Deep Brain Stimulation for Tourette-Syndrome: A Systematic Review and Meta-Analysis

Accepted Manuscript Title: Deep Brain Stimulation for Tourette-Syndrome: a Systematic Review and Meta-Analysis Author: Juan Carlos Baldermann, Thomas Schüller, Daniel Huys, Ingrid Becker, Lars Timmermann, Frank Jessen, Veerle Visser-Vandewalle, Jens Kuhn PII: DOI: Reference:

S1935-861X(15)01227-9 http://dx.doi.org/doi: 10.1016/j.brs.2015.11.005 BRS 831

To appear in:

Brain Stimulation

Received date: Revised date: Accepted date:

29-7-2015 15-10-2015 13-11-2015

Please cite this article as: Juan Carlos Baldermann, Thomas Schüller, Daniel Huys, Ingrid Becker, Lars Timmermann, Frank Jessen, Veerle Visser-Vandewalle, Jens Kuhn, Deep Brain Stimulation for Tourette-Syndrome: a Systematic Review and Meta-Analysis, Brain Stimulation (2016), http://dx.doi.org/doi: 10.1016/j.brs.2015.11.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

1 Title: Deep Brain Stimulation for Tourette-Syndrome: a systematic review and meta-analysis Authors: Juan Carlos Baldermann1, Thomas Schüller1, Daniel Huys1, Ingrid Becker2, Lars Timmermann3, Frank Jessen1, Veerle Visser-Vandewalle4, Jens Kuhn1 Affiliations: 1

Department of Psychiatry and Psychotherapy, University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany 2

Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany 3

Department of Neurology, University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany

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Department of Stereotactic and Functional Neurosurgery, University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany Corresponding author: Juan Carlos Baldermann Department of Psychiatry and Psychotherapy, University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany Email: [email protected] Phone: 0040 (0) 221 4784005

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2 Highlights -

We conducted the first meta-analysis and a systematic review on clinical effects of deep brain stimulation in Tourette syndrome

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A significant median reduction of 53 % in the Yale Global Tic Severity Scale was observed

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Comorbid depressive and obsessive-compulsive symptoms significantly improved

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Different brain targets showed comparable improvement rates, indicating a modulation of a common network

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Overall, younger patients may profit more from deep brain stimulation but different targets also provide different predictive values

Abstract Background: A significant proportion of patients with Tourette syndrome (TS) continue to experience symptoms across adulthood that in severe cases fail to respond to standard therapies. For these cases, deep brain stimulation (DBS) is emerging as a promising treatment option. Objective: We conducted a systematic literature review to evaluate the efficacy of DBS for GTS. Methods: Individual data of case reports and series were pooled, the Yale Global Tic Severity Scale (YGTSS) was chosen as primary outcome parameter. Results: In total, 57 studies were eligible, including 156 cases. Overall, DBS resulted in a significant improvement of 52.68 % (IQR = 40.74, p < 0.001) in the YGTSS. Analysis of controlled studies significantly favored stimulation versus off stimulation with a standardized mean difference of 0.96 (95% CI: 0.36 - 1.56). Disentangling different target points revealed significant YGTSS reductions after stimulation of the thalamus, the posteroventrolateral part and the anteromedial part of the globus pallidus internus, the anterior limb of the internal capsule and nucleus accumbens with no significant difference between these targets. A significant negative correlation of preoperative tic scores with the outcome of thalamic stimulation was found.

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3 Conclusions: Despite small patient numbers, we conclude that DBS for GTS is a valid option for medically intractable patients. Different brain targets resulted in comparable improvement rates, indicating a modulation of a common network. Future studies might focus on a better characterization of the clinical effects of distinct regions, rather than searching for a unique target.

Keywords: Tourette, Tourette Syndrom, Deep Brain Stimulation, DBS, Meta-Analysis, Review

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Introduction Tourette syndrome (TS) is a chronic neuropsychiatric disorder characterized by motor and vocal tics with a typical onset during early childhood. Although symptoms usually subside by adulthood, a significant proportion of patients continue to experience pronounced symptoms across the lifespan that in severe cases fail to respond to standard medical and behavioral therapies. For these cases, deep brain stimulation (DBS) is emerging as a promising neuromodulative treatment option since the first report on a successful surgery in 1999.[1] The precise etiology of GTS is still not known and different approaches are investigated. Nowadays, GTS is understood as a neurodevelopmental disorder based on a complex inheritance, in which different genes account for vulnerability and phenotypic variability.[2] Following the diathesis–stress model, epigenetic and environmental factors such as perinatal events (e.g. hypoxia) or smoking during pregnancy can lead to increased stress exposition and therefore contribute to the manifestation of tic disorders.[3] In line with other movement disorders, GTS is believed to rely on a dysfunction of the basal ganglia and the involving cortical and subcortical networks. A dysfunction of cortico-striato-thalamo-cortical circuits seems to be critical and provides the rationale for DBS in the basal ganglia. Diffusion tension imaging (DTI) supports this assumption, with studies showing that connectivity in tracts between the basal ganglia and the cortex are altered in GTS patients.[4, 5] Congruent to this finding, functional magnetic resonance imaging (fMRI) studies suggested reduced connectivity in tracts between basal-ganglia and the cortex [6] and also point towards deficits in cortical “top-down” inhibitory control.[7] Biochemical changes are also discussed in the pathophysiology and mainly refer to overactive and dysregulated dopaminergic transmissions. Studies could show that phasic presynaptic dopamine release in the basal ganglia is elevated by 21 50% in patients compared to healthy subjects.[8, 9] A postmortem study found decreased cholinergic interneurons in the basal ganglia as well as in the associative and sensorimotor regions which is assumed to be linked with an impaired cortico-thalamic control of striatal activity.[10]

