These results indicate that bilateral GPi-DBS is effective in improving the severity of dystonia in both the short (2–6 months) and long-term (9–15 months). The mean improvement in severity of dystonia at 9–15 months was 25.7%. Compared with preoperative status for the whole group, quality of life also showed an improvement, whereas disability did not improve significantly. At 9–15 months postoperatively, 66.7% of patients showed an improvement in severity of dystonia of 20% or more, and 31.3% showed an improvement in disability of 20% or more. Global quality of life ratings showed a median improvement of 83.3% at 9–15 months, 64.7% of patients improved by 20% or more. Severity of dystonia preoperatively and disease duration predicted improvement in severity of dystonia at 2–6 months. Improvement in disability at 2–6 months, as well as at 9–15 months, correlated with improvement in severity of dystonia. However, none of the preoperative scores were successful in predicting improvement in disability and quality of life. Pharmacotherapy was reduced in 50% of patients 9–15 months after GPi-DBS.
Although these findings are positive and encouraging, our study has several limitations. Due to the retrospective and multi-centre nature of this study, some data were missing. By working in parallel through movement disorders centres, surgical centres and patient support groups we tried to identify as many patients with NBIA implanted with DBS as possible. However, patients who were not organized within the support groups, or underwent surgery at centres not able or willing to participate, may have escaped our survey. A further problem was that due to the wide variability of the NBIA phenotype, clinical scales do not always entirely suit all individuals. In addition, retrospectively obtained caregiver quality of life ratings are subject to bias, as all subjects received GPi-DBS. Furthermore, retrospective assessment of quality of life will exaggerate the effect of therapy due to recall bias. Despite these limitations, we believe that our study shows a realistic picture of the outcome of GPi-DBS in dystonia in NBIA patients. In particular, these results are important because all cases, including those with non-favourable outcomes, were included. This study had no formal monitoring, but was carried out through careful retrospective evaluation of patient records. Thus, under-reporting of adverse events is possible.
In our patient sample, we were not able to assess the efficiency of GPi-DBS in different genetic subtypes of NBIA because all patients in whom genetic testing had been performed had pantothenate kinase-associated neurodegeneration except for one, in whom no mutation was identified. Thus, a statistical comparison between pantothenate kinase-associated and non-pantothenate kinase-associated neurodegeneration was not possible. However, we predict that severity of dystonia, as well as presence or absence of other symptoms, are more powerful predictors of therapeutic outcome than genetic status.
There was a discrepancy in the current survey between the motor outcome of GPi-DBS and the comparatively small effect on disability as assessed using the BFMDRS disability scale. There are several reasons why this might have been the case. The current study was not blinded, causing a potential observer bias by the clinical rater assessing the dystonia. Furthermore, the BFMDRS disability scale was developed for use in patients with primary torsion dystonia and may not be well suited for some of the patients in this cohort, who can be paediatric and severely disabled. For example, the BFMDRS only distinguishes between ‘walking with help’ and ‘wheelchair-bound’. The ability to control the wheelchair independently, or the autonomous transfer in and out of it, is not taken into account. Specific scales for patients with NBIA are unavailable. A scale used in paediatric settings is the Care and Comfort Hypertonicity Questionnaire (Nemer McCoy et al., 2006), which was developed for use in children with cerebral palsy. Since DBS in paediatric patients is still relatively uncommon, patients are frequently attended by adult neurologists, who more frequently use the BFMDRS and are often unfamiliar with paediatric scales. Thus, the BFMDRS as the most frequently employed scale is valuable because it allows comparison with other studies, although it might not adequately reflect changes at all levels of severity.
Likewise, there was a discrepancy between the small effect on disability and the rather impressive improvement in quality of life. Of course, retrospective quality of life ratings may have overestimated the effect of therapy due to a recall bias. However, quality of life in dystonia also reflects numerous factors beyond disability, such as pain due to dystonia, stigma, fatigue due to medication and several other factors (Mueller et al.
all of which are not addressed in the BFMDRS-D. Although not quantified in the current survey, pain was reported to be reduced in many of the patients in the cohort, as was social stigma due to very visible dystonia. Thus, it is conceivable that quality of life improved considerably despite relatively small changes in disability.
The study by Castelnau and colleagues (2005
) reported a 74.6% improvement in severity of dystonia, compared with 25.7% in the current study, as well as a 53% improvement in disability compared with 15.8% improvement in the current study. The patient samples did not differ significantly in age at onset, disease duration, age at surgery, severity of dystonia or severity of disability. The cases reported by Castelnau et al.
