Focused Ultrasound Ablation of the Subthalamic Nucleus for Parkinson’s Disease Tremor

By Harini Sarva, MD

Assistant Professor of Clinical Neurology, Weill Cornell Medical College

SYNOPSIS: This paper demonstrated the long-term efficacy and safety of unilateral magnetic resonance imaging-guided high-frequency ultrasound subthalamotomy for Parkinson’s disease patients with motor fluctuations and dyskinesia three years after the procedure.

SOURCE: Martinez-Fernandez R, Natera-Villalba E, Manez-Miro JU, et al. Prospective long-term follow-up of focused ultrasound unilateral subthalamotomy for Parkinson disease. Neurology 2023;100:e1395-e1405.

In this study, 32 of 45 Parkinson’s disease subjects, who had high-frequency focused ultrasound (FUS) subthalamotomy in prior open-label and randomized clinical trials, were followed for three years. The primary endpoint was efficacy from baseline to three years post-treatment as measured by change in the Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part 3 scores in the off-medication state. Secondary measures included individual MDS-UPDRS motor scores and quality of life scales.

Compared to baseline, the MDS-UPDRS off-medication scores declined by 52.3% at three years, and the initial benefit was sustained during the entire follow-up period. The on-medication state improvement also was statistically significant and durable. Interestingly, there was no statistically significant benefit from baseline in levodopa-induced complications as assessed on Part 4 of the MDS-UPDRS.

Quality of life measures did not show significant improvement from baseline. However, patients were satisfied with their results. Those with longer disease duration and progression of symptoms on the untreated side dropped out of the long-term follow-up period. Three individuals needed additional surgical intervention for their progression of symptoms on the untreated side and chose to have additional FUS-subthalamotomies to treat those symptoms.

Side effects generally were mild and included mild dyskinesia on the treated side, contralateral limb weakness, speech impairment, and unsteady gait. Side effects either resolved after the first six months or were considerably reduced by the end of the follow-up period. Neuroimaging demonstrated progressive lesion reduction without delayed radiographic complications. No change in cognitive function at three years was noted.

COMMENTARY

Magnetic resonance imaging-guided high-frequency FUS ablation is an effective therapy in improving Parkinson’s disease tremor, thus adding to our armamentarium of symptomatic therapies. Thalamic, pallidal, and, now, subthalamic ablations are demonstrating beneficial effect without significant adverse events. However, the durability of these effects is unclear. Whereas thalamotomies for essential tremor have remained durable for at least four years, the exact durability in Parkinson’s disease is unknown. This study suggests that FUS can be effective for longer than the one-year trial periods, providing a potentially effective therapeutic option for those who are not candidates for deep brain stimulation (DBS) or who do not want DBS.

However, several questions remain. Like DBS, patient selection is vital to success. Patients with progressive symptoms on the untreated side may not show an overall significant benefit and may require additional ablations or DBS to control their motor symptoms. However, choosing those with significant unilateral disease or dyskinesia may suggest a greater therapeutic benefit than what is truly achieved by these ablations. Despite the potential for bias, those with more asymmetric disease may be better candidates.

Timing of the procedure also is an important consideration. Those with greater disease duration may not have as robust a treatment response as those with shorter disease duration. However, if the durability is not more than three years, patients who have the procedure earlier may require additional surgical interventions later in their disease course. This can be a potentially difficult situation, since they may develop nonmotor symptoms that do not respond to surgical intervention or hurt their candidacy for additional surgical intervention.

How to manage medications after ablations as compared to DBS also is unclear. With subthalamic nucleus (STN) DBS, medications can be reduced considerably and, even with a later increase in medications, dyskinesia can be treated through modulation of the DBS. Although STN lesioning did not produce significant dyskinesia in this study, that may be a result of inclusion of the pallidothalamic tract in the lesion. With patients potentially needing higher doses of carbidopa-levodopa later in their disease course, it is unclear if the benefit of the pallidothalamic tract lesion will hold. Focused ultrasound lesioning is permanent despite radiographic signs of lesion reduction. Alterations in pathways cannot be adjusted, as would be the case with DBS. Longer-term effects on gait, speech, and cognition need to be studied for candidate selection, decision on the timing of the procedure, and subsequent medication management.