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5 Treatment of choice for most patients is habit reversal training and in severe cases antidopaminergic psychopharmacotherapy (for an overview see[11]). Other drugs known to be involved in the treatment of GTS, such as the α2-adrenergic agonist clonidine and the tetrahydrocannabinol based dronabinol, are less commonly used but potentially beneficial in individualized treatment strategies. However, many patients do not benefit sufficiently from conventional therapies. For severely affected cases with treatment resistant symptoms, DBS is evolving into a further option. The first patient to be treated with DBS was operated in late 90’s.[1] The target chosen by Vandewalle and colleagues was derived from stereotactic based ablative surgeries.[12, 13] Since then, multiple targets have been employed. The thalamus is by far the most common used structure so far. Modulation of thalamic projections to premotor and motor areas is believed to be an essential effect mechanism. However, inhibition of sensomotoric parts of the striatum by stimulation of intralaminar nuclei may also play a role.[14] Following the hypothesis of dopaminergic overbalance, studies using positron emission tomography (PET) could show that DBS of thalamic nuclei can influence the regional dopaminergic transmission [15] assuming that DBS restores the transmitter balance into “healthy” conditions.[16] That being said, speaking of the thalamus as a unified target structure certainly oversimplifies the neuroanatomy. The first successful DBS surgery in a patient with GTS used the centromedian nucleus-substantia periventricularis-nucleus ventro-oralis internus complex (CM-Spv-Voi) which became the main target for future studies.[1] Other studies slightly differed from this target or used different nuclei such as the dorsomedial nucleus of the thalamus or the ventral anterior and ventrolateral motor part of the thalamus.[15, 17, 18] Stimulation of the globus pallidus internus (GPi) included both the anteromedial part (am), based on its projections in associative-limbic loops, and the posteroventrolateral part (pl). For the latter, general effectiveness of stimulation in this region on movement disorders can be assumed based on findings in Parkinon’s disease and comorbid iatrogenic dopamine-induced hyperkinesia (as suspected in the pathogenesis of GTS), where symptoms significantly profited from DBS.[19] The Nucleus accumbens (Nac) with the nearby located anterior limb of the internal capsule (ALIC) is considered to be the functional interface of motor and limbic projections.[20] It has become the main target in DBS for psychiatric disorders such as OCD and Depression.[21, 22] Stimulation of the Nac is further in the focus of research on opioid

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6 and alcohol addiction.[23] The rationale behind the use of this region in GTS is an assumed modulation of fibers connecting the thalamus and other subcortical structures with the frontal lobe. Current knowledge about clinical effects of different DBS targets does not provide sufficient data to assess optimal cost-risk benefit and until today, there is no approval for DBS in GTS by the American Food and Drug Administration (FDA). Moreover, if specific brain targets can provide better help for certain subgroups of GTS is still subject matter of current research and scientific discussion. [24] As the current literature is very heterogenic in terms of the optimal target, the study endpoint measurements, and the clinical outcome [25], our goal was to provide a systematical review with a pooled meta-analysis exploring the clinical impacts of DBS for GTS.

Material and methods Search strategy and selection criteria This systematic review was carried out following the 2015 PRISMA guidelines.[26] A comprehensive systematic search of articles was conducted in PubMed using the terms “Tourette's syndrome OR Tourette syndrome OR Gilles de la Tourette syndrome OR Tourette's disorder OR Tourette OR tic disorder” and “deep brain stimulation OR DBS”. Articles published since 1st of January 1999 were selected and the last update was done on 3rd of March 2015, resulting in 234 results. Furthermore, one recently published review[27] and another previous comprehensive review[28] on this topic were screened for additional papers, and a very recently published paper[29] that was not available at the time of the last update, was included, adding 63 records. After excluding duplicates (n = 56), all abstracts that were available either in English or German were screened for the following inclusion criteria: 1) clinical trials or case reports of DBS for patients with GTS; 2) original, published and peerreviewed articles. After this selection, a total of 60 full-text articles were then checked for eligibility and special exclusion reasons. Among these, five records were discharged because the clinical course of the subjects was not traceable. Overall, 57 articles were included in the final analysis (see figure 1, table 1). Besides a qualitative analysis of the included articles, a quantitative meta-analysis was performed articles that reported

