Impact of biologically effective dose on tremor decrease after stereotactic radiosurgical thalamotomy for essential tremor: a retrospective longitudinal analysis.

This letter to the editor critiques a recent study evaluating the role of biologically effective dose (BED) in stereotactic radiosurgical thalamotomy for essential tremor (ET). The study, conducted retrospectively on 78 ET patients, demonstrates a significant correlation between BED and tremor improvement post-SRS. Moreover, the study suggests adjusting the prescribed dose rather than changing cobalt-60 sources to maintain treatment efficacy while minimizing toxicity. This suggestion aligns with previous research indicating an annual decrease in BED due to cobalt-60 decay. The letter emphasizes the importance of considering BED and cobalt-60 decay in optimizing treatment outcomes for ET patients undergoing stereotactic radiosurgery. Further research is recommended to explore innovative techniques for dose modulation in response to cobalt-60 decay and validate findings in larger cohorts.

Cerebellar and thalamic connector hubs facilitate the involvement of visual and cognitive networks in essential tremor.

INTRODUCTION: Connector hubs are specialized brain regions that connect multiple brain networks and therefore have the potential to affect the functions of multiple systems. This study aims to examine the involvement of connector hub regions in essential tremor. METHODS: We examined whole-brain functional connectivity alterations across multiple brain networks in 27 patients with essential tremor and 27 age- and sex-matched healthy controls to identify affected hub regions using a network metric called functional connectivity overlap ratio estimated from resting-state functional MRI. We also evaluated the relationships of affected hubs with cognitive and tremor scores in all patients and with motor function improvement scores in 15 patients who underwent postoperative follow-up evaluations after focused ultrasound thalamotomy. RESULTS: We have identified affected connector hubs in the cerebellum and thalamus. Specifically, the dentate nucleus in the cerebellum and the dorsomedial thalamus exhibited more extensive connections with the sensorimotor network in patients. Moreover, the connections of the thalamic pulvinar with the visual network were also significantly widespread in the patient group. The connections of these connector hub regions with cognitive networks were negatively associated (FDR q < 0.05) with cognitive, tremor, and motor function improvement scores. CONCLUSION: In patients with essential tremor, connector hub regions within the cerebellum and thalamus exhibited widespread functional connections with sensorimotor and visual networks, leading to alternative pathways outside the classical tremor axis. Their connections with cognitive networks also affect patients' cognitive function.

Outcomes and Prognostic Factors of Magnetic Resonance-guided Focused Ultrasound Thalamotomy for Essential Tremor at 2-year Follow-up.

Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is an effective treatment for essential tremor (ET). However, its long-term outcomes and prognostic factors remain unclear. This study aimed to retrospectively investigate 38 patients with ET who underwent MRgFUS thalamotomy and were followed up for >2 years. The improvement in tremor was evaluated using the Clinical Rating Scale for Tremor (CRST). Adverse events were documented, and correlations with factors, such as skull density ratio (SDR), maximum mean temperature (T-max), and lesion size, were examined. Furthermore, the outcomes were compared between two groups, one that met the cutoff values, which was previously reported (preoperative CRST-B ≤ 25, T-max ≥ 52.5°C, anterior-posterior size of lesion ≥ 3.9 mm, superior-inferior [SI] size of lesion > 5.5 mm), and the other that did not. The improvement rate was 59.4% on average at the 2-year follow-up. Adverse events, such as numbness (15.8%), dysarthria (10.5%), and lower extremity weakness (2.6%), were observed even after 2 years, although these were mild. The factors correlated with tremor improvement were the T-max and SI size of the lesion (p < 0.05), whereas the SDR showed no significance. Patients who met the aforementioned cutoff values demonstrated a 69.8% improvement at the 2-year follow-up, whereas others showed a 43.6% improvement (p < 0.05). In conclusion, MRgFUS is effective even after 2 years. The higher the T-max and the larger the lesion size, the better the tremor control. Previously reported cutoff values clearly predict the 2-year prognosis, indicating the usefulness of MRgFUS.

