the progressive matrices of Raven PM 38, 16 the similarities and arithmetic subtests of the revised Wechsler adult intelligence scale (WAIS-R test), the Grober and Buschke test, 17 and the Wisconsin card sorting test. 18 Mood was assessed with the Beck depression inventory. 19 Healthrelated quality of life was assessed with a validated French version of the medical outcomes study 36-item short-form general health survey questionnaire (SF-36). 20 Cognitive Lancet Neurol 2007; 6: Published Online January 31, 2007 DOI: /S (07) See Reflection and Reaction page 201 *Members listed at end of report INSERM U679, Neurology and Experimental Therapeutics (E Bardinet PhD, J Yelnik MD, M Vidailhet MD, Y Agid MD), Department of Neurology (M Vidailhet, B Pillon PhD, V Hahn-Barma PhD, Y Agid), Centre d Investigation Clinique (Y Agid), CNRS UPR 640 Cognitive Neurosciences and Brain Imaging (E Bardinet), Department of Neuroradiology (D Dormont MD), and Department of Neuro (S Navarro MD), Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Department of Biological and Clinical Neurosciences (C Ardouin PhD, P Pollak MD, L Vercueil MD, C Lagrange PhD), Department of Neuroradiology (S Grand MD), and Department of Neuro (A-L Benabid MD), Grenoble University Hospital, INSERM Unité 704, Joseph Fourier University, Grenoble, France; Neurology and Movement Disorders Unit (K Dujardin PhD, P Krystkowiak MD, A Destée MD) and Department of Neuro (S Blond MD), Lille University Hospital, Lille, France; and Department of Neurology (J-L Houeto MD), Poitiers University Hospital, Poitiers, France Correspondence to: Marie Vidailhet, Université Pierre Marie Curie Paris 6, Paris F-75012, France marie.vidailhet@sat.aphp.fr Vol 6 March

2 function, mood, and quality of life had been assessed in a similar manner before and after 1 year of followup. The localisation of the therapeutic contacts was determined on the postoperative MRI of each patient using a single procedure, which consists of the fusion of an anatomic atlas 21 with the MRI of each patient according to a three-dimensional atlas-mri coregistration method, described previously. 22 The study was approved by the ethics committee of Salpêtrière University Hospital and all patients gave their written informed consent. Statistical analysis The results were analysed on an intention-to-treat basis. Data are reported as mean (SD). The scores on the movement and disability subscales of the Burke-Fahn- Marsden scale, and the neuropsychological, mood, and quality-of-life assessments at 3 years were compared with the scores preoperatively and at 1 year by use of the Wilcoxon signed-rank test for matched pairs. A pair was the same individual but at a different time (eg, 3 years vs baseline). p values below 0 05 were deemed to indicate statistical significance. Role of the funding source The funding sources had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Results Table 1 summarises the clinical characteristics of the patients. Median age at was 30 years (range years), median age at onset of dystonia was 8 years (5 38 years), and the median duration of the disease was 18 5 years (4 37 years). Seven patients had the DYT1 mutation in the torsin A gene (Oppenheim dystonia). After 3 years of follow-up, 17 patients were still receiving bilateral pallidal stimulation and two patients were receiving unilateral pallidal stimulation (figure 1). Neurostimulation had been interrupted bilaterally in three cases. All 22 patients who entered the study could be assessed after 3 years. The effects of pallidal stimulation on dystonia and disability in the 22 patients, assessed with the movement and disability subscales of the Burke-Fahn-Marsden dystonia scale before and 1 and Case Sex Age* Duration Initial DYT1 Movement score Disability score Treatments Preoperative 1 year 3 years Preoperativive 1 year 3 years Preoperative 1 year 3 years 1 F F _ BZD Anti-SP BZD+anti-SP 2 M F _ F 5 10 LL _ THP 45 mg+bzd THP 40mg THP 45 mg 4 F UL _ DA DA+BZD DA+BZD 5 M LL _ THP 10 mg THP 4mg THP 6 mg 6 M 38 4 UL _ THP 30 mg+bzd THP 30 mg+bzd THP30 mg+bzd 7 M LL _ BZD BZD 8 F UL _ THP 6 mg+bzd THP 4mg+BZD BZD 9 M 7 9 UL _ THP 15 mg+tbz BZD+anti-SP 10 F 8 26 UL _ BZD 11 F 7 26 LL _ THP 10 mg+bzd THP 10 mg+bzd 12 F 8 11 LL _ THP 20 mg+bzd THP 20 mg+bzd