L-2 hydroxyglutaric aciduria: report of a Mexican-Mayan patient with the mutation c.569C>T and response to vitamin supplements and levocarnitine.

Background: L-2-hydroxyglutaric aciduria (L2HGA) is a rare inherited autosomal recessive neurometabolic disorder caused by pathogenic variants in the L2HGDH gene which encodes mitochondrial 2-hydroxyglutarate dehydrogenase. Here, we report a case of L2HGA in a Mexican-Mayan patient with a homozygous mutation at L2HGDH gene and clinical response to vitamin supplements and levocarnitine. Case report: A 17-year-old, right-handed female patient with long-term history of seizures, developmental delay and ataxia was referred to a movement disorders specialist for the evaluation of tremor. Her brain MRI showed typical findings of L2HGA. The diagnosis was corroborated with elevated levels of 2-hydroxyglutaric acid in urine and genetic test which revealed a homozygous genetic known variant c.569C>T in exon 5 of L2HGDH gene. She was treated with levocarnitine and vitamin supplements, showing improvement in tremor and gait. Discussion: To our knowledge this is the first report of a Mexican patient with L2HGA. This case adds information about a rare condition in a different ethnic group and supports the findings of other authors which encountered symptomatic improvement with the use of flavin adenine dinucleotide (and its precursor riboflavin), and levocarnitine. Highlights: We report the first case of Mexican-Mayan patient with L2HGA showing a missense homozygous mutation in L2HGDH gene, and improvement of symptoms with vitamin supplements and levocarnitine.

[A case of Holmes tremor in which 123I-IMP SPECT and MRI findings suggest damage to the cerebellothalamic tract and the dentato-rubro-olivary pathway].

A 75-year-old woman was referred to our department in October 2022 with ataxia and involuntary movements of the right upper and lower limbs. She had experienced a left pontine hemorrhage in March 2021, which was managed conservatively. However, she had residual right-sided hemiplegia. In addition, she had cerebellar ataxia and a 2 |Hz resting tremor of the right upper and lower limbs, which was enhanced while maintaining posture and contemplation. Based on her history, and the findings of MRI and nuclear medicine imaging, we diagnosed the patient with Holmes tremor due to pontine hemorrhage. Holmes tremor is a rare movement disorder secondary to brainstem and thalamic lesions, characterized by a unilateral low-frequency tremor. In this case, 123I-IMP SPECT and MRI shows damage to the cerebellothalamic tract and dentaro-rubro-olivary pathway.

[Resting tremor of Parkinson's disease changing into Holmes' tremor by cerebellar hemorrhage: an examination of the pathophysiological mechanism of tremor].

A 71-year-old male who suffered from Hoehn and Yahr stage III Parkinson's disease with bradykinesia, rigidity and a 5-6-Hz tremor at rest in the right extremities was admitted to our hospital due to the sudden onset of vertigo. Right cerebellar hemorrhage was confirmed by CT. The patient's resting tremor in the right extremities disappeared immediately following the cerebellar hemorrhage. Six days later, MRI showed Wallerian degeneration in the cerebello-rubro-thalamic tract. Approximately 5 months later, a 2-3-Hz Holmes' tremor gradually appeared in the right upper extremity. This tremor was improved by increasing L-dopa doses. Case reports of the disappearance of Parkinson's resting tremor and subsequent emergence of Holmes' tremor due to cerebellar lesion are rare. Furthermore, the Wallerian degeneration of the cerebello-rubro-thalamic tract identified on MRI between tremors of the different frequencies is very rare. We hypothesize that the cause of the tremor frequency change was simultaneous damage to the nigro-striatal network and the cerebello-thalamo-cerebral network.

Connectivity-based segmentation of the thalamic motor region for deep brain stimulation in essential tremor: A comparison of deterministic and probabilistic tractography.