Focused Ultrasound for Treatment of Movement Disorders: A Review of Non-Food and Drug Administration Approved Indications.

INTRODUCTION: MRI-guided focused ultrasound (FUS) is an incisionless thermo-ablative procedure that may be used to treat medication-refractory movement disorders, with a growing number of potential anatomic targets and clinical applications. As of this article's publication, the only US Food and Drug Administration (FDA)-approved uses of FUS for movement disorders are thalamotomy for essential tremor (ET) and tremor-dominant Parkinson's Disease (PD), and pallidotomy for other cardinal symptoms of PD. We present a state-of-the-art review on all non-FDA approved indications of FUS for movement disorders, beyond the most well-described indications of ET and PD. Our objective was to summarize the safety and efficacy of FUS in this setting and provide a roadmap for future directions of FUS for movement disorders. METHODS: A state-of-the-art review was conducted on use of FUS for non-FDA approved movement disorders. All movement disorders excluding FDA-approved uses for ET and PD were included. RESULTS: A total of 25 studies on 172 patients were included. In patients with tremor plus dystonia syndromes (n = 6), ventralis intermediate nucleus of the thalamus (VIM)-FUS gave >50% tremor reduction, with no improvement in dystonia and worsened dystonia in 2/6 patients. Ventral-oralis complex (VO)-FUS gave >50% improvement for focal hand dystonia (n = 6) and 100% return to musical performance in musician's dystonia (n = 6). In patients with multiple sclerosis (MS) and tremor (n = 3), improvement in tremor was seen in 2 patients with a favorable skull density ratio; no MS disease change was noted after VIM-FUS. In patients with tremor and comorbid ataxia syndromes (n = 3), none were found to have worsened ataxia after VIM-FUS; all had clinically significant tremor improvement. Subthalamic nucleus (STN)-FUS for PD (n = 49) gave approximately 50% improvement in PD motor symptoms, with dystonia and mild dyskinesias as possible adverse effects. Cerebellothalamic tract (CTT-FUS) for ET (n = 42) gave 55-90% tremor improvement, with gait dysfunction as a rare persistent adverse effect. Pallidothalamic tract (PTT-FUS) for PD (n = 50) gave approximately 50% improvement in motor symptoms, with mild speech dysfunction as a possible adverse effect. CONCLUSION: VIM-FUS appeared safe and effective for heterogenous tremor etiologies, and VO-FUS appeared most effective for isolated segmental dystonia. STN-FUS was effective for PD symptom reduction; postoperative dystonia and mild on-medication dyskinesias required medical management. Tractography-based targeting with CTT-FUS for ET and PTT-FUS for PD demonstrated promising early results. Larger prospective trials with long-term follow-up are needed to the evaluate the safety and efficacy non-FDA approved indications for FUS.

Impact of biologically effective dose on tremor decrease after stereotactic radiosurgical thalamotomy for essential tremor: a retrospective longitudinal analysis.