THP 6 mg+bzd 13 F UL _ M 8 10 LL _ TRP 30 mg TRP 15mg TRP 7 5 mg 15 M 6 18 LL _ THP 20 mg+tbz THP 20 mg+tbz THP 20 mg 16 F 9 9 UL THP 15 mg+anti-sp THP 15 mg+ anti-sp 17 M 7 29 UL BZD+TBZ BZD BZD 18 M 8 32 UL BZD BZD+anti-SP BZD+anti-SP 19 F 8 18 LL THP 15 mg+anti-sp THP 12 mg THP 6 mg +BZD+anti-SP 20 M 5 17 UL BZD + anti-sp+tbz BZD BZD 21 F 7 23 LL THP 40 mg +BZD+TBZ THP 15 mg+bzd THP 10 mg+bzd 22 M 9 21 UL THP 150 mg +BZD+anti-SP THP 30 mg +BZD+anti-SP THP 30 mg+bzd The first symptom of the disease affected the face (F), an upper limb (UL), or a lower limb (LL); no patient had initial trunk involvement. W=woman. M=man. THP=trihexyphenidyl. TRP=tropatepine. BDZ=benzodiazepines. Anti-SP=antispastic drugs (dantrolene, baclofen). TBZ=tetrabenazine. DA=dopaminergic drugs (levodopa or bromocriptine). Table 1: Clinical characteristics of the patients and their movement and disability scores of the Burke-Fahn-Marsden dystonia scale before and 1 and 3 years after Vol 6 March 2007

3 3 years after, are summarised in figure 2 and table 2. Overall, the motor improvement observed at 1 year was maintained at 3 years, with respective mean improvements in the movement score of 51% and 58%. The total movement scores (p=0 03) and the subscores for the upper and lower limbs were significantly better at 3 years than at 1 year (table 2). Overall, the improvement in quality of life observed at 1 year was maintained at 3 years (p=0 05). Relative to preoperative status, the SF-36 questionnaire showed improvements in general health (p=0 02), physical functioning (p=0 008), and pain (p=0 01) after 3 years of follow-up (table 3). Cognition (MMS, WAIS-R tests) and mood (Beck depression inventory) were unmodified at 3 years relative to baseline and 1 year (table 4). The significant improvement in concept formation and reasoning (Raven PM 38) observed at 1 year was sustained after 3 years. Memory (free recall and total recall of the Grober and Buschke tests) was similarly improved at 1 and 3 years relative to preoperative status (p<0 05). Executive functions, measured with the Wisconsin card sorting test total errors, were further improved at 3 years relative to the results at 1 year (table 4). Patients were invited to attend the hospital if they felt an inadequate clinical benefit or experienced adverse effects. Six patients attended the 1 year and 3 year protocol visits only. Two-thirds of the additional visits (28 outpatient visits and 13 brief hospital stays) were related to the usual follow-up of the medical treatment. Botulinum toxin was injected once in three patients to control local pain in the neck or arm. This did not affect the pattern of dystonia and did not modify the assessment of the effect of neurostimulation done at distance from the injection. One patient was treated for laryngeal dystonia every 6 months with mild subjective improvement. One visit was related to transient depression. The other visits were related to the battery or simulation settings control and adjustment. 3 years postoperatively, the simulation settings were similar to those reached after 1 year of follow-up. 29 electrodes were set at 130 Hz, six at 185 Hz, and one at 140 Hz. One contact was used for 24 of the 36 electrodes and two contiguous contacts were used for the other 12 electrodes (monopolar stimulation). At 3 years the mean voltage was 3.8 V (SD 0 7) and the pulse width was 127 µs (SD 107); these values were not significantly different from those reached at 1 year. 18 visits (including 15 hospital stays) were related to the implants and battery life. The battery had to be replaced twice in two patients (at 23 and 35 months) and once in seven patients (between 24 and 36 months). In one case the battery was replaced before complete energy failure because of a risk of life-threatening recurrent dystonia. Five patients had adverse events including three serious adverse events and two stimulation-related adverse events. There were no permanent neurological sequelae. The three patients with serious adverse events had unilateral lead fractures (patients 2 and 6) and one infection (patient 11). Patient 11 developed an infection in the parietal region at the connection between the electrode and the extension lead and the material was Bilateral arrest 13 months Bilateral