The Influence of Deep Brain Stimulation Intensity and Duration on Symptoms Evolution in an OFF Stimulation Dystonia Study

Brain Stimulation 6 (2013) 500e505

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The Influence of Deep Brain Stimulation Intensity and Duration on Symptoms Evolution in an OFF Stimulation Dystonia Study Laura Cif a, b, c, d, *,1, Diane Ruge e,1, Victoria Gonzalez a, b, c, d, Patricia Limousin e, Xavier Vasques b, c, d, f, Marwan I. Hariz e, g, John Rothwell e, Philippe Coubes a, b, c, d a

CHRU Montpellier, Hôpital Gui de Chauliac, Service de Neurochirurgie, Montpellier F-34000, France INSERM, U661, Montpellier F-34000, France c Université de Montpellier 1, Montpellier F-34000, France d CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier F-34000, France e Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, University College London, 33 Queen Square (Box 146), London WC1N3BG, United Kingdom f IBM PSSC Innovation Lab, Center of Advanced Studies, Montpellier, France g Department of Clinical Neuroscience, Umea University, Umea, Sweden b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 10 May 2012 Received in revised form 1 September 2012 Accepted 17 September 2012 Available online 23 October 2012

Background: Deep brain stimulation (DBS) of the internal globus pallidus (GPi) is an established therapy for primary generalized dystonia. However, the evolution of dystonia symptoms after DBS discontinuation after years of therapy has only rarely been reported. We therefore longitudinally studied the main physiological measurements known to be impaired in dystonia, with DBS ON and then again after termination of DBS, after at least five years of continuous DBS. Objective: We studied whether dystonia evolution after DBS discontinuation in patients benefiting from long-term GPi DBS is different from that observed in earlier stages of the therapy. Methods: In eleven DYT1 patients treated with bilateral GPi DBS for at least 5 years, dystonia was assessed ON-DBS, immediately after switch-off (OFF-DBS1) and 48 h after DBS termination (OFF-DBS2). We studied the influence of DBS intensity on dystonia when DBS was discontinued. Results: On average a significant difference in symptoms was measured only between ON-DBS and OFFDBS1 conditions. Importantly, none of the patients returned to their preoperative dystonia severity, even 48 h after discontinuation. The amount of clinical deterioration in the OFF conditions positively correlated with higher stimulation current in the chronic ON-DBS condition. Conclusions: The duration of DBS application influences symptom evolution after DBS termination. DBS intensity seems to have a prominent role on evolution of dystonic symptoms when DBS is discontinued. In conclusion, DBS induces changing modulation of the motor network with less worsening of symptoms after long term stimulation, when DBS is stopped. Ó 2013 Elsevier Inc. All rights reserved.

Keywords: Dystonia evolution Deep brain stimulation duration Intensity and arrest

Introduction/background Chronic high frequency deep brain stimulation (DBS) of the globus pallidus internus (GPi) has demonstrated its effectiveness Conflict of interest: There is no conflict and financial interest relating to this paper. Disclosures of authors’ financial relationships: Laura Cif, Victoria Gonzalez and Philippe Coubes report having received lecture fees from Medtronic Company. Patricia Limousin and Marwan Hariz are supported by the U.K: Parkinsons Appeal, the U.K. Monument Trust and the Edmond J. Safra Philanthropic Foundation and have received occasional travel expenses and honoraria from Medtronic and St. Jude for speaking at meetings. Xavier Vasques reports no disclosures. Diane Ruge is funded by the Dorothy Feiss Scientific Research Grant. John Rothwell is funded by 1935-861X/$ e see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brs.2012.09.005

for medically intractable primary generalized dystonia (PGD) [1]. The early onset generalized forms are frequently caused by a mutation in the DYT1 gene [2] which generates a broad spectrum of phenotypes [3]. In 2000, DBS as a successful treatment for a Grant from the EU (PLASTICISE) and the Dystonia Medical Research Foundation (DMRF). * Corresponding author. Département de Neurochirurgie, Hôpital Gui de Chauliac, 80, Avenue Augustin Fliche, Montpellier 34295 Cedex 5, France. Tel./fax: þ33 4 67 33 74 64. E-mail address: [email protected] (L. Cif). 1 The two first authors contributed equally to this work and are shared first authors.

