By Michael G. Kaplitt, MD, PhD, and Alexander Ramos, MD, PhD
Dr. Kaplitt is Professor and Vice Chairman for Research, Weill Cornell Medical College. Dr. Ramos is Resident, Department of Neurological Surgery, Weill Cornell Medical College.
In this randomized controlled trial, patients with asymmetric Parkinson’s disease were assigned to noninvasive, focused ultrasound-mediated subthalamotomy or sham procedure. The authors reported improved motor function in the focused ultrasound group, with adverse events including weakness, dyskinesia, and gait disturbances.
Martínez-Fernández R, Máñez-Miró JU, Rodríguez-Rojas R, et al. Randomized trial of focused ultrasound subthalamotomy for Parkinson’s disease. N Engl J Med 2020;383:2501-2513.
Magnetic resonance-guided focused ultrasound (MRgFUS) is a promising noninvasive procedure that can be used to precisely lesion deep brain structures. Ablation of the ventral intermediate nucleus of the thalamus is approved by the Food and Drug Administration for the treatment of essential tremor (ET) and parkinsonian tremor.
Martinez-Fernandez et al investigated the use of subthalamic nucleus (STN) ablation with MRgFUS for treatment of the cardinal motor symptoms of Parkinson’s disease (PD) as an alternative method to deep brain stimulation (DBS) for normalization of dysfunctional motor circuits.
Patients with highly asymmetric PD refractory to dopaminergic medication were enrolled in a double-blind, sham-controlled study. The researchers enrolled 40 patients: 27 received MRgFUS targeting the dorsolateral STN and 13 received sham treatment. The primary outcome was change from baseline of the more affected side in the well-validated Movement Disorder Society-revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) at four months following MRgFUS. Unblinded assessment at 12 months was a secondary outcome. Several additional secondary outcomes also were assessed, including quality-of-life scores and change in dopaminergic medication use.
At four months, the treatment group had a decrease in mean MDS-UPDRS score from 19.9 ± 5.0 to 9.9 ± 4.9 vs. a change from 18.7 ± 5.5 to 17.1 ± 6.0 in the control group. The between-group difference in change was 8.1 points and was highly significant (P < 0.001). A similar decrease in mean MDS-UPDRS score after four months was seen in 12 of the 13 subjects in the sham treatment group who crossed over to treatment. Secondary outcomes were not adjusted for multiple comparisons. Therefore, there was no ability to determine statistical significance. With that limitation, most of the secondary outcomes, including change in dosage of dopaminergic medication, trended in the same direction as the primary outcome. There was a similar reduction in MDS-UPDRS score at the 12-month follow-up.
The authors described a significant rate of adverse events. Dyskinesia occurred in 12 patients (44%), half of whom were in the off-medication state. These symptoms persisted in four patients at four months, with three patients having off-medication dyskinesia. Five patients (19%) had weakness immediately after treatment; three patients recovered, and two patients had persistent symptoms at 12 months. Speech disturbance (56%) and gait disturbance (42%) after the procedure were common but resolved in the majority of affected patients at four months.
COMMENTARY
This is the first randomized trial to demonstrate efficacy in the treatment of the non-tremor PD motor symptoms with MRgFUS, which represents a significant advance in the application of this technology. The study was well-designed and controlled by a gold-standard sham procedure. There was a significant improvement in motor symptoms in the treatment group, and this was comparable to other surgical interventions when accounting for the unilateral procedure. The trial focused on patients with severely asymmetric disease, a reasonable patient population for a proof-of-principle first clinical trial. Most patients with PD have bilateral symptoms and most DBS patients receive bilateral surgery. A trial of bilateral MRgFUS thalamotomy for ET is currently ongoing, and future PD trials should examine the safety and efficacy of bilateral MRgFUS.
Although the benefit in reducing PD motor symptoms is clear, the authors reported a high rate of adverse events. Most, but not all, resolved at four months. These deficits included gait disturbance, speech disturbance, weakness, and dyskinesia, all of which could have a significant impact on quality of life. It is unclear in the current trial if these potential deficits outweighed the benefits of treatment. Notably, the authors did examine post-procedural magnetic resonance imaging of patients with new deficits after the procedure and found no evidence of permanent structural damage, in keeping with the transient nature of the majority of these symptoms. Avoidance of off-target effects with new targeting paradigms should be a major focus going forward. The rate of adverse events, such as speech and gait disturbance, while mostly transient, seems to be far greater than with MRgFUS thalamotomy.1 This could be caused by off-target effects on the nearby corticospinal tract. Refinements, such as diffusion tractography to map out adjacent white matter tracts, might help to avoid off-target lesioning and adverse effects.2 Also, it is possible that some adverse events, such as worsening dyskinesia, could be avoided by choosing another target for MRgFUS. An encouraging pilot study of MRgFUS pallidotomy has been reported,3 and a large, multicenter randomized trial is nearing completion.
A key advantage to focused ultrasound is avoiding permanent implantation of hardware and surgery in patients who may be too sick for such a procedure. DBS is proven as efficacious in PD over a long period of time with an extremely low rate of adverse events. The long-term efficacy and safety profile of MRgFUS lesioning of the STN and other targets must be studied and refined further, but this trial represents a promising first step.
REFERENCES
- Fishman PS, Elias WJ, Ghanouni P, et al. Neurological adverse event profile of magnetic resonance imaging-guided focused ultrasound thalamotomy for essential tremor. Mov Dis 2018;33:843-847.
- Chazen JL, Sarva H, Stieg PE, et al. Clinical improvement associated with targeted interruption of the cerebellothalamic tract following MR-guided focused ultrasound for essential tremor. J Neurosurg 2018;129:315-323.
- Jung NY, Park CK, Kim M, et al. The efficacy and limits of magnetic resonance-guided focused ultrasound pallidotomy for Parkinson’s disease: A Phase I clinical trial. J Neurosurg 2018:1-9. doi: 10.3171/2018.2.JNS172514