OBJECTIVE: Deep brain stimulation (DBS) studies have shown that stimulation of the motor segment of the thalamus based on probabilistic tractography is predictive of improvement in essential tremor (ET). However, probabilistic methods are computationally demanding, requiring the need for alternative tractography methods for use in the clinical setting. The purpose of this study was to compare probabilistic vs deterministic tractography methods for connectivity-based targeting in patients with ET. METHODS: Probabilistic and deterministic tractography methods were retrospectively applied to diffusion-weighted data sets in 36 patients with refractory ET. The thalamus and precentral gyrus were selected as regions of interest and fiber tracking was performed between these regions to produce connectivity-based thalamic segmentations, per prior methods. The resultant deterministic target maps were compared with those of thresholded probabilistic maps. The center of gravity (CG) of each connectivity map was determined and the differences in spatial distribution between the tractography methods were characterized. Furthermore, the intersection between the connectivity maps and CGs with the therapeutic volume of tissue activated (VTA) was calculated. A mixed linear model was then used to assess clinical improvement in tremor with volume of overlap. RESULTS: Both tractography methods delineated the region of the thalamus with connectivity to the precentral gyrus to be within the posterolateral aspect of the thalamus. The average CG of deterministic maps was more medial-posterior in both the left (3.7 ± 1.3 mm3) and the right (3.5 ± 2.2 mm3) hemispheres when compared to 30 %-thresholded probabilistic maps. Mixed linear model showed that the volume of overlap between CGs of deterministic and probabilistic targeting maps and therapeutic VTAs were significant predictors of clinical improvement. CONCLUSIONS: Deterministic tractography can reconstruct DBS thalamic target maps in approximately 5 min comparable to those produced by probabilistic methods that require > 12 h to generate. Despite differences in CG between the methods, both deterministic-based and probabilistic targeting were predictive of clinical improvement in ET.

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.

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.

Noninvasive modulation of essential tremor with focused ultrasonic waves.

Objective: Transcranial focused low-intensity ultrasound has the potential to noninvasively modulate confined regions deep inside the human brain, which could provide a new tool for causal interrogation of circuit function in humans. However, it has been unclear whether the approach is potent enough to modulate behavior.Approach: To test this, we applied low-intensity ultrasound to a deep brain thalamic target, the ventral intermediate nucleus, in three patients with essential tremor.Main results: Brief, 15 s stimulations of the target at 10% duty cycle with low-intensity ultrasound, repeated less than 30 times over a period of 90 min, nearly abolished tremor (98% and 97% tremor amplitude reduction) in 2 out of 3 patients. The effect was observed within seconds of the stimulation onset and increased with ultrasound exposure time. The effect gradually vanished following the stimulation, suggesting that the stimulation was safe with no harmful long-term consequences detected.Significance: This result demonstrates that low-intensity focused ultrasound can robustly modulate deep brain regions in humans with notable effects on overt motor behavior.

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.

Stereotatic radiosurgery for the treatment of motor symptoms in Parkinson's disease: A systematic review.

BACKGROUND: Stereotaxic Radiosurgery (SRS) is a non-invasive lesioning technique for movement disorders when patients cannot undergo DBS due to medical comorbidities. OBJECTIVE: To describe and summarize the literature on SRS's application and physical parameters for Parkinson's disease (PD) motor symptoms. METHODS: The MEDLINE/PUBMED and EMBASE databases were searched in July 2022 following the PRISMA guideline. Two independent reviewers screened data from 425 articles. The level of evidence followed the Oxford Centre for Evidence-Based Medicine. Pertinent details for each study regarding participants, physical parameters, and results were extracted. RESULTS: Twelve studies reported that 454 PD patients underwent Gamma KnifeⓇ (GK). The mean improvement time of the treated symptoms was three months after GK. Tremor is the most common symptom investigated, with success rates ranging from 47.5% to 93.9%. Few studies were conducted for caudatotomy (GKC) and pallidotomy (GKP), which presented an improvement for dyskinesia and bradykinesia. Physical parameters were similar with doses ranging from 110 to 200 Gy, use of a 4-mm collimator with an advanced imaging locator system, and coordinates were obtained from available stereotactic atlases. CONCLUSIONS: GK thalamotomy is a good alternative for treating tremor; however, its effects are delayed, and there are cases in which it can regress after years. The outcomes of GKC and GKP seem to be promising. The existing studies are more limited, and effects need to be better investigated.

A rare presentation of Wilson disease with neurological symptoms: Case report and genetic analysis.