L. Cif et al. / Brain Stimulation 6 (2013) 500e505

DYT1 generalized dystonia [4] was reported, and this was subsequently confirmed by others [5]. GPi DBS has been shown to maintain its effectiveness with long term follow-up up to 10 years [6]. Up to date, there is insufficient data to conclude whether eventual loss of beneficial effect achieved with DBS might be secondary to an evolution of the disease [7] and whether an eventual role of DBS programming on the evolution of these new symptoms could be identified. A recently published study [8] showed that an additional surgical approach (i.e. implantation of additional electrodes) seemed justified in a population of 8 DYT1 patients in whom new symptoms occurred under efficient DBS therapy. Time seems to be an important factor when considering DBS treatment in dystonia. Usually, the clinical improvement in dystonia following DBS surgery is delayed and becomes apparent after hours to several months [1,9e11] due to gradual changes that occur at the depth e electrode brain interface (EBI) [12] and a significant and reversible decrease of impedances measured [13] for the activated contact. The normalization of measures of inhibition at various levels of the central nervous system [14,15] has been interpreted as a slow neural reorganization process. In dystonia, a steady state is reached at 6 months post surgery [1,9,10]. Usually no systematic or regular setting adjustments are required to maintain the clinical benefit over time after the steady state has been reached, except for patients with new symptoms or recurrence of previously well controlled symptoms [6]. There is insufficient information about the evolution of motor symptoms in dystonia after DBS discontinuation years after continuous therapy. From the rare available reports, when GPi DBS was discontinued after variable durations of DBS, symptoms reoccurred immediately after arrest of DBS, or at a later time [16], and sometimes a life-threatening rebound of symptoms may appear. DBS effects were thought to be reversible [17,18]. Whether deep brain stimulation can induce remission, thus questioning the issue of complete reversibility of DBS, has only exceptionally been asked and reported [19,20]. The variability of dystonia evolution when DBS is interrupted could be influenced by the duration of the disease prior to surgery and by the way DBS is applied. This is an important issue since it addresses the question of varying effects of DBS to induce and maintain therapeutic benefit over time in dystonia. It also explores disease progression despite efficient continuous therapy. From the therapy perspective, it addresses the question of DBS therapy management to allow the best and longest benefit also while DBS is discontinued.

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Methods Eleven patients (8 females, mean age at inclusion in this study 27.5 years, range 14e72) out of 27 with DYT1 generalized dystonia participated in this observational study, approved by the ethical committee of the University Hospital of Montpellier and conforming with the Helsinki Declaration as revised in 1989. Patients or their caretakers provided written informed consent. The selection criteria were as follows: genetically confirmed DYT1 mutation, generalized dystonia, age above 14 years, surgery with bilateral GPi DBS, follow-up of 5 years or more, and no neurological or psychiatric comorbidity. The main characteristics of the remaining 16 DYT1 patients not included in the study as well as the reasons why patients did not fulfil inclusion criteria are presented as Supplemental material (Table 1-e). Surgical procedure For the eleven patients, the stereotactic MRI-guided electrode implantation into the posteroventral GPi was performed under general anesthesia. Quadripolar electrodes (model 3389) and Soletra pulse generators model 7426 (Medtronic Neurological Division, Minneapolis, USA) were used in all but one patient in whom Kinetra model 7428 pulse generator had been implanted. The stereotactic MRI protocol for the anatomic target localization is based on pre and postoperative 1.5-T MRI (T1 and T2 sequences) [21]. Stimulation parameters All patients were under continuous therapeutic GPi DBS for a mean  SD of 7.15  2.4 years, and a maximum of 11.5 years at the time of the study. DBS was initiated in monopolar mode with one contact activated. Amplitude was progressively increased and additional contacts were activated over time according to clinical response. During the settings adjustment process, in several patients, bipolar stimulation had also been tested and different pulse width values applied (210 and 90 ms). At the time of the study patients were receiving stimulation in monopolar mode with one, two or three adjacent contacts active with the following parameters: frequency 130 Hz, amplitude up to 2.1 V, pulse width 450 ms. The current drain was obtained from the N’Vision Clinician Programmer Model 8840 (Medtronic) according to the individual electrical settings programmed for each patient. No stimulation adjustments were performed during the three months preceding this study. Clinical evaluation

