Reply: Evaluating the Scope and Safety of Bilateral <scp>MRgFUS</scp> Thalamotomy for Essential Tremor: A Critical Analysis

We thank Dr. Mickael Aubignat for reading our paper and for the letter entitled “Evaluating the Scope and Safety of Bilateral MRgFUS Thalamotomy for Essential Tremor: A Critical Analysis,”1 which expands the discussion of important safety aspects of our early-stage trial of bilateral, staged magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy for patients with medication-resistant essential tremor (mrET).2 We implemented a risk-ascending strategy to mitigate the potential for adverse events historically associated with bilateral thalamotomies. In particular, we prespecified an inter-procedural interval of at least 1 year following the first MRgFUS thalamotomy; conservative in comparison to similar trials, including one with an inter-procedural interval of 5 months.3 Akin to other bilateral, staged MRgFUS trials, we defined restrictive eligibility criteria a priori, whereby patients with persistent adverse events (AEs) from the first MRgFUS procedure were excluded from the second.3 While other trials used clinical judgment to exclude patients with significant AEs, we specified objective exclusionary parameters based on the Scale for the Assessment and Rating of Ataxia (SARA) and extensive neuropsychological testing. Patients with SARA gait subscore ≥2 points (ie, gait “clearly abnormal, tandem walking >10 steps not possible” or worse), SARA speech subscore ≥2 points (ie, “impaired speech, but easy to understand” or worse) or who presented with language impairment did not undergo the second thalamotomy. In line with other studies,3 our trial demonstrated the safety of the contralateral MRgFUS procedure following a safe and efficacious first thalamotomy. As such, the current safety evidence from our trial and others may not be generalizable to mrET patients with permanent AEs or suboptimal tremor amelioration following the first intervention. With the recent regulatory approval of bilateral, staged MRgFUS thalamotomy in the United States and Europe,4 we anticipate that more bilateral procedures with less stringent eligibility criteria will be reported in mrET patients. These data will be important in informing the safety profile and eligibility envelope of the second MRgFUS procedure. For instance, in the present phase of our risk-ascending strategy, we are less concerned about cognitive decline following thalamotomy. This decision was based on comprehensive neuropsychological data from recent trials2, 3 and a meta-analysis,5 which collectively indicate that thalamotomy is safe from a cognitive standpoint. However, we remain cautious about performing a second thalamotomy in patients with MRgFUS-induced disequilibrium or pre-existing gait impairment related to other etiologies. Lastly, future multicenter long-term studies will inform data-driven eligibility criteria and prediction of safety and efficacy endpoints. Using neurophysiology, advanced neuroimaging and quantification of safety outcome measures, such as gait and speech analyses, these studies will allow for deep tremor phenotyping and lesioning characterization. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the first draft, B. Review and Critique. N.S.: 1A, 1B, 1C, 3A, 3B J.S.R.: 1A, 3B E.D.S.: 3A, 3B, 3C, 3A, 3B C.H.: 3B M.L.S.: 3B N.L.: 1A, 1B, 1C, 3B A.A.: 1A, 1B, 1C, 3A, 3B Funding Sources and Conflicts of Interest: The authors acknowledge support from the Harquail Centre for Neuromodulation. The authors have no conflict of interest to declare. Financial Disclosures for Previous 12 Months: Grants: The authors acknowledge support from the Harquail Centre for Neuromodulation, Sunnybrook Research Institute and the Hurvitz Brain Sciences Program. J.S.R. also receives support from the Dr. Sandra Black Centre for Brain Resilience & Recovery. N.L. receives support from InSightec, Veteran's Affairs Canada, Power Corporation, the Weston Brain Institute and the Alternate Planning Fund. C.H. and N.L. are supported by the Canadian Institutes of Health Research and the New Frontiers in Research Fund. A.A. and N.L. received support from the Multiple Sclerosis Society of Canada, and the Focused Ultrasound Foundation. A.A. receives support from the ALS Society of Canada. Honoraria: A.A. has received an honorarium from Mitsubishi Tanabe Pharma and Amylyx. Ethical Compliance Statement: All activities were performed under approval of the Sunnybrook Research Ethics Board (Project ID 3341). Written informed consent was obtained from each patient prior to participation. We confirm that we read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

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