Cognitive outcomes following unilateral magnetic resonance-guided focused ultrasound thalamotomy for essential tremor: findings from two cohorts.

Magnetic resonance-guided, focused ultrasound thalamotomy is a neurosurgical treatment for refractory essential tremor. This study examined cognitive outcomes following unilateral magnetic resonance-guided, focused ultrasound thalamotomy, targeting the ventral intermediate nucleus of the thalamus for essential tremor. The research was conducted at two sites: Sunnybrook Research Institute in Toronto, Canada, and West Virginia University School of Medicine Rockefeller Neuroscience Institute in West Virginia, USA. The study focused on cognitive changes at both the group and individual levels. Patients with refractory essential tremor completed cognitive testing before and after magnetic resonance-guided, focused ultrasound thalamotomy at both sites. The cognitive testing assessed domains of attention, processing speed, working memory, executive function, language and learning/memory. Postoperative changes in cognition were examined using paired t-tests and Wilcoxon signed-rank tests, as appropriate. Reliable change indices were calculated to assess clinically significant changes at the individual level. A total of 33 patients from Toronto and 22 patients from West Virginia were included. Following magnetic resonance-guided, focused ultrasound thalamotomy, there was a significant reduction in tremor severity in both cohorts. At the group level, there were no significant declines in postoperative cognitive performance in either cohort. The reliable change analyses revealed some variability at the individual level, with most patients maintaining stable performance or showing improvement. Taken together, the results from these two independent cohorts demonstrate that unilateral magnetic resonance-guided, focused ultrasound thalamotomy significantly reduces tremor severity without negatively impacting cognition at both the group and individual levels, highlighting the cognitive safety of magnetic resonance-guided focused ultrasound thalamotomy for essential tremor.

Cognitive effects of unilateral thalamotomy for tremor: a meta-analysis.

Tremor is a debilitating symptom that can lead to functional impairment. Pharmacotherapy is often successful, but up to 50% of patients are resistant to medications or cannot tolerate side effects. Thalamotomy to the ventral intermediate nucleus of the thalamus is a surgical intervention for refractory tremor. Thalamotomy surgeries include radiofrequency and incisionless procedures, such as Gamma Knife radiosurgery and magnetic resonance-guided focused ultrasound. Cognitive changes following thalamotomy have been inconsistently reported across studies. We performed a meta-analysis to summarize the impact of unilateral thalamotomy to the ventral intermediate nucleus of the thalamus across multiple cognitive domains. We searched MEDLINE, Embase Classic, Embase and EBM Reviews for relevant studies. Neuropsychological tests were categorized into seven cognitive domains: global cognition, verbal memory, non-verbal memory, executive function, phonemic fluency, semantic fluency and visuospatial processing. We calculated standardized mean differences as Hedges' g and 95% confidence intervals of the change between pre- and postoperative cognitive scores. Pooling of standardized mean differences across studies was performed using random-effects models. Risk of bias across studies and quality of evidence for each cognitive domain were assessed with the National Institute of Health quality assessment tool and the GRADEpro Guideline Development Tool, respectively. Of the 1251 records reviewed, eight studies met inclusion criteria. We included 193 patients with essential tremor, Parkinson's disease, or multiple sclerosis in the meta-analysis. There was a small significant decline in phonemic fluency [standardized mean difference = -0.29, 95% confidence interval: (-0.52, -0.05), P = 0.017] and a trend towards a decline in semantic fluency [standardized mean difference = -0.19, 95% confidence interval: (-0.40, 0.01), P = 0.056]. No postoperative changes were observed in the other cognitive domains (P values >0.14). In secondary analyses, we restricted the analyses to studies using magnetic resonance-guided focused ultrasound given its growing popularity and more precise targeting. In those analyses, there was no evidence of cognitive decline across any domain (P values >0.37). In terms of risk of bias, five studies were rated as 'good' and three studies were rated as 'fair'. According to GRADEpro guidelines, the certainty of the effect for all cognitive domains was low. This study provides evidence that unilateral thalamotomy to the ventral intermediate nucleus of the thalamus is relatively safe from a cognitive standpoint, however, there may be a small decline in verbal fluency. Magnetic resonance-guided focused ultrasound might have a more favourable postoperative cognitive profile compared with other thalamotomy techniques.

