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.