Hypothesis Here, we aimed to study the global clinical evolution (i.e. change of motor symptoms) immediately following DBS arrest and 48 h later in a homogeneous group of DYT1 positive patients who are chronically benefiting from long-term bilateral GPi stimulation. Since we wished to assess the influence of the length of continuous DBS therapy on disease symptoms when stimulation is discontinued, we have chosen a duration of DBS discontinuation already reported as being safe [16] but included patients in whom DBS was administered continuously for more than 5 years. The second objective was to study whether the effective settings influence the clinical symptoms after DBS arrest. A secondary objective was to check whether population characteristics have an influence on symptoms evolution immediately at and after 48 h of DBS discontinuation.

Clinical evaluation was conducted using the movement section of the BurkeeFahneMarsden (BFM) dystonia rating scale [22] preoperatively, at one year follow-up after DBS implantation as well as at the three time points of this study (performed under strict medical monitoring during a hospital stay): in “DBS-ON"; in DBSOFF after DBS immediate (i.e. 3 h) switch-off, labeled here “OFFDBS1”; and 48 h after DBS switch-off, labeled here “OFF-DBS2” [22]. The BFM was administered by two separate raters with expertise in the field of movement disorders. Rater #2 performed a blinded evaluation on standardized videotaped sessions. Statistical analysis Statistical analysis was performed using IBM SPSS Statistics 19. Bilateral Wilcoxon signed-ranked test was used for matched pairs

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L. Cif et al. / Brain Stimulation 6 (2013) 500e505

to compare data at baseline and at twelve months post-surgery and to compare the average scores for the three assessments of the protocol. Non-parametric test was chosen because of the small sample size. To establish the level of correlation between the two raters, the Spearman correlation coefficient was used. For factors influencing the clinical change between ON and OFF stimulation conditions, a Spearman test was used for analysis of the following variables: age at onset, age at surgery, disease duration, duration of follow-up with DBS, movement scores previous to surgery, degree of clinical response with DBS (movement scores at one year followup with DBS), voltage for each side, and current drain measured in microamperes. The level of significance was set at P < 0.05. Descriptive analysis used mean  standard deviation or median  standard deviation. Results General data All eleven patients completed the study and were included for statistical analysis. The demographic and clinical characteristics of the patients are summarized in Table 1. The mean age at disease onset was 8.8  3.9 years (median 8, range, 6e20) and the mean age at surgery 20.3  17 years (median 13, range 9e65.5). The mean duration of disease prior to DBS surgery was 11.5  16.7 years (median 5, range 1.25e56.5). Evolution of the BFM movement scores after DBS discontinuation Since the level of agreement between the two raters was significant at all three time points of the protocol for ON DBS (P ¼ 0.032, Spearman test), for OFF-DBS1 (P < 0.0001, Spearman test), and for the OFF-DBS2 (P ¼ 0.001, Spearman test) conditions respectively, the median scores have been used for further analysis. The comparison between preoperative movement scores and at one year follow-up with DBS (P ¼ 0.003, Wilcoxon test) indicated initial good response to DBS therapy, which was maintained at w5 years (only patient one was assessed at 4.5 years) (P ¼ 0.003, Wilcoxon test) (Table 1). At the time of the study, the mean movement scores in ON-DBS condition were 12.5  6.9 (median, 10.75, range 3.5e24). In OFF-DBS1 condition the mean scores were 17.7  10.4 (median 16.8, range 7e43.5) and in OFF-DBS2 condition they were 23  13.7 (median 20.5, range 5.5e47.5) (Table 2). A significant difference was found between movement scores in ONDBS and OFF-DBS1 (P ¼ 0.028, Wilcoxon test) but there was no significant difference between ON-DBS and OFF-DBS2 (P ¼ 0.062, Wilcoxon test).

