Elsevier

The Lancet Neurology

Volume 11, Issue 12, December 2012, Pages 1029-1038
The Lancet Neurology

Articles
Pallidal deep brain stimulation in patients with primary generalised or segmental dystonia: 5-year follow-up of a randomised trial

https://doi.org/10.1016/S1474-4422(12)70257-0Get rights and content

Summary

Background

Severe forms of primary dystonia are difficult to manage medically. We assessed the safety and efficacy of pallidal neurostimulation in patients with primary generalised or segmental dystonia prospectively followed up for 5 years in a controlled multicentre trial.

Methods

In the parent trial, 40 patients were randomly assigned to either sham neurostimulation or neurostimulation of the internal globus pallidus for a period of 3 months and thereafter all patients completed 6 months of active neurostimulation. 38 patients agreed to be followed up annually after the activation of neurostimulation, including assessments of dystonia severity, pain, disability, and quality of life. The primary endpoint of the 5-year follow-up study extension was the change in dystonia severity at 3 years and 5 years as assessed by open-label ratings of the Burke–Fahn–Marsden dystonia rating scale (BFMDRS) motor score compared with the preoperative baseline and the 6-month visit. The primary endpoint was analysed on an intention-to-treat basis. The original trial is registered with ClinicalTrials.gov (NCT00142259).

Findings

An intention-to-treat analysis including all patients from the parent trial showed significant improvements in dystonia severity at 3 years and 5 years compared with baseline, which corresponded to −20·8 points (SD 17·1; −47·9%; n=40) at 6 months; −26·5 points (19·7; −61·1%; n=31) at 3 years; and −25·1 points (21·3; −57·8%; n=32). The improvement from 6 months to 3 years (–5·7 points [SD 8·4]; −34%) was significant and sustained at the 5-year follow-up (–4·3 [10·4]). 49 new adverse events occurred between 6 months and 5 years. Dysarthria and transient worsening of dystonia were the most common non-serious adverse events. 21 adverse events were rated serious and were almost exclusively device related. One patient attempted suicide shortly after the 6-month visit during a depressive episode. All serious adverse events resolved without permanent sequelae.

Interpretation

3 years and 5 years after surgery, pallidal neurostimulation continues to be an effective and relatively safe treatment option for patients with severe idiopathic dystonia. This long-term observation provides further evidence in favour of pallidal neurostimulation as a first-line treatment for patients with medically intractable, segmental, or generalised dystonia.

Funding

Medtronic.

Introduction

Primary dystonias comprise a clinically and aetiologically heterogeneous group of idiopathic movement disorders characterised by sustained muscle contractions, causing repetitive twisting movements or abnormal postures.1 The course of the disease is chronic and no cure is available. Despite the availability of peripheral denervation by botulinum toxin and systemic drug treatment with various combinations of anticholinergic, antidopaminergic, and muscle relaxing drugs, severe forms of primary dystonia are notoriously difficult to manage medically and can result in substantial motor handicap and social stigma.1 Deep brain stimulation (DBS) of the internal globus pallidus has been established as a surgical treatment alternative. Several randomised and open-label studies have reported a reduction of motor symptoms by 50–80%, an alleviation of dystonia-associated pain, and a subsequent improvement in quality of life after bilateral pallidal neurostimulation. DBS is now applied worldwide and the benefit-to-risk ratio of the therapy for dystonia is under scrutiny. A crucial question in this regard is whether or not the generally satisfactory response reported in early short-term studies is sustained after prolonged follow-up, because dystonia is a chronic disorder that requires lifelong symptomatic treatment. A controlled 3-year study of patients with generalised dystonia2 and an open-label series with up to 10 years of follow-up in mixed dystonia populations3, 4, 5, 6, 7, 8, 9, 10 suggest a sustained benefit from pallidal neurostimulation, but some of these reports also raise concern about secondary treatment failures.2, 5, 10

