Elsevier

The Lancet Neurology

Volume 14, Issue 6, June 2015, Pages 595-605
The Lancet Neurology

Articles
Bilateral globus pallidus stimulation for severe Tourette's syndrome: a double-blind, randomised crossover trial

https://doi.org/10.1016/S1474-4422(15)00008-3Get rights and content

Summary

Background

Deep brain stimulation (DBS) has been proposed as a treatment option for severe Tourette's syndrome on the basis of findings from open-label series and small double-blind trials. We aimed to further assess the safety and efficacy of bilateral globus pallidus internus (GPi) DBS in patient's with severe Tourette's syndrome.

Methods

In a randomised, double-blind, crossover trial, we recruited eligible patients (severe medically refractory Tourette's syndrome, age ≥20 years) from two clinics for tertiary movement disorders in the UK. Enrolled patients received surgery for GPi DBS and then were randomly assigned in a 1:1 ratio (computer-generated pairwise randomisation according to order of enrolment) to receive either stimulation on-first or stimulation off-first for 3 months, followed by a switch to the opposite condition for a further 3 month period. Patients and rating clinicians were masked to treatment allocation; an unmasked clinician was responsible for programming the stimulation. The primary endpoint was difference in Yale Global Tic Severity Scale (YGTSS) total score between the two blinded conditions, assessed with repeated measures ANOVA, in all patients who completed assessments during both blinded periods. After the end of the blinded crossover phase, all patients were offered continued DBS and continued to have open-label stimulation adjustments and objective assessments of tic severity until database lock 1 month after the final patient's final trial-related visit. This trial is registered with ClinicalTrials.gov, number NCT01647269.

Findings

Between Nov 5, 2009, and Oct 16, 2013, we enrolled 15 patients (11 men, four women; mean age 34·7 years [SD 10·0]). 14 patients were randomly assigned and 13 completed assessments in both blinded periods (seven in the on-first group, six in the off-first group). Mean YGTSS total score in these 13 patients was 87·9 (SD 9·2) at baseline, 80·7 (SD 12·0) for the off-stimulation period, and 68·3 (SD 18·6) for the on-stimulation period. Pairwise comparisons in YGTSS total scores after Bonferroni correction were significantly lower at the end of the on-stimulation period compared with the off-stimulation period, with a mean improvement of 12·4 points (95% CI 0·1–24·7, p=0·048), equivalent to a difference of 15·3% (95% CI 5·3–25·3). All 15 patients received stimulation in the open-label phase. Overall, three serious adverse events occurred (two infections in DBS hardware at 2 and 7 weeks postoperatively, and one episode of deep-brain-stimulation-induced hypomania during the blinded on-stimulation period); all three resolved with treatment.

Interpretation

GPi stimulation led to a significant improvement in tic severity, with an overall acceptable safety profile. Future research should concentrate on identifying the most effective target for DBS to control both tics and associated comorbidities, and further clarify factors that predict individual patient response.

Funding

UK National Health Service.

Introduction

The clinical hallmark of Tourette's syndrome is the presence of multiple motor and vocal tics, often preceded by premonitory sensations or urges, and frequently complicated by neurobehavioural comorbidities including attention deficit hyperactivity disorder, obsessive-compulsive disorder, impulse control disorder, self-injurious behaviour, and personality and mood disorders.1, 2, 3

Most patients with Tourette's syndrome have a pre-pubertal increase in tic severity, followed by a remission towards late adolescence or early adulthood. Nevertheless, a substantial number of patients can continue to experience disabling symptoms in adulthood, needing lifelong treatment.4 Behavioural therapies, α-2 adrenoceptor agonists, antipsychotic drugs, anticonvulsant drugs, benzodiazepines, and injections of botulinum toxin can all offer some symptomatic relief.2, 3 Nevertheless, in a proportion of patients these approaches are insufficiently effective or accompanied by intolerable side-effects; among this group are a number of severely affected patients for whom surgical approaches such as deep brain stimulation (DBS) could present an alternative treatment option.5

The first report of DBS for the treatment of refractory Tourette's syndrome was published in 1999 by Vandewalle and colleagues,6 targeting the same thalamic nuclei (ie, centromedian-parafascicular complex [CM/Pf] and ventral oral internus nuclei) that were subject to stereotactic ablation by Hassler and Dieckmann in the 1970s.7 Since then, various areas of the brain have been targeted by DBS, including the CM/Pf complex of the thalamus, the subthalamic nucleus, nucleus accumbens and anterior limb of the internal capsule, and the globus pallidus internus and externus, providing variable but generally positive results.5

