Trial of Globus Pallidus Focused Ultrasound Ablation in Parkinson's Disease.

BACKGROUND: Unilateral focused ultrasound ablation of the internal segment of globus pallidus has reduced motor symptoms of Parkinson's disease in open-label studies. METHODS: We randomly assigned, in a 3:1 ratio, patients with Parkinson's disease and dyskinesias or motor fluctuations and motor impairment in the off-medication state to undergo either focused ultrasound ablation opposite the most symptomatic side of the body or a sham procedure. The primary outcome was a response at 3 months, defined as a decrease of at least 3 points from baseline either in the score on the Movement Disorders Society-Unified Parkinson's Disease Rating Scale, part III (MDS-UPDRS III), for the treated side in the off-medication state or in the score on the Unified Dyskinesia Rating Scale (UDysRS) in the on-medication state. Secondary outcomes included changes from baseline to month 3 in the scores on various parts of the MDS-UPDRS. After the 3-month blinded phase, an open-label phase lasted until 12 months. RESULTS: Of 94 patients, 69 were assigned to undergo ultrasound ablation (active treatment) and 25 to undergo the sham procedure (control); 65 patients and 22 patients, respectively, completed the primary-outcome assessment. In the active-treatment group, 45 patients (69%) had a response, as compared with 7 (32%) in the control group (difference, 37 percentage points; 95% confidence interval, 15 to 60; P = 0.003). Of the patients in the active-treatment group who had a response, 19 met the MDS-UPDRS III criterion only, 8 met the UDysRS criterion only, and 18 met both criteria. Results for secondary outcomes were generally in the same direction as those for the primary outcome. Of the 39 patients in the active-treatment group who had had a response at 3 months and who were assessed at 12 months, 30 continued to have a response. Pallidotomy-related adverse events in the active-treatment group included dysarthria, gait disturbance, loss of taste, visual disturbance, and facial weakness. CONCLUSIONS: Unilateral pallidal ultrasound ablation resulted in a higher percentage of patients who had improved motor function or reduced dyskinesia than a sham procedure over a period of 3 months but was associated with adverse events. Longer and larger trials are required to determine the effect and safety of this technique in persons with Parkinson's disease. (Funded by Insightec; ClinicalTrials.gov number, NCT03319485.).

A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor.

BACKGROUND: Uncontrolled pilot studies have suggested the efficacy of focused ultrasound thalamotomy with magnetic resonance imaging (MRI) guidance for the treatment of essential tremor. METHODS: We enrolled patients with moderate-to-severe essential tremor that had not responded to at least two trials of medical therapy and randomly assigned them in a 3:1 ratio to undergo unilateral focused ultrasound thalamotomy or a sham procedure. The Clinical Rating Scale for Tremor and the Quality of Life in Essential Tremor Questionnaire were administered at baseline and at 1, 3, 6, and 12 months. Tremor assessments were videotaped and rated by an independent group of neurologists who were unaware of the treatment assignments. The primary outcome was the between-group difference in the change from baseline to 3 months in hand tremor, rated on a 32-point scale (with higher scores indicating more severe tremor). After 3 months, patients in the sham-procedure group could cross over to active treatment (the open-label extension cohort). RESULTS: Seventy-six patients were included in the analysis. Hand-tremor scores improved more after focused ultrasound thalamotomy (from 18.1 points at baseline to 9.6 at 3 months) than after the sham procedure (from 16.0 to 15.8 points); the between-group difference in the mean change was 8.3 points (95% confidence interval [CI], 5.9 to 10.7; P<0.001). The improvement in the thalamotomy group was maintained at 12 months (change from baseline, 7.2 points; 95% CI, 6.1 to 8.3). Secondary outcome measures assessing disability and quality of life also improved with active treatment (the blinded thalamotomy cohort)as compared with the sham procedure (P<0.001 for both comparisons). Adverse events in the thalamotomy group included gait disturbance in 36% of patients and paresthesias or numbness in 38%; these adverse events persisted at 12 months in 9% and 14% of patients, respectively. CONCLUSIONS: MRI-guided focused ultrasound thalamotomy reduced hand tremor in patients with essential tremor. Side effects included sensory and gait disturbances. (Funded by InSightec and others; ClinicalTrials.gov number, NCT01827904.).

