, new research shows. In the longest follow-up study comparing the subthalamic nucleus (STN) or the globus pallidus (GPi) as treatment targets for Parkinson’s disease, investigators found DBS was effective at 10 years regardless of which of these two brain regions were treated.
“Both STN and GPi DBS maintained motor benefit out to 10 years, with improvements seen in tremor and rigidity, greater than bradykinesia,” said study author, medical director and division chief at the University of California, San Francisco Movement Disorders and Neuromodulation Center.
“Less medication was required, and patients had fewer motor fluctuations and less dyskinesia,” she added. But nonmotor symptoms and other symptoms that are less responsive to DBS progress led to worsening disability over time.
The findings were presented at the American Academy of Neurology’s 2021 annual meeting.
Many studies have examined the GPi and STN as targets for deep brain stimulation in Parkinson’s disease. Some research has compared outcomes between the two targets, but no prospective, randomized trials have evaluated outcomes beyond 3 years of treatment.
For the study, investigators examined data from Study 468, a multicenter, randomized, controlled trial conducted by the U.S. Veterans Affairs (VA) Cooperative Study Program and the National Institute of Neurological Disorders and Stroke (NINDS). In this study, a subset of patients who had been randomly assigned to deep brain stimulation of the GPi or STN were followed for up to 10 years.
Participants were examined at 2 years, 7 years, and 10 years. Eighty-five participants assigned to GPi and 70 assigned to STN completed the visit at 2 years. At 7 years, 68 GPi patients and 49 STN patients completed the visit. Forty-nine patients assigned to GPi and 28 assigned to STN completed the visit at 10 years.
The study’s primary outcome was change in the Unified Parkinson Disease Rating Scale (UPDRS) motor subscale score while off medication and on stimulation between targets. Secondary outcomes included tremor, rigidity, and bradykinesia.
The two groups of patients had comparable baseline characteristics. Mean age was approximately 59 years in both groups. The proportion of male patients was 87% in the GPi group and 83% in the STN group. White patients predominated in the GPi (98%) and STN (94%) groups.
Average disease duration was approximately 11 years, and more than 10% of patients in each group were older than 70 years, indicating a “somewhat more advanced patient cohort,” said Dr. Ostrem.
Although the study’s dropout rate was high, the researchers found no difference in baseline characteristics between patients who did and did not complete the study.
Consistent motor improvement
Motor function improved at all timepoints for patients in both study arms. Baseline UPDRS motor subscale score was 43.2 for patients assigned to GPi stimulation. This score changed to 25.8 at 2 years (P < .001), 35.4 at 7 years (P < .001), and 34.0 at 10 years (P = .10).
Baseline UPDRS motor subscale score also was 43.2 for patients assigned to STN stimulation. This score changed to 27.7 at 2 years (P < .001), 34.4 at 7 years (P < .001), and 28.3 at 10 years (P < .001). Improvements were similar between groups but tended to be greater in the STN group.
Among the study’s secondary outcomes, tremor subscales showed the greatest improvement over time, followed by rigidity subscores. Compared with GPi DBS, STN DBS was associated with greater improvement in bradykinesia subscores at 7 and 10 years (P = .03).
In addition, UPDRS I, II, and IV scores, as recorded in motor diaries, showed significant long-term improvement in both study groups. Part I (which reflects mentation and mood) and part II (which reflects activities of daily living) tended to worsen at 7 and 10 years. There were no differences between groups.
Total score on the Parkinson’s Disease Questionnaire-39 (PDQ-39), which measures function in daily living, no longer showed improvement at 7 or 10 years for either target. Rather, it showed worsening, compared with baseline.
“Cognitive impairment and gait and balance issues result in more issues with quality of life and independence,” said Dr. Ostrem.
Stimulation of both targets reduced medication use significantly. There was no difference between targets for this outcome.
The rate of device-related complications in this cohort was comparatively low, said Dr. Ostrem. In the overall study complication, the rate of DBS malfunction was 7.7%, and the rate of DBS infection was 5.8%.
The finding that both targets had similar long-term sustainability of motor benefit provides reassurance that either target is a reasonable choice, said Dr. Ostrem. “I would suggest target choice be determined by a multidisciplinary team, where individual patient signs and symptoms and goals can be considered.”
Other large DBS trials with shorter follow-up durations have suggested differences between the targets. These data can guide the choice of target, said Dr. Ostrem.
“The field of DBS research has never been more exciting,” she added. Newer systems that include improved hardware and software and can record neurophysiologic data from the implanted brain leads could provide improved outcomes of DBS treatment.
“With modern DBS methods and approaches, we are learning more about Parkinson’s disease and other brain diseases, which I believe will help us to find more treatments and other interventions to slow the progression or minimize symptoms,” Dr. Ostrem concluded.
Commenting on the study,, chair in neuromodulation and multidisciplinary care at University of Toronto, noted that “these are the first long-term findings resulting from a randomized trial, overall supporting the early notion that STN DBS is superior to GPi DBS in terms of bradykinesia improvement, especially in the long-run.”
The findings reflect the clinical practice of considering STN deep brain stimulation for young patients who face a longer disease duration. Younger patients might tolerate the procedure better than older patients. They also may achieve medication reduction, better motor control, and the possibility of increasing medication when side effects make increased stimulation undesirable.
“It’s interesting to note that even GPi DBS maintained an overall good outcome over time,” said Dr. Fasano. This finding contrasts with that of previous studies, but the latter were limited by selection bias, he added. “Older and frail patients were more likely to be treated with GPi DBS.”
Two factors limit the study’s findings, said Dr. Fasano. During the long study duration, many patients dropped out or were lost to follow-up. “Thus, it is conceivable that the study only enrolled the best responders in each group,” said Dr. Fasano.
In addition, the results of the trial that the current investigators analyzed are not necessarily generalizable, as those who conducted it soon recognized. The study by the VA and NINDS did not detect differences between targets, mainly because of a surprisingly low effect of STN deep brain stimulation. The researchers determined that this finding was related to the study’s inclusion criteria.
“The lack of improvement [on the PDQ-39] clearly indicates that simply treating the motor problems of Parkinson’s disease patients is not enough,” said Dr. Fasano. It also emphasizes that DBS is a symptomatic therapy with little or no effect on the disease’s natural history.
“It will be also important to see how the new data reported by Dr. Ostrem compare to the long-term outcome of the other major STN versus GPi trial from Europe,” said Dr. Fasano, referring to the NSTAPS trial.
He added that it will also be interesting to follow these cohorts for at least 5 more years in order to identify possible differences in terms of disease milestones such as dementia and survival. Previous studies have shown a reduction in survival with targets other than STN, but this finding likely reflects selection bias, he concluded.
The study was funded by the National Institute of Neurological Disorders and Stroke and the U.S. Department of Veterans Affairs. Dr. Ostrem previously has accepted consulting funds from Medtronic and Abbott. She receives grant support from Medtronic and Boston Scientific for fellowship training and clinical trial support. These companies were not involved in the study. Dr. Fasano received honoraria and research support and honoraria from Abbott, Boston Scientific, Brainlab, Ceregate, Inbrain, and Medtronic.
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