) were stimulated with very long impulse durations which differ from those used in the current study. Furthermore, Castelnau and colleagues (2005
) have considerable experience with DBS in secondary childhood dystonia, and thus, may have selected suitable patients more carefully than other centres. Also, postoperative programming may have been carried out based on more expertise. The strength of the current study is that patients were included regardless of outcome, thus giving a realistic picture of the outcomes of GPi-DBS in NBIA. In particular, no lethal outcomes were reported in the Castelnau et al.
) study. In our sample, one patient died during the period of observation due to dystonic storm with onset before the operation. A second patient died of pneumonia two years after surgery. No systematic quantification of any accompanying symptoms, such as those due to pyramidal tract degeneration, was done in either the Castelnau et al.
) study or our study. Thus, the difference in outcome may be related to differences in neurological signs and symptoms, other than dystonia itself, between the two population samples. This may be due to differences in (not explicitly stated) selection criteria between different centres.
We found no significant difference in severity of dystonia, disability and quality of life between 2–6 months and 9–15 months after surgery. Castelneau and colleagues (2005) also report a sustained response over a maximum of 42 months. Although there was no significant difference between 2–6 months and 9–15 months outcomes, the data in suggest a relative outcome decline at least in some patients. We think this decline is due to disease progression. In cases where MRI imaging has been repeatedly performed, there is an increase in the area of T2
hypointensity in the putamen and globus pallidus which is paralleled by clinical deterioration (Hayflick et al.
). Of course, there is always the possibility of a placebo effect or an observer bias component, which cannot be ruled out in an open trial. However, the placebo effect of GPi-DBS in dystonia seems to be relatively small (Kupsch et al.
). Recurrence of dystonia during temporary reductions in amplitude, or while turning off the stimulation to change settings, suggest a maintained stimulation effect throughout. Neither this study nor the Castelneau et al.
(2005) study had a control group of patients with NBIA who did not undergo GPi-DBS. However, a randomization of NBIA patients deemed suitable for DBS into a GPi-DBS group and a non-GPi-DBS group is difficult to justify ethically. An open control group of patients who choose not to undergo GPi-DBS may serve as a viable compromise control group for further studies.
Since this was a retrospective study, factors other than GPi-DBS to treat dystonia, e.g. pharmacotherapy, were reported but not controlled. However, out of 22 patients for whom information on pharmacotherapy was available, 18 (82%) either had reduced medication, or their pharmacotherapy was unaltered at three months. Thus, the antidystonic effect can be safely attributed to GPi-DBS and is unlikely to be due to changes in pharmacotherapy. Although the reduction in medication is mostly dictated by the treating physician, it may be relevant because antidystonic drugs frequently cause side effects such as drowsiness. A reduction in medication will reduce side effects, thereby possibly improving quality of life.
We found in patients with NBIA that more severe dystonia preoperatively predicts greater improvement postoperatively. In contrast, in primary generalized dystonia subjects, Vasques and colleagues (2009
) found that higher preoperative BFMDRS scores were associated with less improvement in primary generalized dystonia postoperatively. In addition, longer disease duration and the presence of fixed, skeletal deformities in those with primary generalized dystonia has been shown to be associated with less favourable outcome after treatment with GPi-DBS (Isaias et al.
; Vasques et al.
). These differences in our findings may be related to the course of dystonia in patients with NBIA as compared to patients with primary generalized dystonia. In NBIA, dystonia can develop relatively rapidly, resulting in severe generalized dystonia without fixed skeletal deformities. Therefore, the issue of disease duration and the presence of fixed skeletal deformities may not be relevant to the NBIA patient. Hence, the significant improvement observed in severely affected NBIA patients encourages the consideration of GPi-DBS as a viable treatment in those with severe dystonia and underlying NBIA since skeletal deformities are less likely in these patients.
There were no systematic differences in terms of stimulation settings between patients with good and bad outcome. Given the sample size, the heterogeneity of the clinical picture and the number of other factors likely contributing to outcome, this is not surprising. Other studies of dystonia with larger, more homogeneous patient samples have also not found any particular settings which are more effective than others (Vasques et al.
In summary, we present evidence that secondary dystonia in NBIA improves with bilateral GPi-DBS. However, this improvement does not seem to be equal to the benefit reported in patients with primary generalized or tardive dystonias (Trottenberg et al.
; Vidailhet et al.
; Kupsch et al.
). NBIA patients with more severe dystonia seem to derive greater benefit from GPi-DBS. We recommend operating on patients as soon as dystonia becomes disabling and before any possible secondary skeletal deformities arise. A multi-centre, well-controlled prospective study is necessary to get large numbers of cases of this heterogeneous condition and thus be able to better predict the outcome from surgery. For this purpose, we are maintaining a prospective database of patients with NBIA undergoing DBS. We encourage the DBS community to contribute patients to this database with the aim of collecting systematic evidence of treatment effects in this rare condition.