A smaller trial is also recruiting in the United States. While this study will provide information about the functional benefit of DBS in early Parkinson's, its main goal is to explore the neuroprotective effect of early surgery.
“To date, no therapy–not medication, surgery, stem cell or gene therapy–has been shown to slow the progression of Parkinson's disease,” Dr. David Charles, director of the Movement Disorders Clinic at Vanderbilt University Medical Center, Nashville, Tenn., said in an interview. “But recent animal studies have given us some really exciting insight into just how that might be accomplished.”
The Medtronic-sponsored Vanderbilt trial, which is just wrapping up its recruitment phase, will include 30 patients randomized to DBS plus medication or medication alone. These patients must have very early Parkinson's, with a Hoehn and Yahr stage of 2 when off medication; the follow-up is 2 years.
The study's main safety end point is the time to a 20% worsening in motor scores. “One concern with early stimulation is that we could somehow worsen Parkinson's disease, or cause some unforeseen problem, by applying the therapy early,” Dr. Charles said.
But perhaps more intriguing is the efficacy end point–the reduction in symptoms when the patient is off both medication and stimulation. The level to which symptoms decrease might give researchers insight into whether early DBS slows disease progression. Although he called it “a long shot,” Dr. Charles said the two in vivo studies give reason to hope.
In 2006, investigators at Maastricht (the Netherlands) University explored the neuroprotective effect of DBS in rats with a created model of Parkinson's disease–a toxin that killed up to 50% of the dopaminergic cells when injected into the substantia nigra. During the same procedure, some of the rats also underwent implantation of bilateral DBS electrodes. After 1 week, rats who received DBS had 30% more neurons in the substantia nigra than rats who received no treatment–suggesting that the activation of the electrodes had protected the cells from the toxin (Brain Res. 2006;1120:100–5).
“The most exciting study, though, was one performed in monkeys and published last year,” Dr. Charles said. “This study is superior, not only in its primate model, but in its Parkinsonian model, which more closely simulates the disease in humans.”
The French study, cowritten by DBS pioneer Dr. Alim-Louis Benabid, included 28 macaque monkeys (Brain 2007;130:2129–45).
Again, the researchers used a toxin to induce symptoms; in some monkeys, the toxic drug was delivered a week before surgery, allowing time for the dopaminergic cells to die off before brain stimulation began. “We know that by the time a patient presents with the first symptoms of Parkinson's, up to 70% of the substantia nigra neurons have already been lost,” Dr. Charles said. “This model was more similar to the natural history of the disease in humans.”
Monkeys in the experimental group received DBS for about 7 months. At the study's end, they showed up to 24% more nigral cells than did monkeys that had no stimulation.
Dr. Charles explained the theory behind this preservation effect. “Once the substantia nigra begins to degenerate, the subthalamic nucleus becomes hyperactive and increases its output of glutamate, which is toxic to dopamine-manufacturing cells. Although we don't know why the cells begin to die off in the first place, one strategy for protecting them from further depletion could be to reduce the hyperactive output of the subthalamic nucleus; DBS is thought to do that.”
Dr. Schüpbach is less enthusiastic about any potentially disease-modifying effect of DBS. “It's an open question at best,” he said. “We have more than 10 years of experience with DBS in Parkinson's patients, and we know that they do progress in spite of the treatment–especially with axial symptoms, which don't respond to either medication or simulation.”
Neuroprotection will be hard to prove in a small trial, he said. “We considered including it as a secondary outcome in the EARLYSTIM trial. But a power calculation told us that even with 250 patients, we would probably not be able to show a protective effect. If there is one, it would certainly be partial. There is certainly progression in spite of DBS, and it is certainly wrong to recommend it as a neuroprotective treatment without further evidence.”
All the researchers, however, agreed that the benefits of DBS should no longer be thought of as a last resort. In an editorial that accompanied Dr. Schüpbach's 2007 study, Dr. Riley noted that even under currently accepted surgical practice, too few people are getting the procedure. “Only a minor fraction of patents with Parkinson's who would benefit from DBS currently experience this treatment,” he wrote. Dr. Schüpbach's study “indicates that earlier application of DBS represents an improvement over our current approach to managing Parkinson's.”