The efficacy and limits of magnetic resonance–guided focused ultrasound pallidotomy for Parkinson’s disease: a Phase I clinical trial

Abstract

OBJECTIVE Recently, MR-guided focused ultrasound (MRgFUS) has emerged as an innovative treatment for numerous neurological disorders, including essential tremor, Parkinson's disease (PD), and some psychiatric disorders. Thus, clinical applications with this modality have been tried using various targets. The purpose of this study was to determine the feasibility, initial effectiveness, and potential side effects of unilateral MRgFUS pallidotomy for the treatment of parkinsonian dyskinesia. METHODS A prospective, nonrandomized, single-arm clinical trial was conducted between December 2013 and May 2016 at a single tertiary medical center. Ten patients with medication-refractory, dyskinesia-dominant PD were enrolled. Participants underwent unilateral MRgFUS pallidotomy using the Exablate 4000 device (InSightec) after providing written informed consent. Patients were serially evaluated for motor improvement, neuropsychological effects, and adverse events according to the 1-year follow-up protocol. Primary measures included the changes in the Unified Parkinson's Disease Rating Scale (UPDRS) and Unified Dyskinesia Rating Scale (UDysRS) scores from baseline to 1 week, 1 month, 3 months, 6 months, and 1 year. Secondary measures consisted of neuropsychological batteries and quality of life questionnaire (SF-36). Technical failure and safety issues were also carefully assessed by monitoring all events during the study period. RESULTS Unilateral MRgFUS pallidotomy was successfully performed in 8 of 10 patients (80%), and patients were followed up for more than 6 months. Clinical outcomes showed significant improvements of 32.2% in the "medication-off" UPDRS part III score (p = 0.018) and 52.7% in UDysRS (p = 0.017) at the 6-month follow-up, as well as 39.1% (p = 0.046) and 42.7% (p = 0.046) at the 1-year follow-up, respectively. These results were accompanied by improvement in quality of life. Among 8 cases, 1 patient suffered an unusual side effect of sonication; however, no patient experienced persistent aftereffects. CONCLUSIONS In the present study, which marks the first Phase I pilot study of unilateral MRgFUS pallidotomy for parkinsonian dyskinesia, the authors demonstrated the efficacy of pallidal lesioning using MRgFUS and certain limitations that are unavoidably associated with incomplete thermal lesioning due to technical issues. Further investigation and long-term follow-up are necessary to validate the use of MRgFUS in clinical practice. Clinical trial registration no.: NCT02003248 (clinicaltrials.gov).

Blood–brain barrier opening with focused ultrasound in experimental models of Parkinson's disease

“…Currently, the use of FUS for ablative purposes shows some promise for the treatment of PD. This includes targeting either the ventral intermediate thalamus, the subthalamic nucleus, or the internal pallidum . Phase I trials exploring both of these indications are currently underway (NCT03608553).…”

“…This includes targeting either the ventral intermediate thalamus, the subthalamic nucleus, or the internal pallidum. [80][81][82][83] Phase I trials exploring both of these indications are currently underway (NCT03608553). However, the use of FUS to disrupt the BBB in a focal and temporary way and facilitate the entry of different compounds such as GDNF, antiinflammatory drugs, or antibodies seems to be an extremely promising therapeutic option for the treatment of PD not only as a symptomatic treatment but also to impact the mechanisms underlying neurodegeneration.…”

The role of high‐intensity focused ultrasound as a symptomatic treatment for Parkinson's disease

“…Although most of the improvement was observed on the body side contralateral to the lesion, as previously noted in open pallidotomy, some ipsilateral improvement was noted as well. In a recently published open‐label study by Jung and collegaues, 10 patients with PD underwent unilateral MRgFUS pallidotomy . Of the 8 patients who successfully completed the procedure (ablative levels of temperature elevation could not be obtained in 2 patients, which may uncommonly occur in patients with unfavorable skull characteristics), 6 completed the 1‐year evaluation period.…”

“…In a recently published open-label study by Jung and collegaues, 10 patients with PD underwent unilateral MRgFUS pallidotomy. 71 Of the 8 patients who successfully completed the procedure (ablative levels of temperature elevation could not be obtained in 2 patients, which may uncommonly occur in patients with unfavorable skull characteristics), 6 completed the 1-year evaluation period. They showed an improvement in total UDysRS by 52.7% and had 30.2% reduction in UPDRS off-mediation scores at 6 months.…”

Focused ultrasound as an evolving therapy for Parkinson's disease

“…In spite of continuing discussion regarding the role of ablational therapy in the era of DBS, clinical studies of HIFU in PD and other brain conditions are moving forward quickly with promising preliminary results. All three PD targets for DBS (thalamus, STN, and globus pallidus interna) have been investigated with MRgFUS, and these first studies are reviewed in this issue by Moosa and colleagues, which includes several of the original investigators . They are the first wave of targeted brain ablation with this technology for neurological and psychiatric conditions that include obsessive‐compulsive disorder as well as chronic refractory pain.…”