Stereotactic radiosurgery (SRS) is one of the surgical alternatives for drug-resistant essential tremor (ET). Here, we aimed at evaluating whether biologically effective dose (BEDGy2.47) is relevant for tremor improvement after stereotactic radiosurgical thalamotomy in a population of patients treated with one (unplugged) isocenter and a uniform dose of 130 Gy. This is a retrospective longitudinal single center study. Seventy-eight consecutive patients were clinically analyzed. Mean age was 69.1 years (median 71, range 36-88). Mean follow-up period was 14 months (median 12, 3-36). Tremor improvement was assessed at 12 months after SRS using the ET rating assessment scale (TETRAS, continuous outcome) and binary (binary outcome). BED was defined for an alpha/beta of 2.47, based upon previous studies considering such a value for the normal brain. Mean BED was 4573.1 Gy2.47 (median 4612, 4022.1-4944.7). Mean beam-on time was 64.7 min (median 61.4; 46.8-98.5). There was a statically significant correlation between delta (follow-up minus baseline) in TETRAS (total) with BED (p = 0.04; beta coefficient - 0.029) and beam-on time (p = 0.03; beta coefficient 0.57) but also between TETRAS (ADL) with BED (p = 0.02; beta coefficient 0.038) and beam-on time (p = 0.01; beta coefficient 0.71). Fractional polynomial multivariate regression suggested that a BED > 4600 Gy2.47 and a beam-on time > 70 min did not further increase clinical efficacy (binary outcome). Adverse radiation events (ARE) were defined as larger MR signature on 1-year follow-up MRI and were present in 7 out of 78 (8.9%) cases, receiving a mean BED of 4650 Gy2.47 (median 4650, range 4466-4894). They were clinically relevant with transient hemiparesis in 5 (6.4%) patients, all with BED values higher than 4500 Gy2.47. Tremor improvement was correlated with BED Gy2.47 after SRS for drug-resistant ET. An optimal BED value for tremor improvement was 4300-4500 Gy2.47. ARE appeared for a BED of more than 4500 Gy2.47. Such finding should be validated in larger cohorts.

Dynamic functional changes upon thalamotomy in essential tremor depend on baseline brain morphometry.

Patients with drug-resistant essential tremor (ET) may undergo Gamma Knife stereotactic radiosurgical thalamotomy (SRS-T), where the ventro-intermediate nucleus of the thalamus (Vim) is lesioned by focused beams of gamma radiations to induce clinical improvement. Here, we studied SRS-T impacts on left Vim dynamic functional connectivity (dFC, n = 23 ET patients scanned before and 1 year after intervention), and on surface-based morphometric brain features (n = 34 patients, including those from dFC analysis). In matched healthy controls (HCs), three dFC states were extracted from resting-state functional MRI data. In ET patients, state 1 spatial stability increased upon SRS-T (F1,22 = 19.13, p = 0.004). More frequent expression of state 3 over state 1 before SRS-T correlated with greater clinical recovery in a way that depended on the MR signature volume (t6 = 4.6, p = 0.004). Lower pre-intervention spatial variability in state 3 expression also did (t6 = - 4.24, p = 0.005) and interacted with the presence of familial ET so that these patients improved less (t6 = 4.14, p = 0.006). ET morphometric profiles showed significantly lower similarity to HCs in 13 regions upon SRS-T (z ≤ - 3.66, p ≤ 0.022), and a joint analysis revealed that before thalamotomy, morphometric similarity and states 2/3 mean spatial similarity to HCs were anticorrelated, a relationship that disappeared upon SRS-T (z ≥ 4.39, p < 0.001). Our results show that left Vim functional dynamics directly relates to upper limb tremor lowering upon intervention, while morphometry instead has a supporting role in reshaping such dynamics.

Brain Shift during Staged Deep Brain Stimulation for Movement Disorders.

