Title: Double blind comparison of optimised Deep Brain Stimulation for severe Tourette syndrome
Funder: Medical Research Council

Abstract: The project aims to assess whether Deep Brain Stimulation (DBS) reduces tic severity in patients with disabling Tourette syndrome (TS). _x000D_ TS is a condition characterised by involuntary movements (motor tics) and vocalisations (vocal tics) which start in childhood. The tics are usually mild and diminish over time but in a small number they persist, are severe, debilitating and unresponsive to conventional treatments. Tics can be extremely forceful, cause serious self-harm and distress and constrain normal life activities. A significant number of patients suffer from depression, anxiety, obsessive compulsive symptoms or hyperactivity. They are at increased risk of suicide and have difficulties with social interactions and employment. This trial will recruit 20 participants with the most severe and disabling tics._x000D_ DBS is a surgical procedure which places two electrodes in the deep structures of both sides of the brain that are connected by internal wires to a battery under the surface of the chest wall. This system can be programmed to deliver tiny amounts of electrical stimulation which modulates the abnormal pathways thought to cause tics. DBS is a fairly routine treatment for patients with Parkinson’s disease, and when managed by experienced medical teams, the risks are very low. A small number of patients with TS around the world have had DBS and a significant proportion have benefitted. However, more evidence is needed before it can be made available as an NHS treatment. _x000D_ Patients will be admitted to hospital under the care of a team with expertise in DBS and TS. They will be implanted with a DBS system in a part of the brain known as the "internal pallidum" which has produced the desired effect of tic reduction in previous small studies. Initially, 6 months will be spent adjusting the stimulation settings. In previous studies, this phase was not long enough to obtain the best possible outcome. After 6 months, there will be a 4 week period when patients will be randomly placed into two groups. One group will have DBS kept on and the other will have DBS switched off and all will be assessed after 2 weeks. A few days later patients will be swapped to the other condition for 2 weeks. The patients and doctors doing the assessments will not know if the DBS is on or off. This will test whether any tic reduction is specifically due to DBS. From previous experience, the tics are expected to come back within 1 to 2 days of DBS being discontinued. Patients who cannot tolerate DBS being switched off for two weeks will be assessed and turned on again sooner. All patients will have the choice of coming into hospital for this 4-week period._x000D_ The main way of rating tics will be with a recognised clinical scale. In addition, a number of other scales will assess the impact of tics on quality of life, mood, anxiety, hyperactivity and obsessive compulsive symptoms. A list of any adverse effects and video assessing tic severity will be completed. Part of the study will also be to try to assess potential factors that explain why some patients improve more than others as a result of DBS. After the study patients will remain under the long-term care of the study team. _x000D_ A “Patient and Public Involvement” group of patients, relatives and the Chair of Tourette’s Action has commented on the project. The results will be published in medical journals, presented at medical conferences, communicated to patient associations and by press release to the public.

Lay abstract: The aim of the project is to assess if optimised Deep Brain Stimulation (DBS) of the internal globus pallidum (GPi) reduces tic severity in patients with severe Tourette syndrome (TS)._x000D_ TS is a condition presenting with chronic multiple motor and phonic tics starting in childhood. Although most patients have mild transient symptoms, a small number have severe motor and vocal tics unresponsive to conventional treatments. The violent character of the tics and the self-injuries that can be associated, can result in serious injuries. In addition, patients also often suffer from comorbid depression, anxiety, obsessive compulsive symptoms, hyperactivity and are at risk of suicide. They can also have difficulties engaging in social interactions and in employment. _x000D_ GPi DBS is a neurosurgical procedure which involves the placement of two electrodes into a part of the basal ganglia (GPi), that are then connected to an implantable pacemaker in the chest wall. The system can be programmed to deliver high frequency electrical stimulation. DBS is an accepted treatment for Parkinson’s disease, dystonia and tremor. In experienced teams the risks are very low. A small number of patients with TS have previously benefited from DBS; nevertheless, more evidence is needed before DBS can be made available as an NHS treatment._x000D_ In this study, we are planning to recruit 20 adult patients with severe TS with a Yale Global Tic Severity Score (YGTSS) >50/100. Patients will be implanted with GPi DBS. Our innovative design involves a 6 months open-phase study for stimulation parameter adjustment. In previous studies, this period was shorter and insufficient to obtain an optimal outcome. After these 6 months, patients will be randomized into two groups; one group will be kept with the stimulator on and the other will be switched off for up to two weeks. Tic severity will be re-assessed and patients will be switched to the other condition for another two weeks. The tics are expected to come back within one to two days. Patients who find it difficult to tolerate one condition for two weeks will be assessed and switched to the other condition sooner. Patients and raters will be blind to the stimulation condition. The primary outcome measure will be a validated clinical scale, the Tic Severity Score from the YGTSS. In addition, a video tic assessment will be conducted and rated by an independent blinded scorer using the Modified Rush Video Rating Scale._x000D_ Other scales assessing the impact of tics on quality of life, mood, anxiety, hyperactivity and obsessive-compulsive symptoms will be completed before surgery and at the end of the open-phase. The list of adverse events will also be collected. The mechanistic part of the study will seek to assess the potential variables (i.e. clinical, imaging and electrical) that could explain why some patients show better improvement than others._x000D_ We are planning a 6-month period for contracts and regulatory approvals, 20 months of recruitment and 39 months total duration._x000D_ The outcome of this study will be presented at conferences and published in high impact factor journals. This project has been discussed extensively with NHS England and we hope that it will lead to consideration to making DBS accessible for patients with very severe TS. The results will also be disseminated to patients and to the general public. A PPI group including 3 patients, 2 relatives and the CEO of Tourette’s Action is supporting our trial.

Research activity codes: 5.3 MEDICAL DEVICES;6.3 MEDICAL DEVICES
Health categories: NEUROLOGICAL