Ipsilateral and axial tremor response to focused ultrasound thalamotomy for essential tremor: clinical outcomes and probabilistic mapping.

BACKGROUND: MR-guided focused ultrasound (MRgFUS) thalamotomy has been shown to be a safe and effective treatment for essential tremor (ET). OBJECTIVE: To investigate the effects of MRgFUS in patients with ET with an emphasis on ipsilateral-hand and axial tremor subscores. METHODS: Tremor scores and adverse effects of 100 patients treated between 2012 and 2018 were assessed at 1 week, 3, 12, and 24 months. A subgroup analysis of ipsilateral-hand tremor responders (defined as patients with ≥30% improvement at any time point) and non-responders was performed. Correlations and predictive factors for improvement were analysed. Weighted probabilistic maps of improvement were generated. RESULTS: Significant improvement in axial, contralateral-hand and total tremor scores was observed at all study visits from baseline (p<0.0001). There was no significant improvement in ipsilateral subscores. A subset of patients (n=20) exhibited group-level ipsilateral-hand improvement that remained significant through all follow-ups (p<0.001). Multivariate regression analysis revealed that higher baseline scores predict better improvement in ipsilateral-hand and axial tremor. Probabilistic maps demonstrated that the lesion hotspot for axial improvement was situated more medially than that for contralateral improvement. CONCLUSION: MRgFUS significantly improved axial, contralateral-hand and total tremor scores. In a subset of patients, a consistent group-level treatment effect was observed for ipsilateral-hand tremor. While ipsilateral improvement seemed to be less directly related to lesion location, a spatial relationship between lesion location and axial and contralateral improvement was observed that proved consistent with the somatotopic organisation of the ventral intermediate nucleus. TRIAL REGISTRATION NUMBERS: NCT01932463, NCT01827904, and NCT02252380.

Echo-Focusing in Transcranial Focused Ultrasound Thalamotomy for Essential Tremor: A Feasibility Study.

BACKGROUND: Transcranial magnetic resonance-guided focused ultrasound (TcMRgFUS) systems currently employ computed tomography (CT)-based aberration corrections, which may provide suboptimal trans-skull focusing. OBJECTIVES: The objective of this study was to evaluate a contrast agent microbubble imaging-based transcranial focusing method, echo-focusing (EF), during TcMRgFUS for essential tremor. METHODS: A clinical trial of TcMRgFUS thalamotomy using EF for the treatment of essential tremor was conducted (NCT03935581; funded by InSightec [Tirat Carmel, Israel]). Patients (n = 12) were injected with Definity (Lantheus Medical Imaging, North Billerica, MA) microbubbles, and EF was performed using a research feature add-on to a commercial TcMRgFUS system (ExAblate Neuro, InSightec). Subablative thermal sonications carried out using (1) EF and (2) CT-based aberration corrections were compared via magnetic resonance thermometry, and the optimal focusing method for each patient was employed for TcMRgFUS thalamotomy. RESULTS: EF aberration corrections provided increased sonication efficiency, decreased focal size, and equivalent targeting accuracy relative to CT-based focusing. EF aberration corrections were employed successfully for lesion formation in all 12 patients, 3 of whom had previously undergone unsuccessful TcMRgFUS thalamotomy via CT-based focusing. There were no adverse events related directly to the EF procedure. CONCLUSIONS: EF is feasible and appears safe during TcMRgFUS thalamotomy for essential tremor and improves on the trans-skull focal quality provided by existing CT-based focusing methods. © 2020 International Parkinson and Movement Disorder Society.

Cost-effectiveness analysis of MR-guided focused ultrasound thalamotomy for tremor-dominant Parkinson's disease.

