“Regardless of how we looked at the data, the result was the same,” he said. “This was a very robust finding.”
These 25%–30% reductions in UPDRS III scores are not as great as the 40%–50% improvements that have been reported in open-label, uncontrolled studies. This might be a result of having slightly fewer disabled patients in the current study than in studies described in earlier reports, which included patients with UPDRS III scores in the high 40s and low 50s, Dr. Follett said. He noted the possibility of a “floor effect” to DBS, meaning that “you can only improve patients to a certain point, so the lower the UPDRS starting score, the [lower the percentage of] improvement there's going to be.”
Data from the patients' motor diaries indicated that at 2 years, GPi patients had about 1 hour more of “on” stimulation time without dyskinesias (from 6.5 to 11.4 hours) than did STN patients (from 7 to 11 hours), although this was not statistically significant.
Quality of life assessments at baseline with the Parkinson's Disease Questionnaire (PDQ-39) indicated that STN-targeted patients had slightly worse scores for emotional well-being, social support, and cognition. Dr. Follett suggested that these “very small point differences” might reflect the fact that the STN arm of the trial included slightly fewer men than women, who “tend to report slightly greater disability in chronic disease compared with men.”
At 2 years, there were no differences between the groups on the PDQ-39. With the exception of social support and communication, quality of life improved on each subscale of the PDQ-39. GPi patients reported slightly improved depressive symptoms on the Beck Depression Inventory, compared with slight worsening of symptoms in STN patients. But the difference was not statistically significant.
Baseline assessments of neurocognitive function and mood in category fluency and learning and memory also were slightly worse in STN patients than in GPi patients. After 2 years of DBS, neurocognitive function worsened slightly in both groups. STN patients experienced significantly greater worsening of visuomotor processing speed than did GPi patients, although the change was slight.
No differences between the groups were detected on other UPDRS subscales (I, II, and IV).
Because the trial was not powered to test for differences between secondary outcomes, Dr. Follett noted that further analyses of the data will contend with what to make of very small differences that are detected between groups because of the large sample size.
“The question we need to address is, 'Are those small differences that might be statistically significant [also] clinically significant?' So keep in mind that some of these statistically significant differences are fairly small in terms of points and might not be clinically significant.”
Use of Parkinson's disease medications declined by a significantly greater percentage with STN-DBS (30% decrease) than with GPi-DBS (about a 20% decrease).
Similar numbers of serious adverse events occurred in the GPi (77) and STN (83) arms, and there was no difference in the type of events that were seen, such as prolonged or new hospitalization, repeat surgery, morbidity, or death.
“What's going to be much more important is how these folks do 5 years out, 8 years out, 10 years out. Is there a point at which Parkinson's disease progresses or the beneficial effect of DBS will be lost?” he asked.
My Take
Nonmotor Effects Rise in Importance
STN has been the most common target of DBS for Parkinson's disease ever since deep brain stimulation pioneer Dr. Alim-Louis Benabid of France suggested in the mid-1990s that it was a better target for DBS than the GPi. Given the similar degree of motor improvement observed with either target in this trial, the choice of stimulation site could now depend on the presence of other factors, such as dyskinesia. (Most clinicians would say that the GPi is a better target than the STN for dyskinesia.)
It will be important to follow up with the patients as planned, but previous reports of DBS with longer than 2 years of follow-up seem to indicate that the effect of stimulation does not decline substantially beyond that. However, there are few reports of more than 5 years of follow-up.
Because the trial was designed nearly 10 years ago, the investigators might not be able to analyze their results for some of the issues that have arisen more recently in Parkinson's disease research, such as the dopamine dysregulation syndrome (including pathological gambling and impulsivity).
It will be important to resolve whether the greater level of depressive symptoms observed in the STN patients is a reflection of their greater reduction in medication use or is a potential effect of stimulating that site. If reducing medications increases depressive symptoms in STN patients, then it could be a reason to not reduce medication use.