Nevertheless, individual evolution for the global movement scores and movement subscores for the 11 patients varied greatly between patients (Fig. 1): there was variable degree of immediate worsening of dystonia followed by stabilization in 2 patients (patients 3 and 5), progressive worsening throughout the observational period in 6 patients (1, 2, 6, 7, 8 and 10) while 3 patients remained stable over the observational period (4, 9 and 11). In patients no 6 and no 10 who had the longest follow-up of the group, we observed different patterns of worsening after DBS discontinuation. Patient no 6 had a more severe preoperative score (81 versus 63 for patient no 10) and exhibited a moderate and progressive worsening in body parts already involved by dystonia preoperatively, whereas patient no 10 exhibited a rather faster worsening of symptoms. No rebound of symptoms beyond preoperative level was seen in any of the eleven patients of the study. Equally relevant, none of the patients returned to the preoperative severity of dystonia scores even after 48 h of DBS discontinuation (Fig. 2). Therapy intensity and symptom evolution with DBS discontinued There was a significant influence of chronic DBS therapy (measured in microamperes) on the amount of clinical change when DBS was discontinued. The higher the intensity of DBS, the more severe the global worsening of dystonic symptoms was in OFF-DBS1 (intensity in right side P ¼ 0.016; intensity in left P ¼ 0.020, Spearman test) as well as in OFF-DBS2 (intensity in right side P ¼ 0.019; intensity in left side: P ¼ 0.012, Spearman test). The average of current drain for the right GPi was 81  39.2 mA and for the left GPi 106  29.8 mA. The average of current drain for the three patients in whom no worsening of dystonia occurred when DBS was discontinued was 61  11.7 mA for the right GPi and 59  5.29 mA for the left GPi. None of the other quantitative variables (age at onset, age at surgery, disease duration, duration of follow-up with DBS, movement scores prior to surgery, level of clinical response to DBS. i.e., movement scores at one year follow-up with DBS) were of relevance for the evolution of dystonic symptoms when DBS was discontinued. Discussion Evolution when DBS is discontinued In a population of DYT1 generalized dystonia patients, the switch-off of DBS after 5 years or more of continuous stimulation led to a less severe worsening of dystonic symptoms at a group level (significant difference between scores in ON-DBS and scores in

Table 1 Demographics and clinical characteristics of the patients. Patient number

1

2

3

4

5

6

7

8

9

10

11

Gender Age at onset (year) Age at surgery (year) Age at the study (year) Onset symptom Disease duration at surgery (year) Follow-up with DBS (year) Preoperative BFM scores Postoperative BFM scores at 1 year Postoperative BFM scores at best Amplitude right GPi at 1 year (V) Number of active contacts at 1 year: right GPi Amplitude left GPi at 1 year (V) Number of active contacts at 1 year: left GPi

F

F 20 25 32 LUL 5 7.5 38 0 0 1.1 1 1.1 1

M 8 35 41.5 LLL 27 6 51 23 23 0.8 2 0.9 2

M 8 9.5 14 RUL 1 4.5 89 7 5.5 1 2 1 2

F

F

F

F

F

F

9 12 18 LLL 3 5.5 40 4 4 1.4 1 1.4 1

7.5 10.5 22 LLL 3 11.5 81 0 0 1.7 1 1.7 1

9 65.5 72 RUL 56.5 6 27.5 16 5 0.9 2 1.3 2

6 9 14.5 RLL 3 5.5 42 6 0 1.5 1 1.3 1

M 6 13 21.5 LUL 7 9 69 2 0 1.4 1 1.5 1

7 14 25 RUL 7 11 63 2 0 1.5 1 1.4 1

9 10.5 15.5 Neck 1.5 5 60 5 5 1 1 1 1

6.5 19 26 RUL 12.5 7 64 0 0 1.6 1 2.2 1

RUL ¼ right upper limb; RLL ¼ right lower limb; LUR ¼ left upper limb; LLL ¼ left lower limb; F ¼ female; M ¼ male; BFM ¼ BurkeeFahneMarsden’s score.