arrest at patient s request Absence of effect 29 months Bilateral stimulation arrest Infection: ablation of implanted material 22 patients received bilateral p allidal stimulation 22 patients followed up at 1 year 22 patients assessed at 3 year follow-up 14 months L stimulation arrest Lead breakage 19 months L stimulation arrest Lead breakage (battery failure at 3 years) 26 months L stimulation arrest Worsening of dysarthria Unilateral stimulation Figure 1: Follow-up chart Details of patients who were no longer bilaterally stimulated at 3 years (number of patients and causes of stimulation arrest). All 22 patients were assessed at the 3 year follow-up visit. Movement scale score Disability scale score * * * * Before 1 year 3 years Figure 2: Burke-Fahn-Marsden dystonia scale before and 1 and 3 years after Data are means. Vertical bars represent SEM. *p<0 001 for the comparison with the preoperative score. Vol 6 March

4 Before 1 year after 3 years after baseline) p (3 years vs 1 year) Movement scale (range) Axis: neck and trunk (0 24) 12 5 (7 9) 3 9 (4 1) 4 4 (5 09) < Limbs: lower, upper (0 64) 28 5 (16 3) 13 6 (12 2) 11 8 (13 5) < Face: eyes and mouth (0 16) 2 1 (2 5) 1 3 (2 1) 1 3 (2 0) Speech and swallowing (0 16) 2 8 (3 9) 2 2 (2 8) 2 1 (3 1) Total 46 3 (21 3) 21 0 (14 1) 19 8 (17 4) < Disability scale (range) Speech (0 4) 1 3 (1 3) 1 3 (1 3) 1 4 (1 3) Writing (0 4) 2 0 (1 1) 1 2 (0 9) 1 2 (0 7) Feeding (0 4) 1 6 (0 9) 0 5 (0 7) 0 5 (0 7) Eating and swallowing (0 4) 1 1 (1 0) 0 5 (0 7) 0 3 (0 6) Hygiene (0 4) 1 4 (0 8) 0 5 (0 7) 0 6 (0 9) Dressing (0 4) 1 3 (0 9) 0 5 (0 8) 0 5 (0 8) Walking (0 6) 3 0 (1 6) 2 0 (1 5) 1 9 (1 5) Total 11 6 (5 5) 6 7 (5 2) 6 3 (4 9) Data are mean (SD). A reduction in scores indicates an improvement in dystonia. Table 2: Effect of bilateral pallidal stimulation on Burke-Fahn-Marsden subscores at 1 and 3 years after Before 1 year after 3 years after baseline) General health 47 (24) 63 (27) 64 (21) Physical functioning 41 (28) 62 (29) 68 (32) Role physical 53 (43) 58 (39) 69 (37) Role emotional 59 (48) 77 (37) 71 (39) Social functioning 57 (36) 58 (29) 63 (30) Body pain 39 (32) 56 (36) 61 (25) Vitality 40 (24) 50 (24) 47 (21) Mental health 54 (20) 64 (23) 58 (21) year) Data are mean (SD). The possible score range is An increase in scores indicates an improvement in function. Table 3: Health-related quality-of-life subscores (SF-36) before and 1 and 3 years after thus removed. After an initial improvement with antibiotic treatment, scalp erosion occurred and the infection spread to the electrodes. There were no neurological repercussions, but the entire implant had to be removed 29 months after initial. The patient s motor performance returned to its preoperative status. In patient 6, the left lead was found to have fractured after 18 months of follow-up and battery failure was observed at the 3 year protocol visit. The battery was replaced. In patient 2, the left electrode was fractured but was not replaced because the beneficial effect on dystonia persisted. In the two patients who experienced stimulation-related adverse events, pallidal stimulation was stopped either bilaterally (patient 14) or unilaterally (patient 10). Patient 14 had no improvement, despite correct placement of the electrodes in the posterolateral part of the internal pallidum, and requested that the stimulator be switched off 1 year postoperatively. In patient 10, worsening of speech difficulties and tonic postures of the affected limb necessitated a reduction and then an interruption of stimulation by one electrode. Overall, the beneficial effect of neurostimulation on dystonia persisted. The therapeutic contacts of the electrodes (figure 3) were localised in the globus pallidus internus or the internal medullary lamina (in 95% of the cases). In the three patients for whom an active contact was selected in the globus pallidus externus, the corresponding electrode had no contact available in the globus pallidus internus. In these patients, the contralateral active contact was localised in the globus pallidus internus or internal medullary lamina. Examination of the distribution of all the therapeutic contacts did not reveal any association between contact localisation and clinical outcome (data not shown). Discussion In these