Unilateral focused ultrasound ablation targeted to the globus pallidus internus led to a higher percentage of Parkinson’s disease patients with improved motor function or reduced dyskinesia compared with sham over 3 months but was associated with adverse neurologic effects, a pivotal trial showed.

A total of 45 patients (69%) in the focused ultrasound group had a response at 3 months compared with seven (32%) in the control group, for a difference of 37 percentage points (95% CI 15-60, P=0.003), according to Howard Eisenberg, MD, of the University of Maryland School of Medicine in Baltimore, and colleagues.

Pallidotomy-related adverse events in the treatment group included dysarthria, gait disturbance, loss of taste, visual disturbance, and facial weakness, they reported in the New England Journal of Medicine.

“Longer and larger trials are required to determine the effect and safety of this technique in persons with Parkinson’s disease,” they wrote.

Study findings led to the 2021 FDA approval of focused ultrasound to treat advanced Parkinson’s patients with mobility, rigidity, or dyskinesia symptoms.

“Focused ultrasound is only approved by the FDA to treat one side of the brain in Parkinson’s disease patients, so it may be more appropriate at this time for patients with symptoms predominantly on one side,” co-author Vibhor Krishna, MD, of the University of North Carolina at Chapel Hill, said in a statement.

Challenges in treating advanced Parkinson’s disease include motor fluctuations and dyskinesias in response to antiparkinsonian medications, observed Anette Schrag, PhD, of University College London, in an accompanying editorial.

“The often unpredictable deterioration of motor function in the off-medication state and dyskinesias in the on-medication state can render patients disabled for many hours each day,” Schrag noted.

Deep-brain stimulation is an established treatment for these complications, but not all patients are eligible and some don’t want it because it involves placing electrodes in the brain. “It also requires frequent adjustment and expert monitoring of an implanted stimulator, which makes it inaccessible for some patients,” Schrag added.

This study confirms that focused ultrasound is effective in reducing Parkinson’s motor complications, at least in the short term, Schrag noted. But nearly a third of treated patients in the study did not have a response at 3 months and a third in the control group also were classified as having a response — “a finding consistent with the high rate of placebo response in Parkinson’s disease trials,” she pointed out.

“The results of this trial are promising, but given the nonreversible nature of the intervention and the progressive nature of the disease, it will be important to establish whether improvements in motor complications are maintained over longer periods and whether treatment results in improved overall functioning and quality of life for patients,” Schrag wrote.

The study assigned Parkinson’s patients with dyskinesias or motor fluctuations and motor impairment in the off-medication state to either focused ultrasound ablation opposite the most symptomatic side of the body or a sham procedure. Participants had refractory, advanced, idiopathic Parkinson’s disease.

The primary outcome was a decrease of at least 3 points from baseline either in the Movement Disorders Society-Unified Parkinson’s Disease Rating Scale part III (MDS-UPDRS III) score for the treated side in the off-medication state, or in the Unified Dyskinesia Rating Scale (UDysRS) score in the on-medication state, at 3 months.

Overall, 65 people in the treatment group and 22 controls completed the primary outcome assessment. Of 45 patients in the focused ultrasound group with a response, 19 met MDS-UPDRS III criterion only, eight met UDysRS criterion only, and 18 met both criteria.

Mean MDS-UPDRS III improvement for the treated side in the off-medication state was 4.9 points in the focused ultrasound group and 1.0 in the control group (difference 3.9, 95% CI 1.1-6.6). Mean UDysRS improvement was 2.9 points in the focused ultrasound group and 0.3 in the control group (difference 2.5, 95% CI 1.2-3.9).

Most secondary outcomes supported the primary outcome. However, improvement in activities of daily living, measured by MDS-UPDRS II scores, was not significant (2.8 points in the focused ultrasound group and 0.1 in controls; difference 2.7, 95% CI 0.1-5.4, P=0.06).

An exploratory analysis of open-label data showed that 30 of 39 patients in the treatment group with a response at 3 months continued to have a response at 12 months.

At 3 months, the most common pallidotomy-related adverse events were dysarthria, gait disturbance, and loss of taste. All pallidotomy-related adverse events were mild or moderate. Procedure-related adverse events included complications related to the device frame and headaches at 3 months; most resolved by 12 months.

Limitations included missing primary-outcome data for about 7% of participants and unsatisfactory blinding of assignments, Eisenberg and colleagues acknowledged.

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