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7 sufficient quantitative information about clinical effects using the YGTSS, discharging 9 reports. To ensure correct data collection one researcher extracted the data and a second researcher independently checked the data extraction forms for accuracy and completeness. To avoid biased results we ensured to not include duplicates (e.g. patients that were included in multiple reports), which we identified on the basis of the patient descriptions in the reports to the best of our knowledge. Statistics For the Meta-Analysis, individual data of case reports and case series were pooled with the YGTSS total Score (Tic severity and Impairment) at the last reported clinical follow-up as the primary outcome measure. Secondary outcome measures included sub-scores of the YGTSS (Impairment, Tic Severity comprising motor tics and vocal tics) as well as the modified Rush Videobased Tic Rating Scale (mRVRS). If available, values of the Beck Depression Inventory (BDI) and the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) were also assessed. For the main outcome measures, Wilcoxon signed-rank tests were used to compare the baseline and postoperative scores. Outcome measures for different time categories (T1 ≤ 3; T2 ≤ 6; T3 ≤ 12; T4: > 12 months) were compared with the preoperative baseline scores (T0). Additionally, subgroup analysis was conducted for different brain targets, including thalamus, GPi-am, GPi-pl, external globus pallidus (GPe) and the Nac/ALIC region using a Kruskal–Wallis-test. Possible predictive values were identified by non-parametric correlations using Spearman’s correlations coefficients. Additionally, a meta-analysis using a random-effect model was conducted for randomized controlled designs, using the standardized means of the YGTSS during stimulation on and off conditions. Here, a parametric test was chosen based on the normal distribution of the data. Significance level was set at p = 0.05, analyses were performed with SPSS 22 (Armonk, NY: IBM Corp., 2013) and Review Manager 5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014).

Results For this review, 57 articles were included, reporting a total of 162 patients. For the meta-analysis, 150 patients were identified of which in six patients two different target points were evaluated, resulting in

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8 156 cases. 78 cases were stimulated in the thalamus, 44 in the GPi-am, 20 in the GPi-pl. Nine cases underwent DBS in the region of ALIC/Nac, one combined with thalamic stimulation. In two cases, GPi was indicated as target, without detailed description, whereas two further patients received DBS in both the GPi-pl and –am, which could not be separately assessed. One patient was included after DBS in the GPe and the nucleus subthalamicus (STN). Whether other cases have been either not reported or repeatedly reported without labeling cannot be ensured and is rather likely. An overview of the results is given in table 2. Clinical outcome The median age at operation was 30.0 ± 9.8 years (range 15 – 60) with a median symptom onset age of 7.0 ± 3.3 (range 1 - 23). Overall, DBS resulted in a significant median improvement of 52.68 % (n = 156; IQR = 40·83; p < 0.001) for the Global YGTSS, declining from a median score of 83.0 to 35.0 at last available follow-up. Median improvement rates of 48 % for tic severity (n = 73; IQR = 47.84; p < 0.001) and also for the mRVRS (n = 27; IQR = 11.73; p < 0.001) were found. Motor tics decreased by a median of 38.56 % (n = 71; IQR = 26.31; p < 0.001) and vocal tics by 40.00 % (n = 70; IQR = 35.26; p < 0.001). Comparing reduction rates of motor and vocal tics revealed a significantly higher tic reduction for the latter (mean motor tic reduction 44.96 %; vocal tics 50.72 %; p = 0.012). Across the whole sample, 80.6 % of the cases reached a reduction of the YGTSS of at least 25 %, 54.0 % showed more than 50 % improvement after DBS. Analysis of the different time categories (figure 2) showed that the main decrease took place in the first postoperative months and dropped further afterwards. Taking a closer look at the different target points revealed highly significant changes after thalamic stimulation (median improvement of the Global YGTSS 47.62 %; IQR = 43.61; p < 0.01). Comparable results were assessed for stimulation of the GPi-pl (58.03 %; IQR = 61.09); p < 0.001) and the GPi-am (55.32 %; IQR = 38.13; p < 0.001). Changes after stimulation in the ALIC/Nac region showed improvement to a lesser extent (44.00 %; IQR = 24.58); p = 0.018). There was no significant difference between target’s outcome medians as determined by Kruskal-Wallis test comparing the Thalamus, GPi-am, GPi-pl and the ALIC/Nac (p = 0.496), but the latter’s mean rank was the lowest

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9 (Thalamus: 66.23; GPi-am: 70.20; GPi-pl: 73.36; ALIC/Nac: 49.63). A box plot of the different targets is given in figure 3. A total of four studies were included in the calculation of effect sizes and the forest plot, as seen in figure 4. Taken together, an overall statistically significant effect size of 0.96 (CI: 0.42 – 1.58) was revealed, with a heterogeneity of I² = 0 %, favoring DBS over the controlled condition. According to the literature, this effect size can be viewed as a large effect.[30] Regarding comorbid symptoms, the data revealed a median reduction of 31.25 % (n = 112; IQR = 46.24) of the Y-BOCS scale (median preoperative score = 16.0, IQR = 10.6; median postoperative score = 10.7, IQR = 12.0). Subgroup analysis did not show significant differences between targets (p = 0.812). Results for the BDI showed an overall median reduction of 38.89 % (n = 53; IQR = 57.18, decreasing from a median preoperative score of 18 (IQR = 18.2) to a median postoperative score of 10 (IQR = 10.5)). Again, subgroup analysis did not reveal significant differences (p = 0.692). Correlations with clinical outcome and stimulation parameters Regarding predictive values, a trend towards a negative correlations of age with absolute change in the YGTSS (r = -0.165; p = 0.059) and a congruent trend with the percentage change (r = -0.155; p = 0.078) was observed, implying that younger patients may profit more from the intervention. We found a significant negative correlation between the individual preoperative tic severity and the percentage changes in the global YGTSS score (r = -0.337; p = 0.012). Congruent to that, preoperative tic severity assessed by the mRVRS correlated significantly with the percentage change (r = -0.548; p = 0.002) and the absolute change of the YGTSS (r = 0.396; p = 0.03), suggesting that lower tic scores at baseline predicted a better outcome. In contrast to that, correlations of the preoperative YGTSS impairment scores with the absolute tic reduction scores revealed significant positive correlations (r = 0.342; p = 0.01). There was no significant correlation between comorbid depressive (p = 0.829) or obsessive-compulsive symptoms (p = 0.635) with the outcome measurements. When calculating correlation analysis for subgroups, different significant correlations were found for different brain targets (see figure 5). For the thalamus, preoperative tic scores correlated significantly in a negative way with percentage changes (r = 0.487; p < 0.001) and absolute reductions of the YGTSS (r = 0.686; Page 9 of 25

