Parkinson’s Motor Function Improved with Focused Ultrasound

Focused ultrasound subthalamotomy improved motor function in Parkinson’s disease, but it also led to multiple adverse events that persisted in some patients, a small randomized double-blind trial found.

“Focused ultrasound subthalamotomy in one hemisphere improved motor features of Parkinson’s disease in selected patients with asymmetric signs,” wrote Raul Martinez-Fernandez, MD, PhD, of CEU San Pablo University in Mostoles, Spain, and co-authors in New England Journal of Medicine. “Adverse events included speech and gait disturbances, weakness on the treated side, and dyskinesia.”

Patients with asymmetric Parkinson’s disease who had motor signs not fully controlled with medication and who were not candidates for deep-brain stimulation surgery were randomized to focused ultrasound subthalamotomy on the side opposite their main motor signs (n=27) or a sham procedure (n=13).

The primary outcome was change from baseline to 4 months on the more-affected body side Movement Disorder Society–Unified Parkinson’s Disease Rating Scale motor score (MDS-UPDRS part III; range 0 to 44, higher scores indicate worse Parkinsonism) in the off-medication state.

In the active treatment group, mean score decreased from 19.9 to 9.9 (least-squares mean difference 9.8 points, 95% CI 8.6-11.1). In the sham group, mean score decreased from 18.7 to 17.1 (least-squares mean difference 1.7 points, 95% CI 0.0-3.5). The between-group difference was 8.1 points, 95% CI 6.0-10.3, P<0.001.

Adverse events in the active-treatment group were dyskinesia in 12 patients (persistent at 4 months in four patients), weakness on the treated side in five patients (persistent at 4 months in two), speech disturbance in 15 patients (persisted at 4 months in three), facial weakness in three patients (persistent at 4 months in one), and gait disturbance in 13 patients (persistent at 4 months in two). By 12 months, deficits were still present in six patients.

In an accompanying editorial, Joel Perlmutter, MD, and Mwiza Ushe, MD, both of the Washington University in St. Louis, wrote that the procedure “reduced the motor features of parkinsonism on the opposite side of the body by 50%, as compared with essentially no improvement in a group of patients who underwent a sham procedure. However, in this small trial, the group of patients who underwent focused ultrasound had almost 5 times as many adverse events as those who underwent the sham procedure.”

“Current ultrasound-targeting methods cause at least transient, and occasionally long-lasting, weakness and speech difficulties,” they added. “These adverse events in a group of relatively young patients and the lack of ability to modulate treatment over time to treat prominent tremor raise questions about the appropriate implementation of focused ultrasound-produced lesions for the treatment of Parkinson’s disease.”

Surgical approaches to Parkinson’s disease disrupt abnormal oscillatory signals and can improve symptoms at later disease stages. In addition to deep-brain stimulation, ablative lesions in the nuclei of the basal ganglia introduced mechanically or with other forms of energy (e.g., radiofrequency ablation or ultrasound) are used. The subthalamic nucleus is a well characterized target in this setting.

Both deep-brain stimulation and radiofrequency ablation require a craniotomy and have similar risks for major adverse events such as hemorrhage, stroke, or infection, as well as dystonia, dysarthria, gait impairment, dyskinesia, and other effects. Stimulation also requires implanted electrodes which carry extra risk. Efficacy with the subthalamic nucleus target is comparable for both approaches, with 40-60% reduction of motor signs and medication reduction may approach 50%, though with disease progression symptoms often worsen again.

An advantage of focused ultrasound, which is approved by the FDA to treat essential tremor, is that it obviates the need for craniotomy, which patients may decline for various reasons.

Martinez-Fernandez and colleagues identified 40 asymmetric Parkinson’s patients without severe axial manifestations in the on-medication state between March 2018 and May 2019. Their mean age was 57 and mean disease duration was 6.2 years. Mean MDS-UPDRS III baseline score in the off state was 39.9 and in the on state was 26.3. Males made up 59% of the active treatment group and 77% of the sham procedure group. Mean daily dose of levodopa equivalent was 729.7 mg in the active treatment and 881.7 mg in the sham procedure groups.

A secondary outcome, clinical improvement according to the Patients’ Global Impression of Change at 4 months, was reported by 85% of the active treatment group and 15% of the control group.

Follow-up MRI showed perilesional edema in all active treatment patients; it resolved by 4 months. No intracerebral hemorrhages were seen.

“Focused ultrasound-produced lesions provide an option for patients who decline to receive electrode implantation or who do not have access to the resources necessary for regular reprogramming of a deep-brain stimulation device,” the editorialists noted.

The current trial begins the path to the goal of having another treatment option, they added, suggesting that “improvements in targeting may improve the risk-benefit ratio and permit the use of lesions in both hemispheres, which would widen the population of eligible patients.”

An important limitation of the technique is unilateral use: “Side effects such as dysarthria may limit application to focused ultrasound-produced lesions in one hemisphere because the frequency of dysarthria is likely to be greater with procedures that are conducted in both hemispheres,” the editorialists pointed out. “Limiting the treatment to one side of the brain by ultrasound-produced lesioning constrains the application, since most patients with Parkinson’s disease have progression of symptoms on both sides of the body.”

1. Focused ultrasound subthalamotomy improved motor function in Parkinson’s disease but led to multiple adverse events that persisted in some patients, a small randomized double-blind trial found.

2. Adverse events persistent to 4 months included dyskinesia, weakness on the treated side, speech disturbance, facial weakness, and gait disturbance. By 12 months, deficits were still present in 6 of 27 patients.

Paul Smyth, MD, Contributing Writer, BreakingMED™

Cat ID: 37

Topic ID: 82,37,728,791,730,37,925,481