Pallidal neurostimulation in patients with medication-refractory cervical dystonia: a randomised, sham-controlled trial

Summary

Background

Cervical dystonia is managed mainly by repeated botulinum toxin injections. We aimed to establish whether pallidal neurostimulation could improve symptoms in patients not adequately responding to chemodenervation or oral drug treatment.

Methods

In this randomised, sham-controlled trial, we recruited patients with cervical dystonia from centres in Germany, Norway, and Austria. Eligible patients (ie, those aged 18–75 years, disease duration ≥3 years, Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] severity score ≥15 points) were randomly assigned (1:1) to receive active neurostimulation (frequency 180 Hz; pulse width 120 μs; amplitude 0·5 V below adverse event threshold) or sham stimulation (amplitude 0 V) by computer-generated randomisation lists with randomly permuted block lengths stratified by centre. All patients, masked to treatment assignment, were implanted with a deep brain stimulation device and received their assigned treatment for 3 months. Neurostimulation was activated in the sham group at 3 months and outcomes were reassessed in all patients after 6 months of active treatment. Treating physicians were not masked. The primary endpoint was the change in the TWSTRS severity score from baseline to 3 months, assessed by two masked dystonia experts using standardised videos, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00148889.

Findings

Between Jan 19, 2006, and May 29, 2008, we recruited 62 patients, of whom 32 were randomly assigned to neurostimulation and 30 to sham stimulation. Outcome data were recorded in 60 (97%) patients at 3 months and 56 (90%) patients at 6 months. At 3 months, the reduction in dystonia severity was significantly greater with neurostimulation (–5·1 points [SD 5·1], 95% CI −7·0 to −3·5) than with sham stimulation (−1·3 [2·4], −2·2 to −0·4, p=0·0024; mean between-group difference 3·8 points, 1·8 to 5·8) in the intention-to-treat population. Over the course of the study, 21 adverse events (five serious) were reported in 11 (34%) of 32 patients in the neurostimulation group compared with 20 (11 serious) in nine (30%) of 30 patients in the sham-stimulation group. Serious adverse events were typically related to the implant procedure or the implanted device, and 11 of 16 resolved without sequelae. Dysarthria (in four patients assigned to neurostimulation vs three patients assigned to sham stimulation), involuntary movements (ie, dyskinesia or worsening of dystonia; five vs one), and depression (one vs two) were the most common non-serious adverse events reported during the course of the study.

Interpretation

Pallidal neurostimulation for 3 months is more effective than sham stimulation at reducing symptoms of cervical dystonia. Extended follow-up is needed to ascertain the magnitude and stability of chronic neurostimulation effects before this treatment can be recommended as routine for patients who are not responding to conventional medical therapy.

Funding

Medtronic.

Introduction

Cervical dystonia, also known as spasmodic torticollis, is a chronic neurological disorder in which the head turns or tilts in jerky movements or sustains a prolonged and awkward position due to involuntary contractions of neck muscles. Cervical dystonia is the most frequent focal dystonia, with an estimated prevalence of 57–390 per million people in Europe and North America.1, 2, 3 It has a profound effect on quality of life through a complex interaction of motor impairment, neck pain, and stigma, leading to significant restrictions in daily activities and social participation.4, 5, 6

Although cervical dystonia is thought to arise from pathological neuronal activity within brain motor circuits, the mainstay treatment targets the periphery. Repeated injections of botulinum toxin to denervate dystonic neck muscles are the first-line treatment option for most patients.7, 8 This approach is more efficacious than oral treatment with anticholinergic agents⁹—the most effective oral medications for dystonia.¹⁰ However, chemodenervation does not work in a proportion of patients (the exact figure is not known) because the movement pattern is too complex or involves muscles that are difficult to inject, and because treatment is limited by side-effects such as dysphagia. Moreover, up to 5% of patients develop immunoresistance to botulinum toxin type A or B,¹¹ which is associated with unresponsiveness to chemodenervation. A clinical study in a real-word setting reported a beneficial response to one injection session of botulinum toxin A in 58% (95% CI 53·1–63·4) of 404 patients with cervical dystonia, as defined by physician-rated dystonia severity, self-perceived improvement on a global clinical rating scale, and good tolerance.¹² The proportion dropped to 29% (95% CI 24·0–33·5) when adding sustained benefit throughout the standard 12-week treatment cycle to the response criteria,¹² which shows the need for treatment alternatives, particularly in patients who do not respond after receiving several injection cycles by an experienced therapist.

Deep brain stimulation of the internal segment of the globus pallidus via electrodes implanted in the brain has proven to be an effective and relatively safe treatment for patients with severe generalised or segmental dystonia.13, 14 Results of small retrospective cohort studies15, 16, 17, 18, 19, 20 and one controlled trial with ten patients²¹ also suggest a beneficial effect in cervical dystonia. The risk–benefit ratio of this surgical therapy for patients with cervical dystonia, however, should be scrutinised because focal dystonia is not a life-threatening disease and botulinum toxin treatment provides some symptomatic relief for most patients.

In this study, we aimed to assess the clinical efficacy and safety of bilateral pallidal neurostimulation for patients with medication-refractory cervical dystonia.