OBJECTIVE: The development of transcranial MR-guided focused ultrasound (MRgFUS) has revitalized the practice of lesioning procedures in functional neurosurgery. Previous health economic analysis found MRgFUS thalamotomy to be a cost-effective treatment for patients with essential tremor, supporting its reimbursement. With the publication of level I evidence in support of MRgFUS thalamotomy for patients with tremor-dominant Parkinson's disease (TDPD), the authors performed a health economic comparison between MRgFUS, deep brain stimulation (DBS), and medical therapy. METHODS: The authors used a decision tree model with rollback analysis and one-factor sensitivity analysis. Literature searches of MRgFUS thalamotomy and unilateral DBS of the ventrointermediate nucleus of the thalamus for TDPD were performed to determine the utility and probabilities for the model. Costs in Canadian dollars (CAD) were derived from the Schedule of Benefits and Fees in Ontario, Canada, and expert opinion on usage. RESULTS: MRgFUS was associated with an expected cost of $14,831 CAD. Adding MRgFUS to continued medical therapy resulted in an incremental cost-effectiveness ratio of $30,078 per quality-adjusted life year (QALY), which remained cost-effective under various scenarios in the sensitivity analysis. Comparing DBS to MRgFUS, while DBS did not achieve the willingness-to-pay threshold ($56,503 per QALY) in the base case scenario, it did so under several scenarios in the sensitivity analysis. CONCLUSIONS: MRgFUS thalamotomy is a cost-effective treatment for patients with TDPD, particularly over continued medical therapy. While MRgFUS remains competitive with DBS, the cost-effectiveness advantage is less substantial. These results will help inform the integration of this technology in the healthcare system.

Medulloblastoma has a global impact on health related quality of life: Findings from an international cohort.

BACKGROUND: Understanding the global impact of medulloblastoma on health related quality of life (HRQL) is critical to characterizing the broad impact of this disease and realizing the benefits of modern treatments. We evaluated HRQL in an international cohort of pediatric medulloblastoma patients. METHODS: Seventy-six patients were selected from 10 sites across North America, Europe, and Asia, who participated in the Medulloblastoma Advanced Genomics International Consortium (MAGIC). The Health Utilities Index (HUI) was administered to patients and/or parents at each site. Responses were used to determine overall HRQL and attributes (ie specific subdomains). The impact of various demographic and medical variables on HRQL was considered-including molecular subgroup. RESULTS: The majority of patients reported having moderate or severe overall burden of morbidity for both the HUI2 and HUI3 (HUI2 = 60%; HUI3 = 72.1%) when proxy-assessed. Self-care in the HUI2 was rated as higher (ie better outcome) for patients from Western versus Eastern sites, P = .02. Patients with nonmetastatic status had higher values (ie better outcomes) for the HUI3 hearing, HUI3 pain, and HUI2 pain, all P < .05. Patients treated with a gross total resection also had better outcomes for the HUI3 hearing (P = .04). However, those who underwent a gross total resection reported having worse outcomes on the HUI3 vision (P = .02). No differences in HRQL were evident as a function of subgroup. CONCLUSIONS: By examining an international sample of survivors, we characterized the worldwide impact of medulloblastoma. This is a critical first step in developing global standards for evaluating long-term outcomes.

Clinical significance of posttraumatic intracranial hemorrhage in clinically mild brain injury: a retrospective cohort study.

