In our series of 6 consecutive patients with medically refractory dystonia treated by GPi DBS, we observed significant improvement in dystonic symptoms, with 56%± 7.6 and 67%± 6.8 improvement in BFMDRS at the 6- and 12-month follow-ups in all patients. There was a persistent reduction in BFMDRS motor subscores in four of the six patients during the last follow-up visit. These four patients had idiopathic or genetically isolated dystonia, which included Meige’s syndrome (Patient A), KMT-2b dystonia (Patient D), DYT6 dystonia (Patient E) and primary generalized dystonia of unknown etiology (Patient F). The improvements in patients A, D, E and F were 75%, 82%, 74% and 81%, respectively (mean± sem: 78%± 2.0), at the last follow-up visit. The two patients with acquired dystonia, one with cerebral palsy (Patient B) and the other with PKAN (Patient C), both showed some degree of deterioration in symptoms, as shown by the increase in BFMDRS motor subscore during the last follow-up visit. This discrepancy in results may be related to the influence of the underlying pathology of the secondary dystonia patients. Similar to the observations from previous studies, patients with idiopathic or genetic dystonia respond better and more consistently to GPi DBS than patients with acquired dystonia.3,9,14
Primary dystonia patients with different genetic etiologies, such as DYT-TOR1A (DYT1), DYT-THAP (DYT6), and DYT-KMT2B (DYT28) mutations, may show different responses to DBS treatment.5,6,15 Although variable outcomes were reported in previous studies, Patient D, who had the DYT-THAP mutation and presented with dystonia involving the trunk rather than the orofacial region, showed excellent improvement after a 31-month follow-up.16 DYT-KMT-2B was reported to have good improvement after GPi DBS, and a similar improvement was also observed in Patient E during the 23-month follow-up.17 For Patient F in our cohort, who presented with progressive generalized dystonia that rapidly developed into a dystonic storm, we could find no definite cause even after serial diagnostic work-up and whole-exon sequencing. This patient also responded well after GPi DBS, similar to other patients with primary dystonia. Our results suggest that primary dystonia patients with identifiable genetic causes or idiopathic etiologies should always be evaluated for DBS therapy when other treatments fail and before skeletal deformity develops. In patients with acquired dystonia, more careful evaluation of their underlying pathology and possible benefits of DBS should be performed before DBS because of the heterogeneous pathology and variable long-term outcomes after DBS in this population.9
GPi DBS has been considered one of the most effective treatments for status dystonicus (SD, or dystonic storm).18–20 This is a life-threatening condition that can lead to respiratory, infectious, and metabolic complications and can even result in the need for intubation and ventilatory support. SD can occur in patients with rapidly progressing dystonia and is refractory to other medical treatments.18,20,21 Patient F in our cohort presented with SD three months before surgery. After a brief diagnostic workup, emergent DBS implantation surgery was performed and GPi DBS was initiated urgently. After stimulating bilateral ventral GPi electrodes (contact 0 and 1) for 1 week, this patient showed some early symptomatic relief from SD, which prevented him from a life-threatening condition. This is also compatible with previous literature describing that SD usually responds to DBS sooner than does stable dystonic symptoms.18–20 Although no genetic or other etiology was found in this patient, his dystonic symptoms continued to improve after GPi DBS until the last follow-up (13 months). This case clearly demonstrates that immediate action in performing GPi DBS for patients with SD has great value in relieving this emergent condition and that it can be life-saving.19
Programming of DBS in dystonic patients is still a challenging issue. In contrast to PD, in which the effect of DBS on tremor and rigidity can be observed within seconds to minutes, the DBS effect on dystonic symptoms usually has an onset of several days or weeks after stimulation is initiated, and the peak effect is often not reached until several months of GPi stimulation.8,11 The phasic component of dystonia may respond to GPi DBS much earlier than the tonic component. This delayed effect was observed in our cohort with idiopathic isolated dystonia (Patients A, D, E, F). The BFMDRS motor subscore improved by an average of 56.6% at 6 months and reached 74.8% at 12 months and 78% at the last follow-up visit (average 66 months) after DBS therapy. There is considerable heterogeneity in stimulation settings among centers. Thus, the approach to GPi DBS programming is rather empirical.8,11
Checking whether the DBS electrodes are correctly placed in the posteroventral GPi by postoperative imaging is an important step in good DBS programming. Another step in assuring good DBS outcomes is selecting the best electrode location within GPi. This is usually done over a period of 6 to 8 weeks. The most ventral electrodes of the GPi, just above the optic tract (contact 0), are usually first selected in the first 2 weeks, followed by contacts 1, 2 and 3, each lasting for a 2-week period. Because the stimulation side effects are rather acute and the beneficial effects are often delayed in GPi DBS, the highest tolerable amplitude and pulse width in each electrode, just below the level that elicits adverse effects, are often used to maximize the stimulation effects while avoiding side effects. The side effects of GPi DBS often include paresthesia, muscle spasms, phosphenes, or nonspecific symptoms (malaise, nausea). After determining the location of the most effective electrode during this testing period, the best DBS electrode and its configurations are chosen for long-term treatment.8 In a previous review study, data extraction from 192 publications and 1,505 patients, larger amplitude range (average 3.3 V), wider pulse width range (average 112~446 µs) and common frequency range (average 131 Hz) were used with favorable outcomes.11 In our cohort, the average stimulation parameters (2.0± 0.24 mA in intensity, 252± 43 µs in pulse width, and 99± 6.0 Hz in frequency) were similar to or lower than the average, but there was more common use of double unipolar or interleaving stimulation configurations. These findings may suggest that better stimulation location was more significant than higher stimulation settings for GPi DBS in this cohort.