patients with primary generalised dystonia treated by means of bilateral pallidal stimulation, the substantial improvement in motor symptoms and disability observed at the initial 1 year follow-up examination (51% improvement of movement score) was maintained after a total period of 3 years (58%). Because these percentages of improvement are based on an intention-to-treat analysis and because 17 of the original 22 patients were still receiving bilateral stimulation at 3 years, the benefit of bilateral pallidal stimulation probably exceeds 58%. The improvement in quality of life observed at 1 year persisted at 3 years. As observed after 1 year of follow-up, the benefits of stimulation varied between patients. No clinical or genetic characteristics have been shown to predict the degree of postoperative improvement in this setting. 1,2 The latter could potentially be affected by individual characteristics, such as the surgical procedure (location of the electrodes within the anatomical target) or the pattern of dystonia. The variability in the response to treatment between patients has been observed, 1,2 despite the electrodes being placed in the appropriate posterolateral part of the pallidal target. Moreover, the distribution of all the therapeutic contacts (figure 3) determined by the atlas-mri coregistration procedure did not reveal any obvious association between contact localisation and percentage of improvement of dystonia severity. One hypothesis would be that, even in groups of patients with primary dystonia, the heterogeneity and complexity of the pathophysiological mechanisms underlying the expression of the disease could account for the variability of the therapeutic effects. In line with this hypothesis, and although no consensus has been obtained on the subject because of lack of standard criteria for classifying the patterns of dystonia, the patients who had little improvement tended to have severe tonic posturing. In contrast, those who had phasic hyperkinetic movements 1 or a pattern of electromyographic activity with repeated bursts 23 could have a greater or earlier response to pallidal stimulation Vol 6 March 2007

5 All motor assessments, based on standardised videos, were done by the same independent examiner during the 3 year study period. Although we had done a doubleblind assessment with optimum safety conditions in patients who have been stimulated only for 3 months, 1 we were reluctant to undertake a double-blind cross-over design (stimulation off vs on) in the same patients chronically stimulated for 3 years, for several reasons. First, we did not know whether the effects of stimulation arrest for a short-term period (10 h) and after a short period (3 months) of stimulation could be similar to the effects of stimulation arrest for a longer period (2 3 days) and after a prolonged period (3 years) of stimulation. Second, pallidal stimulation might have a post-effect on dystonia lasting several weeks 24 and we could not be sure that a period of 2 3 days in the off stimulation condition could be sufficient to return to the preoperative state. This point should be specifically studied in the future. Moreover, a life-threatening rebound event can occur 1 and has mainly been described in chronically stimulated patients. Finally, the main objective of the study was to assess the long-term effect of pallidal stimulation and not to show, as has recently been done, 2 the effectiveness of neurostimulation compared with sham stimulation. Therefore, the chosen study design, despite its potential limitations, was selected for reasons of safety and ethics. Other studies 3,6,10,12,13,25 showed no significant further improvement after 1 year, 10 with a mean follow-up of 2 years 3,6,10 or 3 years 11 in patients with generalised dystonia and cervical dystonia. 10,12,13,25 The improvement has been reported to persist for up to 5 years in individual patients. 