We have previously reported the results of the first prospective, blinded, and sham-controlled trial of neurostimulation for primary generalised or segmental dystonia in a large cohort of patients recruited from multiple centres in Germany, Austria, and Norway.11 Idiopathic segmental dystonia is defined by dystonic symptoms in at least two adjacent body segments, but differs in several other regards from primary generalised dystonia: it has a much higher prevalence, typically manifests in adults, frequently involves the neck and face area, shows less tendency to spread to other body areas, and is rarely caused by genetic mutations.1 Both forms of dystonia, however, can cause severe disability justifying a surgical treatment and were therefore included in our original trial. We found a significant effect of 3–6 months of neurostimulation in the masked and open assessments.11 Most patients consented to participate in an open-label extension study with annual follow-up visits for a period of up to 5 years after the activation of the neurostimulation device. Here we describe the development of motor and non-motor symptoms, disability, and adverse events throughout the 5-year period.

Section snippets

Study design and patients

In the parent trial, 40 patients with severe generalised or segmental idiopathic dystonia were implanted with a pallidal neurostimulation device and then randomly assigned to either sham neurostimulation or neurostimulation for a period of 3 months.11 Thereafter, all patients completed a 6-month period of active neurostimulation. Patients were recruited between July, 2002, and May, 2004, at ten academic centres in Germany, Norway, and Austria and had to fulfil the following inclusion criteria:

Results

38 of 40 patients agreed to a study extension. At variable intervals throughout the 5-year period reported here, another three patients withdrew their consent for the long-term extension. The 5-year visit was attended by a total of 32 of 35 patients still in the trial (figure 1).

The clinical baseline characteristics of the study population are shown in table 1. The unmasked investigators tended to score dystonia severity (BFMDRS motor score) higher (7·0 [SD 9·6] points at baseline and 1·5 [8·1]

Discussion

This prospective long-term follow-up of patients with dystonia treated by bilateral pallidal neurostimulation shows sustained improvements in dystonia ratings for up to 5 years after surgery. The mean 67% reduction of dystonia severity at 3 years and 60% reduction at 5 years compared with baseline in the per-protocol population closely match the benefit described by the only other controlled study (the SPIDY [French Stimulation du Pallidum Interne dans la Dystonie] trial) following patients

References (27)

  • M Vidailhet et al.

    Bilateral, pallidal, deep-brain stimulation in primary generalised dystonia: a prospective 3 year follow-up study

    Lancet Neurol

    (2007)
  • A Albanese et al.

    EFNS guidelines on diagnosis and treatment of primary dystonias

    Eur J Neurol

    (2011)
  • IM Skogseid et al.

    Good long-term efficacy of pallidal stimulation in cervical dystonia: a prospective, observer-blinded study

    Eur J Neurol

    (2012)
  • R Reese et al.

    Long-term clinical outcome in Meige syndrome treated with internal pallidum deep brain stimulation

    Mov Disord

    (2011)
  • L Cif et al.

    Long-term follow-up of DYT1 dystonia patients treated by deep brain stimulation: an open-label study

    Mov Disord

    (2010)
  • F Cacciola et al.

    Bilateral deep brain stimulation for cervical dystonia: long-term outcome in a series of 10 patients

    Neurosurgery

    (2010)
  • M Sensi et al.

    Pallidal stimulation for segmental dystonia: long term follow up of 11 consecutive patients

    Mov Disord

    (2009)
  • IU Isaias et al.

    Deep brain stimulation for primary generalized dystonia: long-term outcomes

    Arch Neurol

    (2009)
  • D Gruber et al.

    Long-term effects of pallidal deep brain stimulation in tardive dystonia

    Neurology

    (2009)
  • TJ Loher et al.

    Deep brain stimulation for dystonia: outcome at long-term follow-up

    J Neurol

    (2008)
  • A Kupsch et al.

    Pallidal deep-brain stimulation in primary generalized or segmental dystonia

    N Engl J Med

    (2006)
  • RE Burke et al.

    Validity and reliability of a rating scale for the primary torsion dystonias

    Neurology

    (1985)
  • JE Ware et al.

    The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection

    Med Care

    (1992)
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