A prospective trial of magnetic resonance-guided focused ultrasound thalamotomy for essential tremor: Results at the 2-year follow-up.

OBJECTIVE: Magnetic resonance guided focused ultrasound (MRgFUS) has recently been investigated as a new treatment modality for essential tremor (ET), but the durability of the procedure has not yet been evaluated. This study reports results at a 2- year follow-up after MRgFUS thalamotomy for ET. METHODS: A total of 76 patients with moderate-to-severe ET, who had not responded to at least two trials of medical therapy, were enrolled in the original randomized study of unilateral thalamotomy and evaluated using the clinical rating scale for tremor. Sixty-seven of the patients continued in the open-label extension phase of the study with monitoring for 2 years. Nine patients were excluded by 2 years, for example, because of alternative therapy such as deep brain stimulation (n = 3) or inadequate thermal lesioning (n = 1). However, all patients in each follow-up period were analyzed. RESULTS: Mean hand tremor score at baseline (19.8 ± 4.9; 76 patients) improved by 55% at 6 months (8.6 ± 4.5; 75 patients). The improvement in tremor score from baseline was durable at 1 year (53%; 8.9 ± 4.8; 70 patients) and at 2 years (56%; 8.8 ± 5.0; 67 patients). Similarly, the disability score at baseline (16.4 ± 4.5; 76 patients) improved by 64% at 6 months (5.4 ± 4.7; 75 patients). This improvement was also sustained at 1 year (5.4 ± 5.3; 70 patients) and at 2 years (6.5 ± 5.0; 67 patients). Paresthesias and gait disturbances were the most common adverse effects at 1 year-each observed in 10 patients with an additional 5 patients experiencing neurological adverse effects. None of the adverse events worsened over the period of follow-up, and 2 of these resolved. There were no new delayed complications at 2 years. INTERPRETATION: Tremor suppression after MRgFUS thalamotomy for ET is stably maintained at 2 years. Latent or delayed complications do not develop after treatment. Ann Neurol 2018;83:107-114.

The role of high-intensity focused ultrasound as a symptomatic treatment for Parkinson's disease.

MR-guided focused ultrasound is a novel, minimally invasive surgical procedure for symptomatic treatment of PD. With this technology, the ventral intermediate nucleus, STN, and internal globus pallidus have been targeted for therapeutic cerebral ablation, while also minimizing the risk of hemorrhage and infection from more invasive neurosurgical procedures. In a double-blinded, prospective, sham-controlled randomized controlled trial of MR-guided focused ultrasound thalamotomy for treatment of tremor-dominant PD, 62% of treated patients demonstrated improvement in tremor scores from baseline to 3 months postoperatively, as compared to 22% in the sham group. There has been only one open-label trial of MR-guided focused ultrasound subthalamotomy for patients with PD, demonstrating improvements of 71% for rigidity, 36% for akinesia, and 77% for tremor 6 months after treatment. Among the two open-label trials of MR-guided focused ultrasound pallidotomy for patients with PD, dyskinesia and overall motor scores improved up to 52% and 45% at 6 months postoperatively. Although MR-guided focused ultrasound thalamotomy is now approved by the U.S. Food and Drug Administration for treatment of parkinsonian tremor, additional high-quality randomized controlled trials are warranted and are underway to determine the safety and efficacy of MR-guided focused ultrasound subthalamotomy and pallidotomy for treatment of the cardinal features of PD. These studies will be paramount to aid clinicians to determine the ideal ablative target for individual patients. Additional work will be required to assess the durability of MR-guided focused ultrasound lesions, ideal timing of MR-guided focused ultrasound ablation in the course of PD, and the safety of performing bilateral lesions. © 2019 International Parkinson and Movement Disorder Society.

Neurological adverse event profile of magnetic resonance imaging-guided focused ultrasound thalamotomy for essential tremor.