INTRODUCTION: Deep brain stimulation (DBS) is a routine neurosurgical procedure utilized to treat various movement disorders including Parkinson's disease (PD), essential tremor (ET), and dystonia. Treatment efficacy is dependent on stereotactic accuracy of lead placement into the deep brain target of interest. However, brain shift attributed to pneumocephalus can introduce unpredictable inaccuracies during DBS lead placement. This study aimed to determine whether intracranial air is associated with brain shift in patients undergoing staged DBS surgery. METHODS: We retrospectively evaluated 46 patients who underwent staged DBS surgery for PD, ET, and dystonia. Due to the staged nature of DBS surgery at our institution, the first electrode placement is used as a concrete fiducial marker for movement in the target location. Postoperative computed tomography (CT) images after the first electrode implantation, as well as preoperative, and postoperative CT images after the second electrode implantation were collected. Images were analyzed in stereotactic targeting software (BrainLab); intracranial air was manually segmented, and electrode shift was measured in the x, y, and z plane, as well as a Euclidian distance on each set of merged CT scans. A Pearson correlation analysis was used to determine the relationship between intracranial air and brain shift, and student's t test was used to compare means between patients with and without radiographic evidence of intracranial air. RESULTS: Thirty-six patients had pneumocephalus after the first electrode implantation, while 35 had pneumocephalus after the second electrode implantation. Accumulation of intracranial air following the first electrode implantation (4.49 ± 6.05 cm3) was significantly correlated with brain shift along the y axis (0.04 ± 0.35 mm; r (34) = 0.36; p = 0.03), as well as the Euclidean distance of deviation (0.57 ± 0.33 mm; r (34) = 0.33; p = 0.05) indicating statistically significant shift on the ipsilateral side. However, there was no significant correlation between intracranial air and brain shift following the second electrode implantation, suggesting contralateral shift is minimal. Furthermore, there was no significant difference in brain shift between patients with and without radiographic evidence of intracranial air following both electrode implantation surgeries. CONCLUSION: Despite observing volumes as high as 22.0 cm3 in patients with radiographic evidence of pneumocephalus, there was no significant difference in brain shift when compared to patients without pneumocephalus. Furthermore, the mean magnitude of brain shift was <1.0 mm regardless of whether pneumocephalus was presenting, suggesting that intracranial air accumulation may not produce clinical significant brain shift in our patients.

Outcomes of Focused Ultrasound Thalamotomy in Tremor Syndromes.

BACKGROUND: The current literature comparing outcomes after a unilateral magnetic resonance image-guided focused ultrasound (MRgFUS) thalamotomy between tremor syndromes is limited and remains a possible preoperative factor that could help predict the long-term outcomes. OBJECTIVE: The aim was to report on the outcomes between different tremor syndromes after a unilateral MRgFUS thalamotomy. METHODS: A total of 66 patients underwent a unilateral MRgFUS thalamotomy for tremor between November 2018 and May 2020 at St Vincent's Hospital Sydney. Each patient's tremor syndrome was classified prior to treatment. Clinical assessments, including the hand tremor score (HTS) and Quality of Life in Essential Tremor Questionnaire (QUEST), were performed at baseline and predefined intervals to 36 months. RESULTS: A total of 63 patients, comprising 30 essential tremor (ET), 24 dystonic tremor (DT), and 9 Parkinson's disease tremor (PDT) patients, returned for at least one follow-up. In the ET patients, at 24 months there was a 61% improvement in HTS and 50% improvement in QUEST compared to baseline. This is in comparison to PDT patients, where an initial benefit in HTS and QUEST was observed, which waned at each follow-up, remaining significant only up until 12 months. In the DT patients, similar results were observed to the ET patients: at 24 months there was a 61% improvement in HTS and 43% improvement in QUEST compared to baseline. CONCLUSION: These results support the use of unilateral MRgFUS thalamotomy for the treatment of DT, which appears to have a similar expected outcome to patients diagnosed with ET. Patients with PDT should be warned that there is a risk of treatment failure. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Changes in cerebral cortex activity during a simple motor task after MRgFUS treatment in patients affected by essential tremor and Parkinson's disease: a pilot study using functional NIRS.

Objective.Magnetic resonance imaging-guided focused ultrasound surgery (MRgFUS) is a non-invasive thermal ablation method that involves high-intensity focused ultrasound surgery (FUS) and Magnetic Resonance Imaging for anatomical imaging and real-time thermal mapping. This technique is widely employed for the treatment of patients affected by essential tremor (ET) and Parkinson's disease (PD). In the current study, functional near-infrared spectroscopy (fNIRS) was used to highlight hemodynamics changes in cerebral cortex activity, during a simple hand motor task, i.e. unimanual left and right finger-tapping, in ET and PD patients.Approach.All patients were evaluated before, one week and one month after MRgFUS treatment.Main results.fNIRS revealed cerebral hemodynamic changes one week and one month after MRgFUS treatment, especially in the ET group, that showed a significant clinical improvement in tremor clinical scores.Significance.To our knowledge, our study is the first that showed the use of fNIRS system to measure the cortical activity changes following unilateral ventral intermediate nucleus thalamotomy after MRgFUS treatment. Our findings showed that therapeutic MRgFUS promoted the remodeling of neuronal networks and changes in cortical activity in association with symptomatic improvements.