RATIONALE: Wilson disease is a rare genetic disorder primarily associated with hepatic symptoms; however, its unique neurological presentation remains a subject of interest in the medical literature. This case report contributes to existing knowledge by highlighting the unusual manifestation of Wilson disease with significant neurological symptoms. PATIENT CONCERNS: The patient, pseudonym John Smith, presented with prominent neurological symptoms, including tremors, dystonia, and psychiatric manifestations. Clinical findings corroborated copper accumulation in the brain, prompting a thorough diagnostic investigation. DIAGNOSES: Genetic analysis revealed two ATP7B mutations, confirming the primary diagnosis of Wilson disease. This case underscores the importance of recognizing atypical neurological presentations in the context of this rare genetic disorder. INTERVENTIONS: Chelation therapy, initiated promptly upon diagnosis, targeted copper overload. The intervention led to notable improvements in neurological symptoms and psychiatric manifestations. The dosage and duration of treatment were adjusted based on regular monitoring. OUTCOMES: Regular follow-up revealed a positive trajectory, with reduced tremors and improved overall well-being. Genetic testing, coupled with clinical assessments, contributed to monitoring treatment efficacy and optimizing therapeutic interventions. LESSONS: The main takeaway lessons from this case include the significance of a comprehensive diagnostic approach, personalized therapeutic interventions, and the imperative to acknowledge the diverse clinical spectrum of Wilson disease. Early recognition and tailored treatment contribute to favorable outcomes in cases with atypical neurological presentations.

MR-Guided Focused Ultrasound Thalamotomy in the Setting of Aneurysm Clip.

We report on a 75-year-old woman with a history of right MCA aneurysm clipping and medically refractive right-hand tremor. We successfully performed focused ultrasound thalamotomy of the left ventral intermediate nucleus under MR imaging-guidance at 3T. A thorough pretreatment evaluation of MR thermometry was critical to ensure that adequate precision could be achieved at the intended target. The tremor showed a 75% decrease at 24 hours postprocedure and a 50% decrease at a 3-month follow-up. There were no immediate adverse events.

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.

The Optimal Targeting for Focused Ultrasound Thalamotomy Differs between Dystonic and Essential Tremor: A 12-Month Prospective Pilot Study.

BACKGROUND: Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is increasingly used to treat drug-resistant essential tremor (ET). Data on MRgFUS thalamotomy in dystonic tremor (DT) are anecdotal. OBJECTIVES: To investigate efficacy, safety, and differences in target coordinates of MRgFUS thalamotomy in DT versus ET. METHODS: Ten patients with DT and 35 with ET who consecutively underwent MRgFUS thalamotomy were followed for 12 months. Although in both groups the initial surgical planning coordinates corresponded to the ventralis intermediate (Vim), the final target could be modified intraoperatively based on clinical response. RESULTS: Tremor significantly improved in both groups. The thalamic lesion was significantly more anterior in DT than ET. Considering both ET and DT groups, the more anterior the lesion, the lower the odds ratio for adverse events. CONCLUSIONS: MRgFUS thalamotomy is safe and effective in DT and ET. Compared to classical Vim coordinates used for ET, more anterior targeting should be considered for DT.

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.

Comparative neural correlates of DBS and MRgFUS lesioning for tremor control in essential tremor.

BACKGROUND: Given high rates of early complications and non-reversibility, refined targeting is necessitated for magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy for essential tremor (ET). Selection of lesion location can be informed by considering optimal stimulation area from deep brain stimulation (DBS). METHODS: 118 patients with ET who received DBS (39) or MRgFUS (79) of the ventral intermediate nucleus (VIM) underwent stimulation/lesion mapping, probabilistic mapping of clinical efficacy and normative structural connectivity analysis. The efficacy maps were compared, which depict the relationship between stimulation/lesion location and clinical outcome. RESULTS: Efficacy maps overlap around the VIM ventral border and encompass the dentato-rubro-thalamic tract. While the MRgFUS map extends inferiorly into the posterior subthalamic area, the DBS map spreads inside the VIM antero-superiorly. CONCLUSION: Comparing the efficacy maps of DBS and MRgFUS suggests a potential alternative location for lesioning, more antero-superiorly. This may reduce complications, without sacrificing efficacy, and individualise targeting. TRIAL REGISTRATION NUMBER: NCT02252380.