6 An attempt to explain why the improvement of movement disability reached a plateau would be that a relatively crude technique such as deep-brain stimulation might not be able to deal with all the complex neural dysfunction related to dystonia. One strength of our study is the prospective assessment of cognitive functions and mood. We, 8 and others, 9 have reported that pallidal stimulation does not adversely affect cognition. We found that, after 3 years of follow-up, cognitive test results were still stable relative to those obtained at 1 year, while some were even mildly improved (concept formation and reasoning, memory, and executive functions). A reduction in the use of drugs with potentially adverse effects on cognition could not fully explain these results. The doses were already substantially decreased at the 1 year visit and the subsequent decrease of doses at 3 years follow-up was not very important (table 1). In keeping with the slight further improvement in dystonia and motor performance observed at 3 years relative to 1 year, we think that this improvement in attentional capacities could be related to a reallocation of cognitive resources previously invested in motor control. However, a test learning phenomenon might also have contributed to this mild improvement. The improvement in quality of life at 1 year and at 3 years was mainly observed on general health, physical Before 1 year after 3 years after functioning, and body pain components, in close relation with the improvement of motor control, as previously reported. 2,9 The absence of beneficial effect on social functioning and role-emotional could be associated with psychological factors such as self-esteem and social participation, as in patients with cervical dystonia. 26 It is important to note that the persistent improvements in motor and cognitive performance at 3 years were obtained with the same settings as those used at 1 year. Previous reports on the management of cervical 13 or generalised dystonia 6 have shown little or no need for further programming after 6 9 months. The stimulator was routinely replaced after 2 3 years in nine of our patients, whereas ten patients were still treated with the initial neurostimulator at 3 years of follow-up, in keeping with reported stimulator life expectancy in this setting. 6,11,13,25 By contrast with some previous reports, 10,27 no rebound event and no acute relapse of dystonia was observed when the neurostimulator was replaced, but these are rare events. Nevertheless, a close monitoring of the battery, and when possible, a scheduled replacement should be undertaken before the complete exhaustion of the generator. Most adverse events were hardware-related, and mainly consisted of unilateral or bilateral interruption of neurostimulation because of lead fracture. The baseline) MMS 27 8 (2 3) 28 2 (1 8) 28 3 (1 8) Raven PM 38 Raw score 38 4 (13 3) 39 6 (11 8) (10 7) WAIS-R subtests Similarities 10 2 (2 8) 11 6 (3 8) 11 2 (3 2) Arithmetic 7 8 (3 6) 8 2 (3 5) 8 4 (3 6) Grober & Buschke test Free recall 31 7 (5 8) 33 9 (7 3) 34 3 (5 5) Total recall 44 2 (8 1) 47 2 (1 1) 47 5 (0 8) Recognition 15 6 (1 4) 16 0 (0 0) 16 0 (0 0) Delayed free recall 12 3 (2 1) 12 3 (1 7) 12 8 (2 03) Delayed total recall 15 2 (2 5) 15 9 (0 2) 16 0 (0 0) Wisconsin card sorting test Number of categories 4 8 (1 4) 5 3 (1 5) 5 7 (0 7) Perseverative errors 2 3 (1 6) 2 8 (4 0) 1 1 (1 8) Maintaining errors 1 6 (1 0) 1 0 (1 7) 0 60 (1 1) Total errors 10 3 (7 4) 7 3 (8 6) 3 4 (4 0) < Verbal fluency Literal 10 8 (6 0) 9 5 (4 9) 11 3 (4 3) Category 19 8 (9 3) 17 5 (6 8) 20 0 (8 9) Beck depression inventory 11 3 (7 0) 8 3 (7 9) 7 8 (8 0) Data are mean (SD). Table 4: Cognitive and mood scores before and 1 and 3 years after 1 year) Vol 6 March

6 A B PC+0 5 PC % 50 75% 25 50% 0 25% PC 1 PC 1 5 PC+3 5 PC 4 5 Figure 3: Localisation of therapeutic contacts PC=posterior commissure. A: Fusion of a MRI section of a patient with the corresponding horizontal section of the atlas (PC 0 5). The therapeutic contacts are in the internal globus pallidus, bilaterally. B: Localisation of the therapeutic contacts in the 21 patients, as determined by the three-dimensional atlas-mri coregistration method. The percentage of clinical improvement is indicated by a coloured scale (blue=0 25%; green=25 50%; pink=50 75%; and red=75 100%). The dorsoventral level of the atlas sections is given with reference to the posterior commissural point. implanted material was removed in one case because of an infection. The patient s dystonia returned to its preoperative state, but there were no procedure-related or infection-related sequelae. Hardware-related events such as lead fractures, erosions, and infections have been described in up to 25% of patients with functional. 