10 p = 0.01), whereas for the GPI-am, a positive correlation was found with the preoperative impairment score (r = 0.449; p = 0.036 and r = 0.523; p = 0.013). Regarding stimulation settings, the last used stimulation parameters were traced which was available for n = 83 cases. The amplitude ranged from 1.3 to 7.3 Volt. The given frequencies also varied greatly across the sample from 20 to 200 hertz, as did impulse widths (60 to 210 µs). No significant correlations between stimulation parameters and the outcome was found (Amplitude: r = 0.057, p = 0.625; Frequency: r = -0.034; p = 0.771; Impulse width: -0.060; p = 0.610). The applied amplitudes differed across targets (Thalamus: 3.26 V, GPi-pl: 3.35 V, GPi-am: 3.93 V; ALIC/Nac: 5.23 V), with significantly higher values for the ALIC/Nac region (p = 0.001) and the GPi-am (p = 0.026) compared to the thalamus. Adverse events and side effects A quantitative exploration of side effects was not practicable, as the available data lacked of systematic information about stimulation-related adverse events. Stimulation of the CM-Spv-Voi of the thalamus was associated to gaze disturbances or transient visual symptoms.[14, 17] One study was ended early reporting the same adverse events.[31] Interestingly, these side effects were less prominent in a modification of the thalamic target, which was used by Huys and colleagues, aiming at the motor parts of the thalamus.[18] Here, transient mood deterioration and stimulation-dependent dysarthria were the most frequent side effects. One patient has been described with stimulation-related psychotic symptoms.[32] Another important issue linked to thalamic stimulation were erectile dysfunction, with both hypo- and hypererections being reported.[31, 33]Stimulation-related depressive symptoms were reported after DBS in the GPi-pl, as well as memory impairment.[34] Another group mentioned frequency-dependent anxiety, weight gain and one patient reported “anxiety, agitation and constant tiredness” that was not adjustable by the stimulation settings.[35] Higher anxiety levels were linked to DBS in the GPi-am.[35, 36] One patient suffered from a stimulation-dependent nausea, hypotonia and anxiety and a relatively worse mood and impulsivity when compared to thalamic stimulation.[37] Other stimulation-dependent side effects included individual cases of agitation, transient anxiety, dizziness and poor balance.[38] One patient suffered from impairments of speech

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11 fluency and one patient also reported a worsening of tic symptoms under stimulation. A case of hypomania after GPi stimulation was also detected.[29] The ALIC/Nac region was linked to affective side effects, both hypomania and depression.[39,40] Indeed, there was also one suicide attempt after DBS in the Nac in a patient with known recurrent depressive episodes.[41] Other side effects such as apathy, dizziness or weight changes have been observed across targets and cannot be classified as particular adverse events of one stimulation side.

Discussion To our knowledge, we provide the first systematical review and meta-analysis of the existing data on DBS for GTS. The pooled analysis of individual outcomes of patients with GTS treated with DBS revealed a significant symptom reduction (median 52.62%; IQR = 40.74). Still, the outcome varied a lot across the sample, with some patients experiencing complete remission and others showing no improvement at all. Apart from an absolute YGTSS reduction of 43·5 points (IQR = 31.75), over 80 % showed a symptom reduction of at least 25 % and 54% showed a reduction of at least 50 %. Data of randomized, double-blinded controlled studies support the efficacy of DBS in GTS with a standardized mean difference of 0.96 favoring DBS, indicating a large effect size following the interpretation of Cohen. [30] Comparing vocal and motor tics revealed a significantly larger tic reduction for vocal tics, although both values showed a significant improvement and mean values above 45 % and these subscores were often not indicated (n = 71). Regarding comorbid depression and OCD, the data also revealed significant improvement, but preoperative scores were relatively low. The results of our pooled meta-analysis are encouraging but it should be noted that these results are mainly based on studies that must be classified as evidence level IV, according to the classification of the American Academy of Neurology.[42] Although centers are eager to develop new study designs, there is still a lack of controlled studies and the available data is still scarce due to the small sample sizes and the heterogeneity of the procedure. Further information could be gained by already established international databases and investigators should be encouraged to participate in these efforts. Yet, one has to state that DBS for GTS would still get a low evidence rating (level U), according to the classification of the American Academy of Neurology, due to the before mentioned Page 11 of 25