L. Cif et al. / Brain Stimulation 6 (2013) 500e505

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Table 2 BFM scores evolution, number of activated contacts, right and left globus pallidus internus (GPi) DBS amplitude and intensity. Patient number

1

2

3

4

5

6

7

8

9

10

11

BFM ON assessment (ON-DBS) BFM OFF1 assessment (OFF-DBS1) BFM OFF2 assessment (OFF-DBS2) Amplitude right GPi (V) Number of active contacts right GPi Amplitude left GPi (V) Number of active contacts left GPi Right GPi current drain (mA) Left GPi current drain (mA)

9.5 12 28 1.5 3 1.1 1 97 127

7.5 8 9 1 1 1.1 1 57 49

24 43.5 46.5 1.7 1 1.8 1 81 118

17.5 17.5 14 1 2 1 2 79 67

4.5 22.5 25.5 1.3 3 1.3 2 153 123

3.5 7 19.5 1.7 1 2 1 121 118

22.5 23 24.5 0.5 2 1.1 2 25 94

12 16.5 20.5 1.7 2 1.6 1 100 111

16.5 13.5 13 1.1 1 1.1 1 61 59

10.5 22 47.5 1.6 3 1.3 2 144 106

8.5 8.5 5.5 1 1 1 1 57 57

BFM ¼ BurkeeFanheMasden’s scores; DBS ¼ Deep brain stimulation.

OFF-DBS1) than the worsening reported at earlier stages of DBS therapy. We did not find a significant difference between scores in ON-DBS and the 48 h OFF condition scores at a group level, probably due to larger variance in the OFF-DBS2 condition, thus making the “negative” finding not necessarily surprising. For both OFF conditions, profound differences were seen for motor evolution between patients. Naturally, given the rarity of this disease, a limitation of our study is that the sample size is relatively small. Nevertheless, it represents the total number of the DYT1 disease patients operated in our center, who fulfilled the inclusion criteria, and who accepted to participate in the study, as indicated in Table 1-e. In three patients no worsening of dystonia was recorded during the OFF-DBS state. Earlier studies focusing on patients with shorter duration of DBS treatment did not report this clinical evolution after stopping DBS. In a population of 31 PGD patients treated with GPi DBS for at least two years, Coubes et al. [1] reported on the effect of DBS discontinuation (due to unexpected IPG switch-off, or IPG removal because of infection) in a few patients with symptoms reoccurring within one week and disappearing quickly on reinstallment of stimulation. Grips et al. reported the pattern of reoccurrence of symptoms in a population of 8 patients with segmental dystonia (generalized dystonia in our group) immediately and at 2 hours after switching off DBS [23]. They found that dystonic symptoms returned sequentially with a rapid worsening of phasic components within minutes and slower worsening of the tonic component. The higher age at surgery in the population described by Grips (53.8 (14.4) years vs. 20.3  17 years in our study) could partially account for the differences recorded in the results between the two studies. The population reported by Grips and collaborators was stimulated for a shorter time (11.3 (4.2) months vs. 7.15  2.4 years in our population), a second major difference which could account for the difference of their findings. Vidailhet et al. [5] reported in 22 primary dystonia patients with GPi DBS at three months follow-up, that upon switch-off of

Figure 1. Evolution of the individual BFM movement scores during the study. BFM e BurkeeFahneMarsden scores.