BACKGROUND: Much attention has been focused on management of severe traumatic brain injury (TBI); however, comparatively little is known about management of traumatic hemorrhage in clinically mild TBI. We aimed to clarify the role of clinical observation and repeat radiography for patients with mild TBI and abnormal findings on initial computed tomography (CT) of the head. METHODS: We queried the neurotrauma database of the Ontario Trauma Registry and the Sunnybrook institutional database to identify patients with CT findings of a traumatic hemorrhage or calvarial fracture between November 2014 and December 2016. Exclusionary criteria were age less than 16 years, Glasgow Coma Scale (GCS) score less than 13, anticoagulant use, bleeding diathesis and midline shift greater than 5 mm. The primary outcome was the need for neurosurgical intervention. RESULTS: A total of 607 patients were included. Most (374 [61.6%]) had a GCS score of 15; 185 (30.5%) and 48 (7.9%) had a GCS score of 14 and 13, respectively. Five patients (0.8%) required surgical intervention, all within the first 72 hours, owing to clinical deterioration with subsequently demonstrated radiographic evidence of expanding hemorrhage. Most patients (506 [83.4%]) had routine repeat imaging, without documented change in their neurologic status. INTERPRETATION: The majority of patients in our cohort had repeat imaging, which did not influence surgical management, at substantial cost to the health care system. The findings suggest the need to reevaluate repeat imaging protocols for this subset of patients with TBI.

Predictors of neuropsychological late effects and white matter correlates in children treated for a brain tumor without radiation therapy.

BACKGROUND: Little is known about cognition and predictors of neuropsychological outcomes in pediatric low-grade glioma (PLGG) survivors treated without radiation therapy. This research expands upon our previous work by further identifying the cognitive profile of PLGG patients treated without radiation therapy, investigating the specific medical and demographic variables that predict functioning, and examining white matter structure and its relationship to neuropsychological performance. PROCEDURE: Nineteen PLGG patients (11-19 years) were administered the Wechsler Intelligence Scale for Children/Wechsler Adult Intelligence Scale, and subtests from the Woodcock-Johnson Tests of Cognition (visual matching, rapid picture naming, and pair cancellation) and Cambridge Neuropsychological Test Automated Battery (pattern recognition memory, delayed matching to sample, intra-extra dimensional set shift, motor screening task, rapid visual information processing, and spatial span). RESULTS: The sample had normative weaknesses in verbal working memory, brief attention/vigilance, psychomotor speeded output, visual perception and matching, overall cognition, working memory, and processing speed. Increased surgeries or subtotal resections, hydrocephalus, shunting procedures, chemotherapy, NF1, and supratentorial location were predictive of cognitive deficits. Broad white matter involvement of the frontal, temporal, parietal, and occipital lobes as well as the cerebellum, as inferred from diffusion tensor imaging indices of decreased fiber orientation and increased water diffusion, was related to many cognitive difficulties. CONCLUSIONS: This study comprehensively examines cognitive functioning in PLGG patients treated without radiation therapy, predictors of cognition, and its relation to white matter structure. Our findings indicate that medical and demographic variables other than radiation therapy can lead to cognitive late effects with diffuse white matter involvement.

Accumulated thermal dose in MRI-guided focused ultrasound for essential tremor: repeated sonications with low focal temperatures.

OBJECTIVE: The object of this study was to correlate lesion size with accumulated thermal dose (ATD) in transcranial MRI-guided focused ultrasound (MRgFUS) treatments of essential tremor with focal temperatures limited to 50°C-54°C. METHODS: Seventy-five patients with medically refractory essential tremor underwent MRgFUS thalamotomy at the authors' institution. Intraoperative MR thermometry was performed to measure the induced temperature and thermal dose distributions (proton resonance frequency shift coefficient = -0.00909 ppm/°C). In 19 patients, it was not possible to raise the focal temperature above 54°C because of unfavorable skull characteristics and/or the pain associated with cranial heating. In this patient subset, sonications with focal temperatures between 50°C and 54°C were repeated (5.1 ± 1.5, mean ± standard deviation) to accumulate a sufficient thermal dose for lesion formation. The ATD profile sizes (17, 40, 100, 200, and 240 cumulative equivalent minutes at 43°C [CEM43]) calculated by combining axial MR thermometry data from individual sonications were correlated with the corresponding lesion sizes measured on axial T1-weighted (T1w) and T2-weighted (T2w) MR images acquired 1 day posttreatment. Manual corrections were applied to the MR thermometry data prior to thermal dose accumulation to compensate for off-resonance-induced spatial-shifting artifacts. RESULTS: Mean lesion sizes measured on T2w MRI (5.0 ± 1.4 mm) were, on average, 28% larger than those measured on T1w MRI (3.9 ± 1.4 mm). The ATD thresholds found to provide the best correlation with lesion sizes measured on T2w and T1w MRI were 100 CEM43 (regression slope = 0.97, R2 = 0.66) and 200 CEM43 (regression slope = 0.98, R2 = 0.89), respectively, consistent with data from a previous study of MRgFUS thalamotomy via repeated sonications at higher focal temperatures (≥ 55°C). Two-way linear mixed-effects analysis revealed that dominant tremor subscores on the Fahn-Tolosa-Marin Clinical Rating Scale for Tremor (CRST) were statistically different from baseline at 3 months and 1 year posttreatment in both low-temperature (50°C-54°C) and high-temperature (≥ 55°C) patient cohorts. No significant fixed effect on the dominant tremor scores was found for the temperature cohort factor. CONCLUSIONS: In transcranial MRgFUS thalamotomy for essential tremor, repeated sonications with focal temperatures between 50°C and 54°C can accumulate a sufficient thermal dose to generate lesions for clinically relevant tremor suppression up to 1 year posttreatment, and the ATD can be used to predict the size of the resulting ablation zones measured on MRI. These data will serve to guide future clinical MRgFUS brain procedures, particularly those in which focal temperatures are limited to below 55°C.