12 heterogenic data. However, based on the given overview and the pooled data, we argue that DBS for GTS has left its experimental character and that well designed double-blinded, controlled studies may be able to take it on the next level in the near future. The quest for the ideal target for DBS in GTS is an ongoing debate among the community. We tried to summarize the indicated target points into main areas, being aware of the fact that such a generalization, especially concerning thalamic nuclei, influences the specificity of the results. The actual stimulated area is, however, highly dependent on the exact lead positioning, the individual anatomy and the stimulation settings, which is hardly assignable for the individual case. Therefore, we think that the presented categorization is best suitable for a comparison of different brain targets. Regarding the ongoing debate on the ideal target, our analysis did not provide a conclusive answer. There was no significant difference across the main targets thalamus, GPi-am, GPi-pl, and ALIC/Nac. However, response rates of DBS in the ALIC/Nac were all in all less promising and the patient numbers are very low which make statistical comparisons difficult. As a matter of fact, this region provided the smallest sample sizes and recent studies abandoned it as the target of choice, due to the overall less convincing results that matched the clinical impression of several investigation sites. The inferiority of the ALIC/Nac region was also shown in direct comparisons, where clinical benefits of the Nac stimulation seemed to be less permanent and effective compared to other targets [43, 44] and one individual case study reported worsening of tics and unaltered obsessive-compulsive symptoms.[45] Very promising results were obtained in the few cases that used the GPe as target point but further investigations are needed for this matter. The same applies to stimulation of the STN, which showed great effects on tics in a single subject with GTS and Parkinson’s disease.[46] Stimulation parameters could not predict the clinical outcome in our meta-analysis, but amplitudes used in DBS of the GPi-am and even more in the ALIC/Nac regions were significantly higher. This is indeed of interest, as higher stimulation settings lead to faster battery depletions, which represents an inherent risk due to the necessary replacement of the generator. In the end, it might not even be necessary to find the “one and only” target point for GTS. Experiences in the treatment of Parkinson’s disease taught us that several

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13 target points may lead to higher therapeutic flexibility. However, the high diversity of the data contributes to difficulties in the specification of predictors and prognosis and hence further establishment of the procedure. An important aspect of the presented analysis was the search for predictive values in order to help to improve criteria for patient selection. Predictive for a better outcome, especially after thalamic stimulation, were preoperative tic-scores, such as the YGTSS tic severity and also the mRVRS, implying a better outcome for patients with lower tic scores. This was somehow surprising, as current recommendations and guidelines emphasize on the severity of the disease when considering DBS. All patients were indeed severely affected (97.8 % had a preoperative YGTSS value over 50), but according to our data, patients with less severe tics profited more. One possible explanation for these correlative finding might be that there is a certain ceiling effect and that tics can only ameliorate by a certain magnitude. However the large variance of the outcome speaks against this assumption. Another explanation might be that in very severe cases the neurobiological basis of the tic disorder overtops the therapeutic effect of the DBS and therefore patients would not be able to achieve a full remission, which can also be hypothesized for patients with prolonged duration of their disease, bearing in mind the trend to a decreased response in elder patients. However, contrary to this, higher impairment scores were associated with better outcome after stimulation of the GPi-am. Hence, one might conclude that severe preoperative impairment might be an essential selection criterion, and not tic severity. The future debate might therefore also be mindful of patients with less severe tics, who are yet not satisfactorily treated with conservative approaches. These correlative findings must certainly be interpreted with caution but they indicate that different targets can be associated to different predictive values. Again, in order to develop more ‘tailor-made’ stimulation strategies, we argue that such characteristics of different targets should be further explored, instead of searching for one target for all GTS patients. Neither comorbid symptoms nor age at symptom onset correlated significantly with the outcome. The available data also did not allow to further explore possible subgroups of GTS patients, e.g. with manifest comorbid OCD, as the corresponding scales were relatively low and often not indicated.

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14 Interestingly, there was a trend towards a negative correlation of age with the outcome, implying that younger patients may benefit more from the procedure. This association is also found in DBS for Parkinson’s disease.[47] Due to the neurodegenerative basis of the disorder, an earlier intervention is assumed to be more beneficial for patients, whereas for GTS, as a neurodevelopmental disorder, this finding is noteworthy and should be further investigated. In our analysis, it was mainly elder patients who did not respond very well. For GTS in adulthood, one can assume that in older patients the neurobiological underpinning of the disease is more and more manifested and therefore less accessible for DBS. We identified numerous patients under 18 years old that underwent surgery, most of them with good results.[38, 44, 48-52] In the revised guidelines of 2014, the Tourette Syndrome Association International Deep Brain Stimulation (DBS) Database and Registry Study Group stated that age should not be seen as a strict criterion, which can be supported by our analysis.[27] Still, ethical implications are broad in severe affected patients under the age of 18, as the majority of patients can still experience a substantial improvement in adulthood. As the authors of the guidelines state, it has to be emphasized that the decision to operate on an underage patient has to be evaluated carefully and should involve local ethic committees. Regarding adverse events, we had difficulties to get a clear picture. Side effects in DBS can be classified into procedure related or stimulation related events. The latter is primarily important for the question, if several targets can contribute to more individualized therapeutic concepts, which was the reason why we tried to focus on that. Unfortunately, the available data lacked of systematic information about stimulation-related adverse events. Gaze disturbances and erectile dysfunctions seem to be specifically related to thalamic stimulation, whereas stimulation of the ALIC/Nac was more linked to affective symptoms and stimulation of the GPi may come in hand with increased anxiety. However, such an assignment can only be vague and clinical experience shows that the range of possibilities is broad. Overall, lack of energy and apathy was reported across targets, which can be interpreted as the other side of the coin of tic reduction. Although the exact side effect profiles remained unclear, it can be stated that most adverse events were dependent on the applied stimulation settings and therefore not permanent. In general, authors reported that stimulation was well tolerated