stimulation, the initial pattern of dystonia reappeared in all patients. They postulated that the symptoms severity did not reach the preoperative values because of incomplete “washout” effects after only 10 h of discontinuation. Grabli et al. [16] evaluated the effect of interrupting chronic DBS for 13 patients of the previously mentioned study. They followed the clinical evolution during a DBS-OFF protocol of 48 h and found a progressive worsening of dystonia in all patients. Only 4 out of 13 patients did not return to presurgical severity of disease while off stimulation for 48 h, as illustrated by the BFMDRS scores. Significant progressive worsening was reported at the 24 h assessment with significant subsequent worsening at the 48 h assessment. Several patterns of evolution occurred and included patients, in whom dystonia worsened further, reaching preoperative level or even more severe symptoms. In our study, the results are very different: none of the patients returned to baseline severity. This could be due to differences between the two populations. Nevertheless, the study of Grabli included several DYT1 dystonia patients. Furthermore, the clinical evolution of our patients during this offeDBS period is supported by physiological data recently published in a parallel work performed in DYT1 dystonia. This study showed that plasticity measures at group level did not change when DBS was switched OFF for 48 h, suggesting that prolonged continuous DBS produced long-term neural reorganization in the motor system [24]. The pathophysiology of dystonia involves an increased associative plasticity in DBS-naïve dystonia patients which might drive DBS mechanisms and was shown to normalize on DBS at early stages [14]. At early stages (six months after GPi-DBS surgery), plasticity measures seemed to be reversible [25], but not later [24]. Our study demonstrates the different clinical evolution in a long-term DBS treated dystonia population after withdrawal of DBS which is supported by the physiological findings.

Figure 2. Evolution of the individual BFM movement scores before surgery and during the follow-up for DBS; BFM e BurkeeFahneMarsden scores; DBS-deep brain stimulation.

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The non-reappearance of dystonia in some patients may further question the complete reversibility of DBS effects in dystonia. In our study, one of the patients in whom dystonia did not worsen when DBS was discontinued presented with a dystonic storm prior to DBS surgery. Similar to the report of Hebb et al., in this patient, DBS discontinuation at earlier stages of the therapy was followed by reoccurrence of dystonic symptoms. A pallidotomy-like effect should also be considered for a lasting improvement when DBS is discontinued. One argument against this is that no lasting improvement of dystonic symptoms was noticed when DBS was discontinued three months after start of DBS as shown in another study [5]. Influence of electrical intensity on the clinical evolution in the OFF-DBS condition In our study, the intensity of chronic stimulation influenced the degree of clinical change in the OFF-DBS conditions: the higher the stimulation levels were, the greater the worsening of dystonia when DBS was discontinued. Compared to the literature, our patients had a pulse width of 450 ms, which is a larger value than usually reported in GPi DBS for dystonia. Nevertheless, it has been shown that pulse width does not have a specific influence on the clinical outcome [26]. Most often, when DBS therapy is started, side effect thresholds are tested for the active contacts and then chronic stimulation is maintained with the highest amplitude below the threshold of side effects [27], especially in patients in whom the therapeutic effect is not immediately visible but may take days to several months. Frequently, the highest amplitude to obtain the best benefit to side effect ratio is used to treat dystonia [28]. Such a high level of stimulation might in fact not be required and a therapeutical window might exist. Several reports have been published about various DBS side effects, but their mechanism remains incompletely clarified [29,30]. An intrinsic deleterious effect of high levels of stimulation should be considered, independently of the side effects linked to the stimulation of anatomical structures in the vicinity of the DBS targets (i.e., internal capsule stimulation inducing tonic muscle contractions). Inactivation of the GPi in normal non-human primates has been shown to decrease the amplitude and speed of arm movements [31]. Tisch et al. [32] reported the development of delayed onset akinesia with gait slowing in two PGD patients treated with bilateral GPi DBS. Berman et al. [33] reported bradykinesia in patients with cranial-cervical dystonia, sometimes late, after several years of DBS, which points against spread of stimulation to the corticospinal/-bulbar tracts as a cause, as this should have appeared at early stages of stimulation. Ostrem et al. reported that despite improvement in dystonia on DBS, mild worsening of motor function was reported in previously nondystonic body regions, and concluded that the influence of GPi DBS on nondystonic body regions deserves further investigation [34]. Schrader et al. [35] reported that increasing voltage improved dystonic symptoms but triggered hypokinetic gait disorder with freezing of gait. This raises the question whether in patients with chronic long term DBS, new symptoms (dystonia or hypokinetic disorders) several years after surgery are exclusively due to disease progression or represent side effects caused by high DBS levels. In our joint study on an overlapping sample after long term DBS treatment, we showed a different “electrophysiological signature” with altered dystonia hallmarks, such as plasticity responses compared to normal subjects, and compared to untreated dystonia patients, and a reduction of inhibition in GABA-ergic circuits that differed from normal subjects and from untreated dystonia patients, but (at group level) resembled that of untreated Parkinson’s disease patients [24]. Interestingly, the level of current drain of

