Genetic Subtypes and Deep Brain Stimulation in Dystonia

In a review of his 20-year experience performing stereotactic ablations for dystonia, Irving Cooper concluded that of all the dystonia subtypes he treated, those with dystonia musculorum deformans responded best to surgery; and of all the targets, lesions within the internal globus pallidus (GPi) yielded the best results.1 Forty years later, we can conclude that what Cooper found to be true of ablation is also true of deep brain stimulation (DBS): patients with DYT-1 associated torsion dystonia respond most consistently and robustly to stimulation, and the internal pallidum remains the target of choice. In the current issue, two well-respected groups report very modest improvement in motor function (and perhaps even short-term worsening) in two patients with genetically proven DYT-12 dystonia, the mutation that underlies the disorder known as rapid-onset dystonia-parkinsonism (RODP). In one case,2 the authors targeted the subthalamic nucleus (STN), citing prior reports that GPi DBS had failed to yield significant improvement in clinically diagnosed RODP patients. In the other,3 the patient failed sequential bilateral DBS treatment; first at the GPi and then at the ventralis oralis posterior (VOP) nucleus of the thalamus. Both, the journal and authors are to be commended for reporting these negative results for, while it is commonly held that we learn more from failure than success, the bias toward publishing positive results remains a well-known problem both for the peer-reviewed scientific literature and the lay press, which is always eager to hype the latest medical “breakthrough.” The publication of negative trials and individual cases is essential so that future patients are not subjected to the risks of DBS, at least without some plan to try something different. On the other hand, just as we must avoid becoming too enthralled with a new therapy after only a few positive open-label results, we must also recognize that (at least from a statistical standpoint) one or two poor responses may not reflect a true lack of efficacy, particularly for a therapy as multi-varied and complex as DBS. Declarations of both success and failure must be made cautiously. With these publications, DYT-12 joins the ranks of heritable childhood primary dystonias whose response to DBS may be predicted preoperatively, based not on clinical presentation, but on genetic profile.4-6 Prior examples include DYT-1 (dystonia musculorum deformans),7-16 DYT-3 (Lubag X-linked dystonia/parkinsonism),17-22 DYT-6/THAP1,5, 23-29 and DYT-11 (myoclonus dystonia),30-35 all of which are considered to be responsive to DBS, though to varying degrees (Table 1). Patients with DYT-5 (dopa-responsive dystonia) are typically responsive to levodopa and should not undergo DBS surgery unless an adequate trial of this medication has been undertaken.36 Among these disorders, DYT-12 is unique in presaging a poor response to DBS, at least according to the few cases reported.2, 3, 37-41 DYT23, CACNA1B, CACNL1A5 It is widely understood that the varied responses we observe in Parkinson's disease (PD) patients who are treated with DBS at either the GPi or STN result from the fact that DBS is effective for only a subset of PD symptoms so that the overall effectiveness of DBS for a given patient is determined not only by the accuracy of lead placement and the optimization of stimulation parameters but by the patient's unique symptom profile and overall levodopa responsiveness. Viewed in this manner, dystonia appears to represent the converse problem in that it is not one disorder with varied symptoms, but a neurological symptom common to many disorders, each with a unique pathophysiology that may manifest as dystonia phenotypically, but which may not be equally amenable to electrical stimulation at the standard targets, with the standard range of stimulation parameters, or at all. Consequently, it is vital that we as a community continue to construct a literature-based experience of treating various dystonia subtypes, particularly those that are defined by strict genetic criteria. We must recognize that, given the rarity of these disorders, meaningful data can only be accumulated through “crowd-sourcing” and therefore dedicate ourselves to cooperate in this endeavor. In order to be valuable, these reports should include detailed descriptions of the patients' clinical course both before and after surgery, as well as appropriate clinical rating scale scores, confirmation that the patients do indeed possess the specific genetic mutation in question, technical details of the surgery, stimulation parameters, and imaging that demonstrates lead placement. Ideally, we should have a centralized database containing all of this information along with high-resolution post-operative CT scans that future researchers can employ to map the implanted leads within the various tractography or 7 Tesla-based anatomical atlases, which are currently under development. Such detailed reporting is necessary, for as the neurophysiology of these dystonia subtypes is revealed, we may come to understand better the physiological underpinnings of the response of dystonia to DBS as a whole. Moreover, new targets for stimulation may be revealed through “connectomics,” or as (yet unknown) physiological mapping techniques. The recent publication resulting from the International Tourette Syndrome Deep Brain Stimulation Public Database and Registry demonstrates this potential and should serve as a model for similar endeavors.42 It would seem that the time has come to construct such a database for the genetic dystonias. 1. Research project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. RLA: 1A, 1B, 1C, 3A, 3B AF: 1C, 3A, 3B Ethical Compliance Statement: The authors confirm that the approval of an institutional review board was not required for this work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.