Can DBS in Early Parkinson's Disease Reduce Disease Progression?

Erik Greb

July 09, 2020

Data suggest that in patients with early Parkinson's disease, deep brain stimulation (DBS) of the subthalamic nucleus (STN) reduces the need for polypharmacy and decreases the risk of disease progression, compared with standard medical therapy, over 5 years of treatment. According to the investigators, a larger trial is needed to confirm these findings, which were published online ahead of print June 29 in Neurology.

Adverse events were similar between patients who underwent DBS and drug therapy and those who underwent drug therapy alone. This result is a preliminary indication of the safety of long-term DBS therapy, according to the researchers. Furthermore, patients who received DBS required a significantly lower levodopa equivalent daily dose (LEDD) and were less likely to need polypharmacy than were patients who received medical treatment alone.

"While we can be really excited about these findings, we can't change our practice, what we recommend to patients, based on this [study]," said David Charles, MD, professor and vice chair of neurology at Vanderbilt University, Nashville, Tenn. "We have to do the next trial to get that class of evidence."

An Extension of a Pilot Trial

Previous research has indicated that treatment with DBS and optimal medical therapy provides benefits beyond those of medical therapy alone in patients with mid-stage or advanced Parkinson's disease. Dr. Charles and colleagues conducted a randomized, single-blind pilot study to examine the safety and tolerability of STN DBS in 30 patients with early Parkinson's disease. Eligible participants had Hoehn and Yahr stage II off medication, were between 50 and 75 years of age, had taken medication for 6 months to 4 years, and had no dyskinesia or other motor fluctuations.

Patients were randomly assigned in equal groups to optimal drug therapy plus STN DBS or to drug therapy alone. Investigators evaluated patients every 6 months for 2 years. The results suggested that STN DBS was safe and slowed the progression of rest tremor in this population.

Apart from research that included patients with advanced Parkinson's disease, data relating to long-term follow-up of patients undergoing DBS for Parkinson's disease have been limited. Prospective studies have found that DBS provides motor benefits in patients with advanced Parkinson's disease after 5-10 years, but they have not included control groups of patients randomly assigned to medication alone. Understanding the durability of effect of DBS is particularly important in patients with early Parkinson's disease, because they could be exposed to stimulation for a longer time than other patients.

DBS May Slow Progression of Rest Tremor

Dr. Charles and colleagues invited patients who completed their pilot study to participate in an observational follow-up study. All 29 patients who completed the pilot study consented to participate in the follow-up. The investigators conducted annual outpatient examinations at 3, 4, and 5 years after baseline. These examinations were similar to those conducted at baseline in the pilot trial. Patients' scores on the Unified Parkinson's Disease Rating Scale (UPDRS) Part III were obtained through blinded video assessment. Rigidity was not assessed. The investigators calculated patients' levodopa equivalent daily dose (LEDD) and total electrical energy delivered (TEED). Adverse events were classified as mild, moderate, or severe.

Because of a problem with study funding, the investigators examined only eight patients in the optimal therapy group and nine patients in the DBS group at 3 years. The final analysis included 28 patients, because one patient was found not to have met inclusion criteria after the trial was completed.

At 5 years, participants' mean age was 66.1 years. Participants had been taking medications for Parkinson's disease for a mean duration of 7.2 years. No deaths occurred during the study. Four participants who had been assigned randomly to optimal drug therapy chose to receive STN DBS during the study. The investigators evaluated these participants in the treatment group to which they had been assigned at randomization using an intention-to-treat analysis that compared early STN DBS plus drug therapy with drug therapy alone.

Among patients with early DBS, the odds ratio (OR) of worse UPDRS III scores during 5 years was 0.42, compared with the medical therapy group. The difference in mean UPDRS III score between groups due to randomization was 3.70, which was a clinically important difference, according to the investigators.

In the early DBS group, the OR of worse rest tremor was 0.21, compared with the drug therapy group. The between-group difference in mean rest tremor score favored the DBS group. Excluding rest tremor from participants' UPDRS III scores eliminated between-group differences in the odds of having worse motor symptoms and in the magnitude of difference of motor symptom score.

In the early DBS group, the OR of requiring a greater LEDD was 0.26, compared with the drug therapy group. The between group difference in mean LEDD significantly favored the DBS group. In addition, at 5 years, the proportion of patients requiring polypharmacy was 93% in the drug therapy group and 43% in the DBS group.

The investigators found no difference between groups in the prevalence of dyskinesia at baseline. At 5 years, the prevalence of dyskinesia was 50% in the drug therapy group and 21% in the DBS group. The difference was not statistically significant, however.

The study groups had similar adverse event profiles. Five adverse events during follow-up were related to surgery or the DBS device. The most common of the 13 study-related adverse events was nausea.

The study's most significant finding is that "DBS implanted in early Parkinson's disease decreases the risk of disease progression," said Dr. Charles. No therapy, including DBS, has been proven to decrease this risk. "This is class II evidence. We have to get class I evidence before we change practice."

Dr. Charles and colleagues have received Food and Drug Administration approval for a multicenter phase 3 trial to obtain this evidence. The new trial may extend findings regarding DBS in mid-stage and advanced Parkinson's disease to early-stage Parkinson's disease. That is, it may show that DBS plus drug therapy in early stage Parkinson's disease is safe, efficacious, and superior to standard medical therapy alone. "But the reason to do the trial is to determine if it changes or slows the progression of the disease," said Dr. Charles.

Effect on Dyskinesia Is Unclear

"If a patient does go on to develop problems that need DBS management, and only a small fraction of patients with Parkinson's disease evolve to this need, then this procedure can be performed at that time," said Peter A. LeWitt, MD, Sastry Foundation Endowed Chair in Neurology at Wayne State University in Detroit.

"One confound of the study is that DBS provides symptomatic relief of dyskinesias if a patient has developed this problem after a few years of levodopa treatment," Dr. LeWitt added. "To demonstrate that early use of DBS prevented the development of dyskinesias, the study design should have included a period of turning off the stimulators to determine whether the generation of dyskinesias was prevented, rather than merely suppressed by DBS, as any patient would experience.

"Finally, the goal of reducing use of levodopa dose medications or polypharmacy doesn't justify subjecting a patient to a brain operation that is not without risks and great expense," Dr. LeWitt continued. "The results of this underpowered study add to my opinion that the 'premature' use of DBS is not a good idea for the management of Parkinson's disease."

Medtronic, which manufactures the DBS device that the investigators used, provided part of the study's funding. Vanderbilt University receives income for research or educational programs that Dr. Charles leads. Dr. LeWitt had no pertinent disclosures.

Neurology. Published online June 29, 2020. Abstract

Erik Greb can be reached at This article originally appeared on MDedge.

For more news, follow Medscape on Facebook, Twitter, Instagram, and YouTube.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.