28 This relatively high risk of lead fracture in dystonia 2,29 might be related to some persistence of abnormal axial movements leading to more mechanical stress of the implant. The most frequent stimulation-related adverse event is worsening of voice intelligibility and freezing of speech. 2,4,11 13 This adverse effect, associated with stiffening of the dystonic arm, limited the therapeutic efficacy in one of our patients and was probably related to current diffusion to corticobulbar and spinal tracts (concomitant tonic postures of the limb could be elicited by increasing voltage to the therapeutic setting). Overall, the various adverse events account for the 2 8% rate of complications reported for deep-brain stimulation 29,30 and the overall rate of hardware-related complications of 4 3% per electrode year. 30 A close followup of dystonia patients should be recommended both for prevention (advice on potentially at-risk activities, anticipation of the battery end-of-life) and rapid adequate treatments (drugs, adjustment of parameter settings, infection, battery or leads replacements). In conclusion, this prospective 3 year follow-up study of 22 patients with primary generalised dystonia shows a sustained benefit of bilateral pallidal stimulation, and, in some cases, a further mild improvement in limb disability, quality of life, and attention relative to the results at 1 year. When the optimum therapeutic settings are determined within the first year, few if any changes are needed and most patients need to be seen only one to four times a year. Infections and hardware-related adverse events are the most frequent long-term problems and must be closely monitored. Contributors YA, AD, JLH, PK, CL, PP, LV, and MV participated in the conception of the study. CA, KD, DD, SG, VH-B, JLH, PK, and CL gathered and analysed the data, including (AB, SB, SN) and neuroanatomy (EB, JY). EB, JLH, PK, CL, PP, LV, MV, and JY participated in the redaction of the paper. All authors have seen and approved the final version. Conflicts of interest AB, SB, AD, and YA have received unrestricted research grants from Medtronic through INSERM. All other authors have no conflicts of interest Vol 6 March 2007

7 Acknowledgments This study was supported by a national grant (PHRC 98 and CIRC 2005) from the Direction Régionale de la Recherche Clinique (DRRC) Assistance-Publique-Hôpitaux de Paris, the INSERM French National Dystonia Network, GIS Maladies Rares, and an unrestricted grant from Medtronic, Minneapolis, Minnesota. We thank the doctors, nurses and technicians from the Centre d Investigation Clinique Salpêtrière for their very efficient work. Members of the French SPIDY Study Group Neurologists: Grenoble, France: Olivier Detante, Valérie Fraix, Pierre Pollak, Laurent Vercueil. Paris, France: Yves Agid, David Grabli, Jean-Luc Houeto, Valérie Mesnage, Marie Vidailhet, Marie-Laure Welter, Pierre Césaro. Lille, France: Luc Defebvre, Alain Destée, Pierre Krystkowiak. Neurosurgeons: Grenoble, France: Alim-Louis Benabid, Stephan Chabardes, Adnan Koudsie. Paris, France: Philippe Cornu, Soledad Navarro. Lille, France: Serge Blond, Gustavo Touzet. Intraoperative neurophysiologists: Grenoble, France: Abdelhamid Benazzouz. Paris, France: Bernard Pidoux. Lille, France: François Cassim. MRI specialists: Grenoble, France: Sylvie Grand, Jean-François Le Bas. Paris, France: Didier Dormont. Lille, France: Jean-Pierre Pruvo, Christine Delmaire. Neuropsychological evaluation: Grenoble, France: Claire Ardouin. Paris, France: Bernard Pillon, Valérie Hahn-Barma. Lille, France: Kathy Dujardin. Clinical Research Monitor: Grenoble, France: Christelle Lagrange. References 1 Vidailhet M, Vercueil L, Houeto JL, et al. Bilateral deep-brain stimulation of the globus pallidus in primary generalized dystonia. N Engl J Med 2005; 352: Kupsch A, Benecke R, Muller J, et al. Pallidal deep-brain stimulation in primary generalized or segmental dystonia. N Engl J Med 2006; 355: Cif L, El Fertit H, Vayssiere N, et al. Treatment of dystonic syndromes by chronic electrical stimulation of the internal globus pallidus. 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