Postmortem Analysis 35 Months after Magnetic Resonance-Guided Focused Ultrasound Thalamotomy for Essential Tremor

Introduction

Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy has emerged as an incisionless therapy for refractory essential tremor (ET) [12]. However, neuropathological studies on the long-term effects of MRgFUS on lesioned brain tissue are limited. Only two previous studies have investigated MRgFUS in postmortem settings, both of which focused on patients with Parkinson disease with a relatively short time to death (10 days and 7 months) [34]. Additional postmortem analyses after MRgFUS are needed to understand the neuropathological effects of this procedure in relation to temperature rise during treatment, magnetic resonance imaging (MRI) findings, and long-term clinical efficacy. We performed postmortem analysis of a patient with ET who underwent MRgFUS thalamotomy with a follow-up period of 35 months before death.

Case Report

The patient was an 86-year-old man with a 23-year history of bilateral hand tremor diagnosed as ET. He had persistent functional impairment despite medical therapy with propranolol and primidone trialed for multiple years. His minimum tremor disability score was 2 on the Clinical Rating Scale for Tremor, indicating at least moderate functional impairment affecting his ability to perform fine motor tasks and self-care independently. On patient survey he stated that his tremor significantly interfered with activities of daily living, including making handwriting, using utensils, and buttoning clothing difficult.

Because the patient was not a candidate for deep brain stimulation (due to advanced age) and had a personal preference against surgery, he elected to undergo MRgFUS thalamotomy. Preoperative MRI with T2 weighting and diffusion weighting confirmed no contraindications, and the target for lesioning was the left ventral intermediate nucleus of the thalamus.

The procedure was performed in February 2021 using the Exablate Neuro system (Insightec Ltd., Tirat Carmel, Israel). A stereotactic frame was placed, and sonications were guided by real-time MR imaging. A total of 11 sonications were delivered at energy levels ranging between 1350 and 4946 J. Intraoperative temperature elevations between 49°C and 61°C were recorded. The first four sonications were used for alignment of the FUS. Upon alignment, five additional sonications were performed. Between sonications, tremor reduction and potential side effects such as facial numbness were assessed, and adjustments were made accordingly. The final two sonications resulted in sustained tremor reduction without immediate side effects.

On day one after the procedure, high-resolution three-dimensional T2-weighted imaging showed a 7-mm hyperintense lesion in the thalamus with a hypointense core suggestive of necrosis surrounded by mild edema (Figure 1A–C). Diffusion-weighted imaging at the same time point showed hyperintensity with apparent diffusion coefficient isointensity correlating with reduced diffusivity. Diffusion tractography revealed the lesion’s proximity to the corticospinal tract (Figure 1D). At 3-month follow-up, MRI demonstrated significantly reduced lesion size consistent with expected tissue response (Figure 1E–G).

Figure 1

Postoperatively, the patient experienced transient gait disturbances that resolved within three months. He reported a 95% reduction in tremor severity, with significant improvement in activities of daily living including ability to write, use utensils independently, and dress. Clinical follow-up at six months, one year, and two years confirmed continued tremor suppression without side effects. The patient died from unrelated causes 35 months after treatment. The patient’s family consented to the postmortem examination and publication of his case and images. As a single-patient case study, institutional review board approval was not required.

Postmortem MRI, including diffusion tensor imaging, was performed on the ex vivo brain to evaluate the MRgFUS-induced lesion. The lesion remained localized to the initial site of the thalamotomy, with no evidence of lesion expansion (Figure 2). Tractography demonstrated focal disruption of the dentatorubrothalamic tract (DRTT) fibers at the lesion site correlated with the patient’s clinical improvement.

