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Deep Brain Stimulation for Parkinson's Disease: A Randomized, Controlled Study Answers Many Remaining Questions
Abstract & Commentary
By Michael G. Kaplitt, MD, PhD, Vice-Chairman for Research and Associate Professor of Neurological Surgery and Neurology, Director of Stereotactic and Functional Neurosurgery, Weill Cornell Medical College. Dr. Kaplitt reports no financial relationship relevant to this field of study.
Synopsis: Deep brain stimulation significantly increases "on" time, reduces dyskinesias, reduces "off" time, and improves various quality-of-life measures compared with best medical therapy in patients with moderate to advanced Parkinson's disease.
Source: Weaver FM, Follett K, Stern M, et al. Bilateral deep brain stimulation vs. best medical therapy for patients with advanced Parkinson's disease: A randomized controlled trial. JAMA 2009;301:63-73.
Deep brain stimulation (DBS) for Parkinson's disease (PD) has been approved in the United States and other countries for nearly a decade, and has clearly benefited thousands of patients who develop motor fluctuations, resistant tremors, increasing "off" times, and/or dyskinesias following years of medical therapy. Despite this long experience, however, many practitioners who manage PD patients remain unclear as to the role of DBS in the management of this disorder due to the surprising lack of large, well-controlled, and well-designed studies evaluating the true benefits and risks of this procedure in a diverse patient population.
Recently, a large, multicenter, randomized, controlled trial comparing DBS with best medical therapy clarified many of these residual questions. A consortium of Veterans Affairs and university hospitals randomized 255 patients with idiopathic PD to DBS (n=121) or best medical therapy (134). Patients were at least Hoehn and Yahr stage 2 or greater off medication, had poorly controlled motor symptoms ("off") for at least three hours per day, had disabling symptoms despite ongoing medication (such as severe motor fluctuations or adverse effects such as dyskinesias), and did not have significant medical contraindications for surgery, dementia, or prior surgical interventions. Outcomes were assessed by a rater blinded to treatment, and patients were additionally randomized based upon age, as this study uniquely included a fairly large number (25%) of patients older than 70 years.
The most striking findings of this study were the substantial improvements in most standard motor measures six months following DBS, with virtually no changes in the best medical therapy group. "On" time without disabling dyskinesias increased in the DBS group from 6.4 to 10.9 hours per day (p<0.001). This is even more impressive when considering that the average sleep time in both groups remained relative stable over time, at roughly seven hours per night, indicating that DBS improved good "on" time from 38% percent of waking hours to nearly 65% of waking hours following surgery. The improvement was due to both a decrease in the number of hours "on" with disabling dyskinesias as well as a decrease in the amount of "off" time. Similarly, the off-medication motor scores improved by nearly 30%, which is a bit lower than some earlier open-label studies but was still substantially greater than in the best medical group, which improved only 4% (p<0.001). Activities of daily living and several other quality-of-life measures also significantly improved in the DBS group, with no change in the best medical group, reflecting the genuine benefit that patients derived from these objective motor changes.
As with any therapy involving surgery and implants, several adverse events were observed which have long been familiar to DBS practitioners. A single patient died from a serious intracerebral hemorrhage following surgery, while 12 patients (10%) developed infections that required removal of all or part of the DBS system, and eight patients experienced hardware malfunctions or lead migrations. Surprisingly, the rate of adverse events was no greater in the group older than 70 years of age compared with younger patients, while the motor outcomes were also similar between groups, suggesting that properly chosen older patients can derive equivalent benefit with no greater risk than younger patients.
While DBS has been subjected to a variety of small studies as well as evaluations of patients on and off stimulation, the absence of large, randomized studies has somewhat restrained patient referrals due to ongoing confusion as to which patients should undergo surgery and what benefit can they expect to achieve. The current results build upon an earlier report by a European consortium which was the first large. randomized study comparing DBS and best medical therapy.1 Similar benefits of DBS were reported there again with no further benefit of best medical therapy and with a similar adverse-event profile. That was a smaller study (155 patients) and all patients were younger than 75 years old. The current report now adds a second major study to the literature, which confirms the longstanding belief that DBS, in the properly chosen patient, can provide significant improvements in motor function and quality of life with an acceptable adverse event profile given the level of pre-surgical disability.
A particularly important finding in the current study is the lack of differences in both benefits and adverse events following surgery in older (>70) patients compared with younger patients. It has long been believed, based upon anecdotal observations, that older patients have higher complications and less improvement following DBS. Since PD is a disease of aging, and with improvements in general health of the population over the past 40 years, the current result refutes that belief and suggests that withholding surgery based solely upon age is not justified and that this procedure should be considered for a larger group of patients in need. It is also interesting that best medical therapy by very experienced experts in PD management resulted in no change in any major motor parameters over time. This suggests that patients with sufficient disability after many years of good response to medication are unlikely to derive substantial benefit from delaying surgery for incremental changes in medications.
Certainly any surgical therapy must be carefully considered on an individual basis, and there were adverse events unique to the surgical group that were not surprising. All surgeons in this study were highly experienced and all used stereotactic frames and microelectrode recording, so these results cannot determine if other methodologies or differing levels of surgical experience influence outcomes. Longer-term follow-up is also needed to determine the stability of DBS effects, which have been anecdotally believed to be stable over several years, but which has never been formally studied in such a large patient population. Weaver and colleagues confirm that DBS, performed by experienced practitioners using this methodology, can substantially benefit patients who have responded well to medical therapy in the past but who now have significant motor fluctuations, "off" time, and/or disabling dyskinesias, and do not have significant medical or neurocognitive deficits regardless of age. Combined with the earlier report, this study should increase confidence in the value of DBS for this patient population and should be seriously considered when symptoms responsive to DBS become difficult to manage medically and significantly impair the quality of life.
1. Deuschl G, Schade-Brittinger C, Krack P, et al. A randomized trial of deep-brain stimulation for Parkinson's disease. N Engl J Med 2006;355:896-908.