Primary Generalized Dystonia: Encouraging Results For Deep-Brain Stimulation

Abstracts & Commentary

Synopsis: The findings support the efficacy and safety of the use of bilateral stimulation of the internal globus pallidus in selected patients with primary generalized dystonia.

Source: Vidhailet M, et al. Bilateral Deep-Brain Stimulation of the Globus Pallidus in Primary generalized Dystonia. N Engl J Med. 2005;352:459-467.

This prospective, controlled, multicenter study evaluated safety and efficacy of bilateral deep brain stimulation (DBS) of the ventral internal globus pallidus (GPi) in 22 patients with disabling and longstanding primary, progressive, generalized dystonia. Median age at surgical intervention was 30 years (range 14-54), median disease duration was 18 years (range 4-37), and 20 were receiving medical treatment for dystonia (14 taking anticholinergic agents). Seven patients carried the DYT1 mutation. All but 1 patient underwent postoperative MRI, confirming adequate electrode-contact position. Primary outcome measures were scores on movement and disability subscales of the Burke-Fahn-Marsden scale (BFMS), a validated instrument to assess dystonia severity. Assessments were performed preoperatively (baseline) and at 3, 6, and 12 months. Blinded raters evaluated videotaped, standardized BFMS examinations presented randomly, and patients served as their own controls. Secondary outcome measures included scores, with stimulators on and off at 3 months and quality of life at 12 months. At 12 months, BFMS movement score improved by >50% (P < 0.001), compared to baseline. Scores in a subset of individuals improved with time, with 14/22 improved by >50% at 12 months, compared to 11/22 at 3 months. Clinical improvement was attributable to DBS; turning off the stimulator at 3 months led to worsened dystonia within hours. Global disability score improved at month 3. Of the 14 taking anticholinergic medications preoperatively, mean dose was reduced by month 12. Five complications affected 3 patients: 1 patient experienced asymptomatic frontal lobe edema and other adverse events were hardware-related (lead fracture, scalp necrosis, hematoma, infection); all of these resolved without permanent effect.

Commentary

Generalized dystonia is a chronic, progressive, heterogeneous disorder, typically affecting children and young adults. Treatment is often challenging. Its medical therapy commonly requires polypharmacy, with slow and painstaking dose adjustments, and drug side effects limit potential benefits. Botulinum toxin injections are impractical (in contrast to focal or segmental disease), given the number of muscles are involved. Surgical treatment of dystonia, exploiting DBS technology, was approved by the FDA in April 2003. However, reports in the literature are based on small case series or isolated cases, mostly without controls. The current study is important in 2 respects: 1) patient selection and treatment was highly standardized and 2) blinded assessments, on and off stimulation at 3 months, provided an important internal control. The study demonstrates that bilateral GPi DBS was effective in these severely impaired, carefully selected individuals up to 12 months after surgery. The exact neurophysiology of this observation remains speculative.1,2 However, GPi neurons fire irregularly with reduced overall rates in dystonia, so presumably, DBS jams this abnormal signal. Most fascinating in the present study is the heterogeneous response of individuals, with 4/22 failing to improve. Indeed, overall improvement in scores seemed to be driven by subjects with diffuse, phasic hyperkinetic movements, as opposed to those with tonic postures. There is clearly a need for further refinement of criteria for patient selection for surgery. In parallel to our experience with DBS for Parkinson’s disease, this step will no doubt be crucial in improving outcomes in this potentially devastating disorder. — Claire Henchcliffe

References

1. Vitek JL. Pathophysiology of Dystonia: A Neuronal Model. Mov Disord. 2002;17(suppl; 3):S49-S62.

2. Krauss JK, et al. Deep Brain Stimulation for Dystonia. J Clin Neurophysiol. 2004;21:18-30.