Data from new studies suggest that patients with Parkinson's disease might benefit from deep brain stimulation surgery much earlier in their disease course, offering tantalizing hints that early surgery could actually delay progression by protecting the cells that Parkinson's destroys.
Since its 2002 approval for Parkinson's, bilateral subthalamic nucleus stimulation–a form of deep brain stimulation–has been reserved as a last resort for the most severely affected patients: those whose motor symptoms can no longer be controlled by medications because they experience severe side effects of chronic le-vodopa therapy.
But findings from at least one recent study suggest that early implantation of the electrodes also significantly improves quality of life for patients when some of these issues are just beginning to appear. Experts say this approach might be particularly beneficial for young patients who can be expected to have a long disease course and thus are at greater risk of developing complications of medical treatment.
“The idea behind earlier surgery is not to wait until the last minute, or just consider it a last-ditch effort,” Dr. David Riley, director of the Movement Disorders Center at the Neurological Institute of University Hospitals Case Medical Center, Cleveland, said in an interview. “The studies tell us that people who develop motor fluctuations will do better with surgery than with any combination of medications we can develop. Once a patient is spending more than 25% of the day in the 'off' state, we should be considering him or her for DBS surgery.”
While anecdotal reports and case series have described the results of earlier DBS surgery, researchers are only now beginning to explore the question systematically, said Dr. Michael Schüpbach, a movement disorders researcher at the Groupe Hospitalier Pitié-Salpêtrière, Paris. His 2007 pilot study examined the issue in a small group of patients with earlier disease (Neurology 2007;68:267–71).
“Our patients in general profited from DBS, not only on the motor symptom level, but in their activities of daily living, their disease-specific quality of life, and their overall psychiatric state,” he said in an interview.
The trial, sponsored by Medtronic, included 20 patients with disease duration of 5–10 years, a Hoehn and Yahr stage of 3 or lower, and motor fluctuations during “off” periods for 25% or more of the day. Half of the group received best medical therapy; the other half underwent DBS surgery while continuing on their medication, adjusted as necessary. They were followed for 18 months.
By the end of the follow-up period, Dr. Schüpbach and his colleagues observed several differences between the groups:
▸ Activities of daily living ratings declined significantly in patients who had been medically treated during their “off” periods, while they improved significantly throughout the study in the DBS group.
▸ Motor disability scores during “off” periods declined significantly in the medically treated group, dropping 29% by the study's end. In the DBS group, these scores improved by 69% at the same time point.
▸ By 18 months, medically managed patients experienced a significant 12% increase in their levodopa dosage, whereas their drug-induced motor complications worsened by 15%. Among the DBS patients, however, levodopa dosage decreased by 57% at 18 months, and the severity of drug-induced motor complications lessened by 83%.
▸ Anxiety and overall psychiatric morbidity improved significantly only in the DBS group. These patients also showed a trend toward improved mood, although the change was not significant.
“While this was only a pilot study that needs confirmation, I think it provided a very strong argument not to withhold surgery for the longest possible time, as we now do,” Dr. Schüpbach said.
However, he cautioned, both patients and physicians must carefully weigh the risks and benefits. There were no serious surgical adverse events in his study, but four DBS patients did develop depression, compared with three medically managed patients. “However, with only 20 patients, it's difficult to conclude anything about side effects,” Dr. Schüpbach said. “That would take a bigger study, and in fact, we're recruiting for one now.”
The EARLYSTIM trial, sponsored by the French government, will include 250 patients at 16 centers in France and Germany. Patients must have a Hoehn and Yahr stage of 2.5 or lower while on medication, and disease duration of more than 4 years. Again, the comparator arms are DBS plus medication, or best medical management alone. The patients will be followed for 2 years.
“We want to include patients with extremely early disease with the goal to keep them functional in their work and social context,” Dr. Schüpbach said. “I'm cautiously optimistic that the EARLYSTIM trial will replicate our pilot study.”