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15 and safe, but there is a need for a more systematic and comprehensive report of stimulation-related side effects after DBS. The presented analysis comes in hand with some relevant limitations. As Figee and colleagues mentioned, pooled meta-analysis in DBS have to be particularly interpreted with caution.[53] Pooling data from different stimulation targets can only give a rough overview and does not take account to the complex neuroanatomy of the brain. We tried to differentiate to the best of our knowledge but pooling the results of e.g. different subregions of the thalamus or the ventral striatum already challenges the interpretation of the results. Furthermore, the actual stimulated area is highly dependent on the applied stimulation settings. It would be much more accurate to calculate the individual stimulation area by using the given coordinates and the individual settings. However, this data are rarely indicated and we question if these data could be sufficiently collected. Another critical point is the lack of controlled studies, which would allow more valid statistical analysis. Most included cases are case reports or small prospective case series, which does not allow deriving relative strengths of treatment effects across studies. On the other hand, it is indeed difficult to establish double-blinded controlled designs. Problems include adequate blinding of patients and investigators, as well as the missing opportunity to optimize stimulation settings, when fixed parameters are chosen, which was addressed in a recent comment by Jimenez-Shahed.[54] Overall, the number of patients and was still small and the available data about comorbid symptoms was limited which may cause an underpowered analysis and did not allow to identify subphenotypes of GTS. Another important issue, that we were not able to address, was the ongoing pharmacotherapy which might have changed after DBS and therefore influenced the outcome. We tried to identify patients that were reported repeatedly by thoroughly screening the articles for hints and also looked closely at the indicated scores and demographic data to avoid duplicates. Whether some patients have been either not reported or repeatedly reported without labeling cannot be ensured and is rather likely with the possibility of reporting bias. It must therefore be concluded that our results only allow a broad overview and should be viewed as a first systematic insight into the growing data of DBS for GTS.

Conclusion

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16 The presented data provide the first systematic review and meta-analysis on the existing literature on DBS for GTS. Our results support the findings of numerous case reports and few controlled studies with significant beneficial effects. Although there is a lack of controlled studies and the number of patients treated with DBS is limited, we conclude that DBS for GTS is a valid option for otherwise therapy-resistant patients. Apart from controlled and randomized designs, standardized outcome measurements and comprehensive indications of surgery procedures and clinical outcomes, including adverse events, can help to gain more comparable and reliable results. The question of the ideal target remains open; DBS in the thalamus, GPi-am and GPi-pl, the ALIC/Nac region all resulted in comparable improvement rates although clinical impressions and comparative studies of the latter were less convincing. One explanation for this finding is the possible affection of a common network. In the future, researchers may therefore focus on the influence of DBS on tic-related networks. If such a network can be equally addressed by different brain targets, the challenge must be to better characterize the characteristics of each target, regarding side effects and predictive values. In our analysis, a trend towards a better outcome in younger patients was observed compared to elder patients. Relatively low preoperative tic scores correlated with better outcomes, especially after thalamic stimulation, whereas higher preoperative impairment scores predicted a better outcome. This raises the question if patients with less severe tics may also be suitable for DBS and if preoperative impairment might be more crucial for patient selection than tic severity. Based on our overview and the results of the meta-analysis we believe that DBS for GTS should be considered on its final way for being an established treatment for severely affected, treatment refractory patients and we believe that it has left its experimental character. Improvement rates are overall convincing, but the efficacy and the individual side effect profile must be further tested by double-blinded, randomized controlled trials, ideally multicentric with larger sample sizes. Regarding this next step, researchers are encouraged to carefully overthink study designs and patient selection due to the numerous pitfalls of clinical DBS trials.

Declaration of interests and acknowledgment

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17 JK has received financial support for investigator initiated trials-DBS studies from Medtronic GmbH (Meerbusch, Germany). FJ has received fees for advisory boards and presentations from: AC Immune, Lilly, Piramal Imaging, Novartis, Schwabe, Nutricia, Tromsdorf, Boehringer Ingelheim. The other authors report no further biomedical financial interests or potential conflicts of interest. This work was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, KFO-219 Grant). We thank Josephine Owens for help with the data acquisition.