Research in context

Evidence before this study

We searched PubMed up to Dec 1, 2014, with the terms “Tourette” and “deep brain stimulation” or “DBS” for double-blind randomised trials. We identified four small trials incorporating double-blind randomised methods. In two trials that included five and six patients, the efficacy of thalamic deep brain stimulation (DBS; centromedian-parafascicular and ventralis oralis complex of the thalamus) was assessed. In another two trials, the effect of thalamic and anteromedial globus pallidus internus (GPi) stimulation was compared in one and three patients, respectively. These studies, including very small numbers of patients, each showed a benefit from stimulation, and thus partly support the overall positive outcomes presented in open-label studies. However, the scientific literature about DBS for the treatment of Tourette's syndrome consistently highlights the paucity of the highest level of evidence for its use. There remains a need for double-blind, randomised, controlled trials, with a sufficient number of patients to address several unresolved issues, including the magnitude and consistency of the efficacy of this treatment, its clinical relevance, its effect on comorbid disorders, and the overall safety of this approach. The brain target, and stimulation settings that can optimally address these issues, also remain to be determined.

Added value of this study

To our knowledge, this prospective, randomised trial is the largest double-blind trial of DBS in patients with Tourette's syndrome so far, which assessed the safety and efficacy of pallidal DBS. Our results provide high-quality evidence that GPi DBS can significantly improve tics while having an acceptable safety profile.

Implications of all the available evidence

The outcomes of this study provide further justification for the use of GPi DBS as a treatment for patients with severe medically refractory Tourette's syndrome, which previously was supported by limited evidence. Future trials will probably need international collaboration to recruit larger numbers of patients to assess the relative merits of different targets for DBS and identify factors predictive of response to surgery.

Supportive evidence is, however, based mostly on case reports or small case series, typically non-blinded studies with small numbers of patients.8 Two small, randomised, double-blind trials9, 10 (including five and six patients, respectively) have provided evidence to partly support the beneficial effects of DBS targeting the CM/Pf thalamic nuclei, but raised important issues about the safety and tolerability of this target.

Extensive evidence supports the efficacy of globus pallidus internus (GPi) DBS in other hyperkinetic movement disorders (eg, levodopa-induced dyskinesia and various forms of dystonia), making GPi an attractive alternative target for DBS in Tourette's syndrome.11, 12 In a double-blind trial of three patients, Welter and colleagues13 compared bilateral thalamic stimulation, bilateral anteromedial GPi stimulation, stimulation at both targets combined, and sham stimulation, and showed an advantage of anteromedial GPi DBS that was sustained for 20–60 months of follow-up.13 Further findings from open-label studies have also suggested that GPi DBS might be a promising therapeutic alternative for severe, medically refractory Tourette's syndrome, with an acceptable safety profile.14, 15, 16

However, several unanswered questions about DBS for Tourette's syndrome remain, including the objective demonstration of its efficacy for different aspects of Tourette's syndrome, the factors that predict individual patient responsiveness, the methods to derive optimum stimulation parameters, and the precise optimum choice of brain target. Thus, DBS for Tourette's syndrome is still viewed as an experimental approach. Well designed, randomised, double-blind trials involving a multidisciplinary team approach are needed to help address these questions. In a randomised, double-blind trial, we aimed to assess the clinical safety and efficacy of bilateral GPi DBS in patients with treatment-refractory, severe Tourette's syndrome.

Section snippets

Study design and participants

We did a randomised, double-blind, crossover trial of bilateral GPi DBS to compare tic severity during 3 months on stimulation with tic severity during 3 months off stimulation, followed by an open-label phase. The study was sponsored by University College London, and was done in two academic centres in the UK (UCL Institute of Neurology, London, and Salford Royal NHS Foundation Trust, Manchester).

Patients were eligible for inclusion if: they were adults with stable Tourette's syndrome; they

Results

Between Nov 5, 2009, and Oct 16, 2013, we assessed 18 patients and enrolled 15 patients into the study (figure 2). 11 patients were men and four were women, with a mean age of 34·7 years (SD 10·0). Table 1 summarises their clinical characteristics.

All DBS procedures were done between Sept 27, 2011, and April 8, 2014. 13 patients had bilateral electrodes in the anteromedial GPi. Two patients with concurrent dystonia or dystonic tics had bilateral electrodes placed slightly more posteriorly

Discussion

In this double-blind, crossover trial of 15 patients with severe medically refractory Tourette's syndrome, globus pallidus stimulation led to a significant improvement in tics during the on-stimulation blinded period compared with the off-stimulation blinded period, with an overall acceptable safety profile. We noted a wide range of improvements during the double-blind assessment, with more consistent improvements in tics compared with baseline after the initiation of open-label stimulation

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