PPAR and GST polymorphisms may predict changes in intellectual functioning in medulloblastoma survivors.

PURPOSE: Advances in the treatment of pediatric medulloblastoma have led to improved survival rates, though treatment-related toxicity leaves children with significant long-term deficits. There is significant variability in the cognitive outcome of medulloblastoma survivors, and it has been suggested that this variability may be attributable to genetic factors. The aim of this study was to explore the contributions of single nucleotide polymorphisms (SNPs) in two genes, peroxisome proliferator activated receptor (PPAR) and glutathione-S-transferase (GST), to changes in general intellectual functioning in medulloblastoma survivors. METHODS: Patients (n = 44, meanage = 6.71 years, 61.3% males) were selected on the basis of available tissue samples and neurocognitive measures. Patients received surgical tumor resection, craniospinal radiation, radiation boost to the tumor site, and multiagent chemotherapy. Genotyping analyses were completed using the Illumina Human Omni2.5 BeadChip, and 41 single nucleotide polymorphisms (SNPs) were assessed across both genes. We used a machine learning algorithm to identify polymorphisms that were significantly associated with declines in general intellectual functioning following treatment for medulloblastoma. RESULTS: We identified age at diagnosis, radiation therapy, chemotherapy, and eight SNPs associated with PPARs as predictors of general intellectual functioning. Of the eight SNPs identified, PPARα (rs6008197), PPARγ (rs13306747), and PPARδ (rs3734254) were most significantly associated with long-term changes in general intellectual functioning in medulloblastoma survivors. CONCLUSIONS: PPAR polymorphisms may predict intellectual outcome changes in children treated for medulloblastoma. Importantly, emerging evidence suggests that PPAR agonists may provide an opportunity to minimize the effects of treatment-related cognitive sequelae in these children.

Magnetic resonance-guided focused ultrasound thalamotomy for treatment of essential tremor: A 2-year outcome study.

BACKGROUND: Magnetic resonance-guided focused ultrasound is an emerging, minimally invasive thermoablation technique for medically refractory essential tremor. Beyond the initial year, data regarding efficacy and potential predictors of efficacy are still preliminary. OBJECTIVES: The objective of this study was to assess the outcome at 2 years and the association between lesion volume and outcome 1 year after treatment. METHODS: We reviewed data from 37 patients who underwent unilateral magnetic resonance-guided focused ultrasound thalamotomy, with primary outcome being dominant tremor subscore of the Clinical Rating Scale for Tremor. We used multivariable linear regression to model initial lesion volume with 1-year outcome, adjusting for other clinically relevant variables. RESULTS: Although we detected a trend in loss of clinical benefit within the first year, the dominant tremor score at 2 years continued to be significantly improved (43.4%, 95% confidence interval 27.8%-59.0%) from baseline. Secondarily, initial lesion volume is significantly associated with 1-year outcome. CONCLUSION: Our findings show that magnetic resonance-guided focused ultrasound thalamotomy results in sustained tremor reduction for medically refractory essential tremor even in the long term, and we highlight areas for improvement.