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21 [60] Dehning, S., et al., Functional outcome and quality of life in Tourette's syndrome after deep brain stimulation of the posteroventrolateral globus pallidus internus: long-term follow-up. The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry, 2014. 15(1): p. 66-75. [61] Dehning, S., et al., Therapy-refractory Tourette syndrome: beneficial outcome with globus pallidus internus deep brain stimulation. Movement disorders : official journal of the Movement Disorder Society, 2008. 23(9): p. 1300-2. [62] Motlagh, M.G., et al., Lessons Learned from Open-label Deep Brain Stimulation for Tourette Syndrome: Eight Cases over 7 Years. Tremor Other Hyperkinet Mov, 2013. 1(3): p. 03-170. [63] Piedimonte, F., et al., Behavioral and motor improvement after deep brain stimulation of the globus pallidus externus in a case of Tourette's syndrome. Neuromodulation : journal of the International Neuromodulation Society, 2013. 16(1): p. 55-8. [64] Okun, M.S., et al., A trial of scheduled deep brain stimulation for Tourette syndrome: moving away from continuous deep brain stimulation paradigms. JAMA neurology, 2013. 70(1): p. 85-94. [65] Porta, M., et al., Deep brain stimulation for treatment of refractory Tourette syndrome: longterm follow-up. Acta neurochirurgica, 2012. 154(11): p. 2029-41. [66] Porta, M., et al., Neurosurgical treatment for Gilles de la Tourette syndrome: the Italian perspective. Journal of psychosomatic research, 2009. 67(6): p. 585-90. [67] Servello, D., et al., Long-term, post-deep brain stimulation management of a series of 36 patients affected with refractory gilles de la tourette syndrome. Neuromodulation : journal of the International Neuromodulation Society, 2010. 13(3): p. 187-94. [68] Dong, S., et al., Unilateral Deep Brain Stimulation of the Right Globus Pallidus Internus in Patients with Tourette's Syndrome: Two Cases with Outcomes after 1 Year and a Brief Review of the Literature. Journal of International Medical Research, 2012. 40(5): p. 2021-2028. [69] Duits, A., et al., Unfavourable outcome of deep brain stimulation in a Tourette patient with severe comorbidity. European child & adolescent psychiatry, 2012. 21(9): p. 529-31. [70] Hwynn, N., et al., Improvement of both dystonia and tics with 60 Hz pallidal deep brain stimulation. The International journal of neuroscience, 2012. 122(9): p. 519-22. [71] Maling, N., et al., Increased thalamic gamma band activity correlates with symptom relief following deep brain stimulation in humans with Tourette's syndrome. PloS one, 2012. 7(9): p. e44215. [72] Rzesnitzek, L., et al., Suppression of extrapyramidal side effects of doxepin by thalamic deep brain stimulation for Tourette syndrome. Neurology, 2011. 77(18): p. 1708-9. [73] Kaido, T., et al., Deep brain stimulation for Tourette syndrome: a prospective pilot study in Japan. Neuromodulation : journal of the International Neuromodulation Society, 2011. 14(2): p. 123-8; discussion 129. [74] Lee, M.W., et al., Deep brain stimulation in a Chinese Tourette's syndrome patient. Hong Kong Med J, 2011. 17(2): p. 147-50.

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22 [75] Marceglia, S., et al., Thalamic single-unit and local field potential activity in Tourette syndrome. Movement disorders : official journal of the Movement Disorder Society, 2010. 25(3): p. 300-8. [76] Ackermans, L., et al., Long-term outcome of thalamic deep brain stimulation in two patients with Tourette syndrome. Journal of neurology, neurosurgery, and psychiatry, 2010. 81(10): p. 106872. [77] Dueck, A., et al., Deep brain stimulation of globus pallidus internus in a 16-year-old boy with severe tourette syndrome and mental retardation. Neuropediatrics, 2009. 40(5): p. 239-42. [78] Neuner, I., et al., Deep brain stimulation in the nucleus accumbens for intractable Tourette's syndrome: follow-up report of 36 months. Biological psychiatry, 2009. 65(4): p. e5-6. [79] Shields, D.C., et al., Microelectrode-guided deep brain stimulation for Tourette syndrome: within-subject comparison of different stimulation sites. Stereotactic and functional neurosurgery, 2008. 86(2): p. 87-91. [80] Welter, M.L., et al., Internal pallidal and thalamic stimulation in patients with Tourette syndrome. Archives of neurology, 2008. 65(7): p. 952-7. [81] Bajwa, R.J., et al., Deep brain stimulation in Tourette's syndrome. Movement disorders: official journal of the Movement Disorder Society, 2007. 22(9): p. 1346-50. [82] Kuhn, J., et al., Deep brain stimulation of the nucleus accumbens and the internal capsule in therapeutically refractory Tourette-syndrome. Journal of neurology, 2007. 254(7): p. 963-5. [83] Gallagher, C.L., P.C. Garell, and E.B. Montgomery, Jr., Hemi tics and deep brain stimulation. Neurology, 2006. 66(3): p. E12. [84] Ackermans, L., et al., Deep brain stimulation in Tourette's syndrome: two targets? Movement disorders: official journal of the Movement Disorder Society, 2006. 21(5): p. 709-13. [85] Diederich, N.J., et al., Efficient internal pallidal stimulation in Gilles de la Tourette syndrome: a case report. Movement disorders: official journal of the Movement Disorder Society, 2005. 20(11): p. 1496-9. [86] van der Linden C., et al., Successful treatment of tics with bilateral internal pallidum (GPi) stimulation in a 27-year-old male patient with Gilles de la Tourette’s syndrome (GTS). Movement disorders: official journal of the Movement Disorder Society, 2002. 17: p. 341.

Figures: Figure 1: Adapted PRISMA Flowchart: Process of literature search. [25] Figure 2: Time course of YGTSS after DBS on different time categories (n = 156 on baseline, n = 25 for ≤ 3 months, n = 32 for ≤ 6 months, n = 58 for ≤ 12 months and n = 54 for > 12 months). Error bars represent 95 % confidence Interval (CI).

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23 Figure 3: Boxplot of target-specific YGTSS chances before and after DBS surgery in percent for the thalamus (n = 78), GPi-pl (n = 20), GPi-am (n = 44) and the ALIC/Nac (n = 9). As only one case was reported with stimulation in the GPe, we excluded this target for display. Figure 4: Forest plot of randomized, double-blinded controlled studies indicating percentage changes in the YGTSS after DBS ON and OFF-condition. Graphic was created in Review Manager 5.3. Figure 5: Exemplary correlation analysis for a) Thalamus an b) the anteromedial part of the globus pallidus internus of preoperative scores with the outcome.

