Deep brain stimulation for dystonia: Make the lame walk

Generalized dystonia characterized by abnormal movements and tonic postures with involvement of the limbs, trunk, and orofacial region is a severe motor disorder with major limitations in daily living activities. Pharmacological treatments have limited efficacy, and pallidal deep brain stimulation (DBS) has been recommended for patients with severe dystonia. To date, a sustained improvement in motor symptoms and disability have been demonstrated in a prospective controlled study of bilateral DBS in primary generalized dystonia, in heterogeneous small studies, and in an uncontrolled, larger 2-year follow-up series with positive results in DYT1 and non-DYT1 children and adult patients. In contrast, patients with secondary dystonia showed less and more variable benefit. Because of the wide variability of causes and the lack of specific studies for each cause, no general conclusions or recommendations on the effects of surgery can be drawn. In this issue of the Annals, Castelnau and colleagues report the beneficial effect of bilateral stimulation of the posteroventral part of the internal globus pallidus (GPi) in six patients with genetically proven diagnosis of PKAN, who developed pharmacologically intractable early-onset, progressive, severe generalized dystonia. The 74% mean global motor improvement and the 53% disability improvement on the Burke-FahnMarsden dystonia scales were similar to those observed in primary dystonia. Benefit was obtained from month 3 and was stable thereafter with a 20-month follow-up. Several remarks can be drawn from this report, which may be extended to other types of dystonia. (1) Good and long-lasting improvement of dystonia can be obtained with bilateral DBS by targeting the posteroventral GPi, assumed to be the sensorimotor part, in not only primary dystonia but also selected forms of secondary or heredodegenerative dystonia. (2) Improvement is still possible in patients who have suffered from dystonia for decades, because those PKAN patients were operated on up to 22 years after disease onset. (3) In PKAN patients, painful muscle spasms disappeared and dystonic postures decreased. This may support the observation, already mentioned by other groups, that phasic forms of dystonia (with spasms and abnormal movements) may have a better improvement with DBS than tonic forms (fixed abnormal postures). (4) Although limb and trunk dystonia is improved by DBS, the benefit on speech intelligibility is more critical. This differential effect of DBS should be considered in patient’s selection for surgery. (5) Castelnau and colleagues used a 450 spulse width, 130Hz frequency setting, but other groups used shorter pulse widths (60 –210 s) with similar results. To date, the optimal parameters are still to be determined. (6) The most intriguing part is that, despite iron accumulation, neuronal degeneration, and gliosis, the GPi may not be totally damaged, because stimulation of its posterolateral portion is still effective. Therefore, one may hypothesize that in PKAN patients studied by Castelnau and colleagues, dystonia is associated with a residual, although abnormal, activity of the pallidal neurons, which is altered by high-frequency stimulation. In contrast, despite little visible lesions in the pallidum, DBS is less effective in generalized dystonia secondary to birth injury, suggesting that a widespread dysfunction of the sensorimotor pathways may be present and cannot be restored to a more physiological pattern by pallidal DBS. However, we should keep in mind that two in the six patients reported in Castelnau and colleagues’ study have an atypical PKAN with onset at teenage years and a more slowly progressive course. Besides, this is an open study and partial placebo effects cannot be ruled out. In more severe PKAN patients, the necrotic lesion may be larger and include the posterolateral GPi preventing so the effects of stimulating the same target area. Despite improvement at 2-year follow-up, there are still issues on the long-term benefit, because PKAN has a relentless progressive course and may include several features apart from dystonia, such as corticospinal symptoms, pigmentary retinopathy, and cognitive and psychiatric impairment. Only selected PKAN patients may experience great functional benefit from GPi DBS. As a conclusion, the analysis of open-labeled studies, in heterogeneous groups of patients with secondary dystonia, may be misleading: reputed intractable types of dystonia can be markedly improved by DBS as illustrated by the results in PKAN patients. Controlled studies, in homogeneous groups of either primary or secondary dystonia are essential to determine EDITORIAL