Positive Effects on Rest Tremor Progression in Parkinson Shown by Deep Brain Stimulation

David Charles, MD, the chief medical officer of the Vanderbilt Neuroscience Institute

David Charles, MD

In patients with early Parkinson disease, new trial results have suggested that deep brain stimulation (DBS) may slow the progression of rest tremor in the disease.¹

A team of investigators, including David Charles, MD, the chief medical officer of the Vanderbilt Neuroscience Institute, conducted a post-hoc analysis of the Unified Parkinson Disease Rating Scale—III (UPDRS-III) score after a 7-day washout from the 2-year DBS in early Parkinson pilot trial dataset, with an objective of assessing if earlier use of the stimulation could alter the disease course. The trial included 30 patients with idiopathic Parkinson disease who had been taking medication for 6 months to 4 years.

“The DBS in early [Parkinson] pilot trial suggests that [subthalamic nucleus] stimulation may slow rest tremor progression,” Charles and colleagues wrote. “More investigation is needed in a larger cohort, and the FDA has approved the conduct of a multicenter, pivotal clinical trial testing [subthalamic nucleus]-DBS in early [Parkinson].”

In total, 28 patients were included in the analysis. They were randomized 1:1 to receive either optimal drug therapy (ODT) alone (n = 14), or ODT plus DBS (n = 14). From baseline, the mean UPDRS-III total “off” scores worsened for both groups at 24 months. Rest tremor “off” scores were 3.1 points better for combination group than the ODT alone group, which was the lone significant item after multiple comparison adjustments (P = .002).

In examining the rest tremor “off” scores, it was observed that the ODT group experienced a 3.2-point worsening over the 2 years, with a minimal change of 0.2-points more for the ODT plus DBS group. The ODT plus DBS group showed a -2.0 points/y differences compared to the ODT only group in rest tremor “off” score slope (P <.001).

The risk of a ≥2-point worsening of rest tremor “off” score was 2.6 times greater for the ODT only group (hazard ratio [HR], 2.6; 95% CI, 0.8 to 8.3; P = .07). In total, 70% (n = 10) of the ODT only group experienced a ≥2-point worsening, compared to only 31% (n = 4) of the combination group by 24 months. When undergoing sensitivity analysis, similar results were observed (HR, 2.8; 95% CI, 0.9 to 9.1; P = .047).

At 2 years, the mean number of limbs per patient affected by rest tremor was 1.5 ±1.3 for the ODT plus DBS group compared to 2.8 ±1.3 for the ODT only group, a change from baseline favoring the combination group (P = .001). Additionally, of the patients receiving only ODT, 86% (n = 12) developed rest tremor in previously unaffected limbs compared to 46% (n = 6) of those in the ODT plus DBS group (odds ratio [OR], 7.0; 95% CI, 1.10 to 45.45; P = .046). In total, 4 of the combination patients had rest tremor in a limb resolved that was present at baseline, and 1 patient in this group had rest tremor disappear from all affected limbs (baseline, 4; 24 months, 0).

“While the importance of [Parkinson] tremor is sometimes downplayed, up to 75% of patients are affected by this cardinal motor feature,” Charles and colleagues wrote. “Tremor is especially distressing in the early stages of the disease due to challenges faced in vocational and social settings. The importance of tremor control in early [Parkinson] is also reflected by DBS patients in this study, with nearly half responding that the greatest benefit of undergoing surgery was [the] management of their tremor.”

The study did suffer some limitations. First, the cohort was small—notably, the FDA has already approved a much larger, multicenter study to better assess the findings. Second, there were symptoms of Parkinson that the videos could not measure, such as rigidity. Charles and colleagues acknowledge these, writing that “these results should be interpreted with caution due to limitations of this study including its post hoc comparisons, small sample size, and open-label design.”

In an accompanying editorial, Steven C. Karceski, MD, the Director of Clinical Trials at the Weill Cornell Epilepsy Center, wrote that “there are many ways to interpret a study like this. First, the study findings need to be confirmed in a larger trial. If both trials show the same thing, it may mean that early use of DBS is an effective way to manage [Parkinson]. Not only would DBS reduce the symptoms of [Parkinson], but it may also decrease the speed at which PD progresses.”²

Karceski noted that while DBS is traditionally used in addition to medication for Parkinson, notably, it is almost always utilized once the condition has progressed to middle or late stages—often when the medicines are working sub-optimally or not at all.

“Part of the reason that DBS is used late in the course of [Parkinson] is that a deep brain stimulator is invasive. In order for DBS to be used, an electronic device must be surgically implanted,” Karceski wrote. “Electrodes are most often placed in the subthalamic nucleus, a group of nerve cells in the brain that are affected by [Parkinson]. DBS is not new. For many years, DBS has been used to send a small electrical impulse to the cells of the subthalamic nucleus, thereby reducing or stopping the tremor (and other symptoms) that occurs in [Parkinson].”

REFERENCES:

1. Hacker ML, DeLong MR, Turchan M, et al. Effects of deep brain stimulation on rest tremor progression in early-stage Parkinson disease. Neurology. 2018;91(5):e463-e471.

doi

: 10.1212/WNL.0000000000005903.

2.

Kaerceski

S. Does deep brain stimulation help early or mild Parkinson disease? Neurology. 2018;91(5):e495-e497.

doi

: 10.1212/WNL.0000000000005918