Successful MRI-Guided Focused Ultrasound Thalamotomy after Ipsilateral Gamma Knife Radiosurgery for Essential Tremor: A Case Report with Video.

We report the case of a 67-year-old left-handed female patient with disabling medically refractory essential tremor who underwent successful right-sided magnetic resonance-guided focused ultrasound (MRgFUS) of the ventral intermediate nucleus after ipsilateral gamma knife radiosurgery (GKRS) thalamotomy performed 3 years earlier. The GKRS had a partial effect on her postural tremor without side effects, but there was no reduction of her kinetic tremor or improvement in her quality of life (QoL). The patient subsequently underwent a MRgFUS thalamotomy, which induced an immediate and marked reduction in both the postural and kinetic tremor components, with minor complications (left upper lip hypesthesia, dysmetria in her left hand, and slight gait ataxia). The MRgFUS-induced lesion was centered more medially than the GKRS-induced lesion and extended more posteriorly and inferiorly. The MRgFUS-induced lesion interrupted remaining fibers of the dentatorubrothalamic tract (DRTT). The functional improvement 1-year post-MRgFUS was significant due to a marked reduction of the patient's kinetic tremor. The QoL score (Quality of Life in Essential Tremor) improved by 88% and her Clinical Rating Scale for Tremor left hand score by 62%. The side effects persisted but were minor, with no impact on her QoL. The explanation for the superior efficacy of MRgFUS compared to GKRS in our patient could be due to either a poor response to the GKRS or to a better localization of the MRgFUS lesion with a more extensive interruption of DRTT fibers. In conclusion, MRgFUS can be a valuable therapeutic option after unsatisfactory GKRS, especially because MRgFUS has immediate clinical effectiveness, allowing intra-procedural test lesions and possible readjustment of the target if necessary.

Magnetic Resonance-Guided Focused Ultrasound Thalamotomy Rebalances Atypical Functional Hierarchy in Patients with Essential Tremor.

Magnetic resonance-guided focused ultrasound (MRgFUS) has brought thalamotomy back to the frontline for essential tremor (ET). As functional organization of human brain strictly follows hierarchical principles which are frequently deficient in neurological diseases, whether additional damage from MRgFUS thalamotomy induces further disruptions of ET functional scaffolds are still controversial. This study was to examine the alteration features of brain functional frameworks following MRgFUS thalamotomy in patients with ET. We retrospectively obtained preoperative (ETpre) and postoperative 6-month (ET6m) data of 30 ET patients underwent MRgFUS thalamotomy from 2018 to 2020. Their archived functional MR images were used to functional gradient comparison. Both supervised pattern learning and stepwise linear regression were conducted to associate gradient features to tremor symptoms with additional neuropathophysiological analysis. MRgFUS thalamotomy relieved 78.19% of hand tremor symptoms and induced vast global framework alteration (ET6m vs. ETpre: Cohen d = - 0.80, P < 0.001). Multiple robust alterations were identified especially in posterior cingulate cortex ([Formula: see text] ET6m vs. [Formula: see text] ETpre: Cohen d = 0.87, P = 0.048). Compared with matched health controls (HCs), its gradient distances to primary communities were significantly increased in [Formula: see text] ETpre patients with anomalous stepwise connectivity (P < 0.05 in ETpre vs. HCs), which were restored after MRgFUS thalamotomy. Both global and regional gradient features could be used for tremor symptom prediction and were linked to neuropathophysiological features of Parkinson disease and oxidative phosphorylation. MRgFUS thalamotomy not only suppress tremor symptoms but also rebalances atypical functional hierarchical architecture of ET patients.