Treatment of a Patient With Task-Specific Writing Tremor Using Magnetic Resonance-Guided Focused Ultrasound.

Task-specific dystonia is characterized by abnormal repetitive movements or postures in a specific body part that is triggered and ends with a task, such as writing. Failing medications, surgery, specifically disruption of key nuclei in the thalamus, can provide excellent symptomatic relief. Transcranial magnetic resonance (MR)-guided focused ultrasound is an emerging incision-less thermoablation technique. We describe MR-guided focused ultrasound tandem ablation of the ventral intermediate and ventralis oralis posterior nuclei in a 60-year-old patient with writer's cramp. The clinical improvement was immediate with incremental benefit from the latter lesion, which was sustained at 6 months follow-up.

Development of short-range white matter in healthy children and adolescents.

Neural communication is facilitated by intricate networks of white matter (WM) comprised of both long and short range connections. The maturation of long range WM connections has been extensively characterized, with projection, commissural, and association tracts showing unique trajectories with age. There, however, remains a limited understanding of age-related changes occurring within short range WM connections, or U-fibers. These connections are important for local connectivity within lobes and facilitate regional cortical function and greater network economy. Recent studies have explored the maturation of U-fibers primarily using cross-sectional study designs. Here, we analyzed diffusion tensor imaging (DTI) data for healthy children and adolescents in both a cross-sectional (n = 78; mean age = 13.04 ± 3.27 years) and a primarily longitudinal (n = 26; mean age = 10.78 ± 2.69 years) cohort. We found significant age-related differences in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) across the frontal, parietal, and temporal lobes of participants within the cross-sectional cohort. By contrast, we report significant age-related differences in only FA for participants within the longitudinal cohort. Specifically, larger FA values were observed with age in frontal, parietal, and temporal lobes of the left hemisphere. Our results extend previous findings restricted to long range WM to demonstrate regional changes in the microstructure of short range WM during childhood and adolescence. These changes possibly reflect continued myelination and axonal organization of short range WM with increasing age in more anterior regions of the left hemisphere. Hum Brain Mapp 39:204-217, 2018. © 2017 Wiley Periodicals, Inc.

Somatosensory evoked potentials after decompressive craniectomy for traumatic brain injury.

Somatosensory evoked potentials (SSEPs) are used for neuroprognosis after severe traumatic brain injury (TBI). However decompressive craniectomy (DC), involving removal of a portion of the skull to alleviate elevated intracranial pressure, is associated with an increase in SSEP amplitude. Accordingly, SSEPs are not available for neuroprognosis over the hemisphere with DC. We aim to determine the degree to which SSEP amplitudes are increased in the absence of cranial bone. This will serve as a precursor for translation to clinically prognostic ranges. Intra-operative SSEPs were performed before and after bone flap replacement in 22 patients with severe TBI. SSEP measurements were also performed in a comparison non-traumatic group undergoing craniotomy for tumor resection. N20/P25 amplitudes and central conduction time were measured with the bone flap in (BI) and out (BO). Linear regressions, adjusting for skull thickness and study arm, were performed to evaluate the contribution of bone presence to SSEP amplitudes. Latencies were not different between BO or BI trials in either group. Mean N20/P25 amplitudes recorded with BO were statistically different (p = 0.0001) from BI in both cohorts, showing an approximate doubling in BO amplitudes. For contralateral-ipsilateral montages r2 was 0.28 and for frontal pole montages r2 was 0.62. Cortical SSEP amplitudes are influenced by the presence of cortical bone as is particularly evident in frontal pole montages. Larger, longitudinal trials to assess feasibility of neuroprognosis over the hemisphere with DC in severe TBI patients are warranted.