Figure 2

Neuropathological examination of the brain revealed no evidence of generalized edema, infarction, or hemorrhage in the cerebral hemispheres, thalamus, cerebellum, or brainstem. Serial coronal sections of the thalamus appeared grossly unremarkable. Both thalami were entirely submitted for histopathological evaluation. Luxol fast blue staining of the thalamus demonstrated normal myelination in anterior section (Figure 3A) with prominent demyelination appearing in the left posterior thalamus (Figure 3B, C), extending into the adjacent subthalamic region and internal capsule (Figure 3C). Based on these findings, detailed histologic assessment focused on the posterior thalamus (Figure 4). Hematoxylin and eosin staining shown in Figure 4A revealed a 1-mm cavitary lesion indicative of remote necrosis in the area corresponding with the boxed area in Figure 3B (left) and the FUS lesion identified in Figure 2. The surrounding tissue exhibited mild vacuolation without overt neuronal loss and marked demyelination confirmed by luxol fast blue staining, whereas the corresponding region on the right side appeared normal. Glial fibrillary acidic protein immunostaining demonstrated moderate gliosis on the left, in contrast to minimal gliosis on the right. Neurofilament (NF) staining showed preserved axonal integrity bilaterally. CD163 immunostaining revealed a mild increase in macrophage infiltration on the treated (left) side. In the adjacent internal capsule, more extensive demyelination, along with mildly increased gliosis and macrophage infiltration, was observed on the left compared with the right, consistent with secondary involvement of nearby white matter tracts (Figure 4). The adjacent subthalamic nucleus exhibited changes similar to those seen in the thalamus, including marked demyelination without neuronal loss, moderate gliosis, mildly increased macrophage infiltration, and preserved axonal architecture.

Figure 3

Figure 4

Discussion

MRgFUS thalamotomy has emerged as a non-invasive alternative for patients with medication-refractory essential tremor, demonstrating significant symptom reduction and improved quality of life [12]. Although prior studies have characterized lesion evolution using imaging, the histopathological consequences of MRgFUS beyond the first year remain largely unknown [34]. This is the longest follow-up of a patient treated with MRgFUS with postmortem data available, offering direct neuropathological validation of lesion integrity, structural specificity, and long-term safety.

At 35 months after treatment, the lesion remained well-demarcated within the ventral intermediate nucleus with no evidence of expansion on postmortem MRI. These findings corroborate prior imaging studies suggesting that MRgFUS lesions stabilize over time without progressive pathology [567]. Early MRI findings after treatment demonstrate temporary necrosis and surrounding edema at the lesion site [56]. Our postmortem analysis at 35 months confirms the resolution of these acute changes, with the lesion maturing into a well-demarcated area without ongoing tissue damage.

Neuropathological examination identified a 1-mm remote necrotic lesion in the left posterior thalamus, consistent with healing and resolution of the MRgFUS lesion. Interestingly, despite the absence of overt neuronal loss, demyelination was observed in adjacent structures of the treatment site, including the surrounding posterior thalamic tissue, internal capsule, and subthalamic nucleus. These findings support the hypothesis that MRgFUS primarily affects white matter pathways involved in tremor generation [348]. However, the potential for progressive demyelination and its clinical significance warrant further investigation.

Nevertheless, the absence of significant gliosis or neuronal loss reinforces MRgFUS as a targeted intervention with a favorable safety profile. This contrasts with radiofrequency ablation and stereotactic radiosurgery, which have been found to induce tissue necrosis and collateral damage in cardiac tissue and in porcine brain models, respectively [8910]. MRgFUS appears to achieve therapeutic efficacy through precise disruption of tremor circuitry while sparing adjacent structures. The stability of the lesion observed at 35 months further supports the durability of the treatment outcomes and the lack of late-stage complications, aside from localized demyelination of uncertain clinical significance.

Clinically, the patient’s sustained 95% tremor reduction over nearly three years aligns with long-term functional outcomes reported in MRgFUS trials [125]. Although transient gait disturbances were noted postoperatively, these resolved within three months, consistent with prior studies showing that most adverse effects are mild and self-limited [57]. The absence of delayed neurological deterioration in postmortem analysis further underscores that MRgFUS is a safe, long-term intervention. However, it is important to note that the patient had a mild tremor and our data are limited by infrequent follow-up.

This study provides critical neuropathological evidence that MRgFUS is a precise and effective intervention for treatment of medically refractory ET. Further postmortem studies are needed to confirm whether similar histopathologic patterns are observed across larger cohorts and whether specific lesion characteristics correlate with treatment response.

Ethics and Consent

We confirm that the approval of an institutional review board was not required for this work. The patient’s family gave written and informed consent for publication of the case report and images. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Competing Interests

The authors have no competing interests to declare.

Author Contributions

(1) Case: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: Not Applicable; (3) Paper Preparation: A. Writing the First Draft, B. Review and Critique.

SJ: 3A, 3B

LS: 1B, 1C, 3A, 3B

HO: 1B, 3A, 3B

LR: 1B, 1C, 3B

VR: 1B, 3A, 3B

QM: 1B, 1C, 3B

HW: 1B, 1C

JA-C: 1B, 3B

SR: 1A, 1B, 1C, 3B