therapeutical use was correlated also with the amount of LTP (long term potentiation)-like plasticity when DBS was ON. The higher the current drain used for therapy, the lower the level of plasticity and the higher the amount of worsening of the clinical symptoms when DBS was discontinued. Characterizing the impedance of DBS electrodeetissue interface is necessary to determine the charge delivery to the brain. This interface impedance contributes to the distribution of current density on the electrode which may influence neural excitation but also may provoke tissue damage during DBS [36]. Publications dealing with DBS settings often present the amplitude of stimulation (V) as relevant for the level of stimulation. Nevertheless, the final level of chronic stimulation for a given patient will depend on several factors, the current drain being the most significant parameter to provide information about the amount of stimulation within a target [37e39]. Could the low level of current drain chronically used in the patients who did not worsen when DBS was discontinued be due to a more precise electrode position within the therapeutical target? No correlation was found for the level of stimulation (current drain) either with the amount of individual neuroplasticity or for the localization of the active contact within the GPi [24]. Vasques et al. [40], using a 3D model of the electric field during DBS within the GPi, demonstrated that increase of the level of stimulation produces a limited increase of the electric field around the electrode: only a subvolume of the GPi has to be stimulated to provide an optimal clinical effect without necessarily covering the entire motor GPi. Hence, increasing the amplitude of stimulation will not compensate for lead misplacement. This makes the sustained relief after DBS arrest in some of the patients unlikely to be caused by simply better lead placement. On the other hand, based on the results of our study, the adaptability of DBS would allow maintaining a longer clinical benefit when DBS is discontinued by programming lower levels of current drain during DBS. These findings may have an impact on DBS programming. We have changed our routine for stimulation settings, such that a progressive increase of the amplitude of stimulation is performed until the therapeutic effect is obtained. We now aim to determine the “symptom arrest threshold” [41] and not the highest stimulation amplitude that does not induce acute side effects [1]. A lower level of DBS intensity may provide a better retention of DBS effects in dystonia. These results should encourage stimulation intensity at the threshold of beneficial clinical effect and not at a level of stimulation just below the threshold of side effects when initiating DBS therapy for dystonia. Our impression is that in several patients on continuous DBS, over time the amplitude of stimulation can even be reduced without loss of therapeutic effect which stresses the importance of re-evaluation of the patient. Here we aimed to provide valuable information concerning therapy reversibility, symptom evolution under DBS and at DBS discontinuation after years of continuous DBS. We suggest ways of programming DBS settings that might provide better management of DBS therapy with the aim of prolonging its effect beyond discontinuation. It would be of interest to determine whether a minimum duration of continuous DBS is required to prevent (partial) reoccurrence of dystonia when DBS is discontinued. In any case, the complete and systematic reversibility of DBS seems in need of reevaluation and this issue should be addressed in further studies.

Supplementary data Supplementary data related to this article can be found, in the online version, at http://dx.doi.org/10.1016/j.brs.2012.09.005.

L. Cif et al. / Brain Stimulation 6 (2013) 500e505

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