Hemorrhagic Safety of Magnetic Resonance-Guided Focused Ultrasound Thalamotomy for Tremor without Interruption of Antiplatelet or Anticoagulant Therapy.

INTRODUCTION: Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is an incision-less ablative technique used to treat medically refractory tremor. Although intracerebral hemorrhage has not been reported with MRgFUS thalamotomy for the treatment of movement disorders, clinicians commonly interrupt active blood thinning medications prior to the procedure or offer gamma knife radiosurgery instead. However, MRgFUS uses focal thermoablation, and bleeding risk is likely minimal. This study aimed to evaluate the safety of MRgFUS thalamotomy in patients with essential tremor (ET) and tremor-dominant Parkinson's disease (PD) without interrupting anticoagulant or antiplatelet therapies. METHODS: This was a single-center retrospective case series of all patients with ET or PD undergoing MRgFUS from February 2019 through December 2022 (n = 96). Demographic variables and medications taken at the time of surgery were obtained. Our primary outcome was the type and frequency of hemorrhagic complications noted on the operative report or postoperative imaging. RESULTS: The mean age of patients was 74.2 years, and 26% were female. Forty patients were taking ≥1 antiplatelet or anticoagulant medications. No patient actively taking anticoagulant or antiplatelet therapies had a hemorrhagic complication during or <48 h after the procedure. CONCLUSION: The frequency of intra- or postoperative complications from MRgFUS was not higher in patients actively taking anticoagulant or antiplatelet therapies relative to those who were not. Our findings suggest that MRgFUS thalamotomy does not necessitate interrupting anticoagulant or antiplatelet therapies. However, given the limited number of patients actively taking these therapies in our cohort (n = 40), additional testing in large, prospective studies should be conducted to further establish safety.

[Experience of staged and simultaneous bilateral thalamotomy using MR-guided focused ultrasound in the treatment of essential tremor]. / Opyt poetapnoi i odnomomentnoi dvustoronnei talamotomii metodom fokusirovannogo ul'trazvuka pod kontrolem magnitno-rezonansnoi tomografii v lechenii essentsial'nogo tremora.

OBJECTIVE: To show that effective and safe bilateral MR-guided focused ultrasound (MRgFUS) treatment of essential tremor (ET) is achievable. MATERIAL AND METHODS: Four male patients underwent bilateral thalamotomy. Two patients underwent staged thalamotomy, with the ≥12 month interval between operations. Two patients underwent simultaneous bilateral thalamotomy. RESULTS: After six months, all patients noted a significant reduction in symptoms on both sides: when assessing tremors with the Clinical Rating Scale for Tremor, the severity of hyperkinesis decreased by 57.5-69.7%. We did not observe any complications in any of the cases. CONCLUSION: Our experience indicates that simultaneous bilateral MRI-guided focused ultrasound treatment of ET can be performed safely and effectively. Further research is necessary to estimate the effectiveness and adverse effect rates.

Essential Tremor - Deep Brain Stimulation vs. Focused Ultrasound.

INTRODUCTION: Essential Tremor (ET) is one of the most common tremor syndromes typically presented as action tremor, affecting mainly the upper limbs. In at least 30-50% of patients, tremor interferes with quality of life, does not respond to first-line therapies and/or intolerable adverse effects may occur. Therefore, surgery may be considered. AREAS COVERED: In this review, the authors discuss and compare unilateral ventral intermedius nucleus deep brain stimulation (VIM DBS) and bilateral DBS with Magnetic Resonance-guided Focused Ultrasound (MRgFUS) thalamotomy, which comprises focused acoustic energy generating ablation under real-time MRI guidance. Discussion includes their impact on tremor reduction and their potential complications. Finally, the authors provide their expert opinion. EXPERT OPINION: DBS is adjustable, potentially reversible and allows bilateral treatments; however, it is invasive requires hardware implantation, and has higher surgical risks. Instead, MRgFUS is less invasive, less expensive, and requires no hardware maintenance. Beyond these technical differences, the decision should also involve the patient, family, and caregivers.