Tables Table 1: Overview of included studies (n = 57), if the outcome was not assessed by the YGTSS cases were not included in the pooled meta-analysis (*) (n = 48). If two targets were evaluated in one patient, an additional case was added to the analysis. Table 2: Overview of YGTSS outcome after DBS according to different target points, presented are cases included in the meta-analysis. * Cases in which the outcome could not be assigned to one of the specific targets. Measures of dispersion in brackets are Interquartile ranges and standard deviations for the mean values.

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24 Table 1 Author, year

Target

Number of patients/cases

Level of evidence

Kefalopoulou et al 2015 [29]

GPi-am, GPi-pv (2)

15

III

Dong et al 2014 [55]

GPi-pv

1

IV

Wardell et al 2015, Martinez-Fernandez et al 2011 [56, 35]

GPi-am (3); GPi-pv (2), both (1) GPi-am, 2 + Nac

6

IV

17

IV

Huys et al 2014, Kuhn et al. 2012, Vernaleken et al. 2009 [15, 16, 18] Patel & Jimenez-Shahed 2014 [57]

Thalamus (2 unilateral)

10

IV

GPi

1

IV

Dong et al 2014b [58]

GPi

1

IV

Nair et al 2014 [52]

GPi-am

4

IV

Huasen et al 2014 [59]

GPi-am

1

IV

Dehning et al 2014, Dehning et al 2008 [60, 61]

GPi-pv

6

IV

Motlagh et al 2013a [62]

8

IV

Massano et al 2013 [51]

Thalamus (5), GPi-pv (2), + GPi-am (1) GPi-am

1

IV

Piedimonte et al 2013 [63]

GPe

1

IV

Okun et al 2013 [64]

Thalamus

5

III

Porta et al 2012, Porta et al 2009, Servello et al 2010 Servello et al 2008 [17, 65, 66, 67] Dong et al 2012 [55]

Thalamus

18

IV

GPi-pv (unilateral)

2

IV

Duits et al 2012 [69]

Thalamus

1

IV

Savica et al 2012 [49]

Thalamus

3

IV

Hwynn et al 2012 [70]

GPi

1*

IV

Maling et al 2012 [71]

Thalamus

5

IV

Rzesnitzek et al 2011 [72]

Thalamus

1

IV

Kaido et al 2011 [73]

Thalamus

3

IV

Ackermans et al 2011 [31]

Thalamus

6

III

Pullen et al 2011 [50]

Thalamus

1

IV

Dehning et al 2011 [34]

GPi-pv

4

IV

Lee et al 2011 [74]

Thalamus

1

IV

Burdick et al 2010 [45]

ALIC/Nac

1

IV

Marceglia et al 2010 [75]

Thalamus

7

IV

Ackermans et al 2010 [76]

Thalamus

2*

IV

Martinez-Torres et al 2009 [46]

STN

1*

IV

Dueck et al 2009 [77]

GPi

1*

IV

Servello et al 2009 [43]

ALIC/Nac, + Thalamus (3)

4

IV

Neuner et al 2009b [78]

ALIC/Nac

1

IV

Kuhn et al 2008 [40]

ALIC/Nac

1

IV

Shields et al 2008 [79]

ALIC/Nac, Thalamus

1/2

IV

Houeto et al 2005, Welter et al 2008[37, 80]

GPi-am, Thalamus

3/6

III

Bajwa et al 2007 [81]

Thalamus

1

IV

Maciunas et al 2007 [32]

Thalamus

5

III

Kuhn et al 2007 [82]

ALIC/Nac

1

IV

Shahed et al 2007 [44]

GPi-pv

1

IV

Gallagher et al 2006 [83]

GPi

1*

IV

Ackermans et al 2006 [84]

GPi, Thalamus

1/2*

IV

Diederich et al 2005 [85]

GPi-pv

1

IV

Sachdev et al 2014, Cannon et al 2012 [38, 36]

Page 24 of 25

25 Flaherty et al 2005 [39]

ALIC/Nac

1

IV

Visser-Vandewalle et al 2003 [14]

Thalamus

3*

IV

van der Linden et al. 2002 [86]

GPi

1*

IV

Vandewalle et al 1999 [1]

Thalamus

1*

IV

Table 2 N

Preoperative median

Postoperative median

Median Reduction

Median change (%)

Mean change (%)

Thalamus

78

GPi-pl

20

GPi-am

44

ALIC/Nac

9

GPe Other*

1 4

80·50 (21·00) 85·00 (20·00) 84·00 (14·00) 81·00 (33·00) 78·00 78 (-)

36·5 (38·50) 27·50 (52·75) 37·00 (29·00) 40·00 (26·00) 23·00 42·00 (-)

38·8 (32·50) 45·55 (59·50) 47·00 (27·00) 37·00 (26·00) 55·00 47·00 (-)

47·62 (43·61) 58·03 (61·09) 55·32 (38·13) 44·00 (24·58) 52·81 (-)

Total

156

83.00 (17·00)

37·00 (32·50)

43·50 (31·75)

52·68 (40·74)

53·02 (26·18) 56·55 (35·00) 51·96 (55·32) 43·70 (15·41) 70·51 44·59 (27·14) 52·62 (26·61)

≥ 25 % response (%) 81·5

≥ 50 % response (%) 52·3

77·8

61·1

77·3

65·9

75·0

37·5

66·7

66·7

80·6

54·0

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