BACKGROUND: Magnetic resonance imaging-guided focused ultrasound thalamotomy is approved by the U.S. Food and Drug Administration for treatment of essential tremor. Although this incisionless technology creates an ablative lesion, it potentially avoids serious complications of open stereotactic surgery. OBJECTIVE: To determine the safety profile of magnetic resonance imaging-guided focused ultrasound unilateral thalamotomy for essential tremor, including frequency, and severity of adverse events, including serious adverse events. METHODS: Analysis of safety data for magnetic resonance imaging-guided focused ultrasound thalamotomy (186 patients, five studies). RESULTS: Procedure-related serious adverse events were very infrequent (1.6%), without intracerebral hemorrhages or infections. Adverse events were usually transient and were commonly rated as mild (79%) and rarely severe (1%). As previously reported, abnormalities in sensation and balance were the commonest thalamotomy-related adverse events. CONCLUSION: The overall safety profile of magnetic resonance imaging-guided focused ultrasound thalamotomy supports its role as a new option for patients with medically refractory essential tremor. © 2018 International Parkinson and Movement Disorder Society.

Prognostic models for patients with brain metastases after stereotactic radiosurgery with or without whole brain radiotherapy: a validation study.

PURPOSE/OBJECTIVE(S): To compare the performance of five prognostic models [RTOG recursive partitioning analysis (RPA), Score Index for Radiosurgery in Brain Metastases (SIR), Barnholtz-Sloan-Kattan nomogram (BSKN), diagnosis-specific Graded Prognostic Assessment (dsGPA), and Graded Prognostic Assessment for Lung Cancer Using Molecular Markers (Lung-molGPA)] against actual survival in patients with brain metastases treated with SRS +/- WBRT. MATERIALS/METHODS: 100 consecutive patients treated with SRS +/- WBRT between January 2006 and July 2012 were retrospectively analyzed. Patients were binned according to 33 percentiles of the predicted survival distribution for the BSKN and dsGPA models to compare with LungmolGPA, RPA and SIR. Pearson's correlation coefficients between predicted and observed survival were estimated to quantify the proportion of variance in observed survival. RESULTS: Median survival for the entire cohort was 13.5 months, with predicted vs actual MS by BSKN, SIR, dsGPA, RPA, adenocarcinoma Lung-molGPA, and nonadenocarcinoma Lung-molGPA was 3.8 vs 15.6 months, 7 vs 13.5 months, 9.4 vs 13.5 months, 10.3 vs 13.5 months, 13.7 vs 13.7 months, and 9.8 vs 9.7 months, respectively. The BSKN model and adenocarcinoma LungmolGPA created three groups with a statistically significantly different MS (p = 0.002 and p = 0.01, respectively). CONCLUSION: All models under-predicted MS and only the BSKN and Lung-molGPA model stratified patients into three risk groups with statistically significant actual MS. The prognostic groupings of the adenocarcinoma Lung-molGPA group was the best predictor of MS, and showed that we are making improvements in our prognostic ability by utilizing molecular information that is much more widely available in the current treatment era.

Advances and Future Applications of Augmented Peripheral Nerve Regeneration.

Peripheral nerve injuries remain a significant source of long lasting morbidity, disability, and economic costs. Much research continues to be performed in areas related to improving the surgical outcomes of peripheral nerve repair. In this review, the physiology of peripheral nerve regeneration and the multitude of efforts to improve surgical outcomes are discussed. Improvements in tissue engineering that have allowed for the use of synthetic conduits seeded with neurotrophic factors are highlighted. Selected pre-clinical and available clinical data using cell based methods such as Schwann cell, undifferentiated, and differentiated stem cell transplantation to guide and enhance peripheral nerve regeneration are presented. The limitations that still exist in the utility of neurotrophic factors and cell-based therapies are outlined. Strategies that are most promising for translation into the clinical arena are suggested.

Focused Ultrasound Central Lateral Thalamotomy for the Treatment of Refractory Neuropathic Pain: Phase I Trial.

BACKGROUND AND OBJECTIVES: Magnetic resonance-guided focused ultrasound (MRgFUS) central lateral thalamotomy (CLT) has not yet been validated for treating refractory neuropathic pain (NP). Our aim was to assess the safety and potential efficacy of MRgFUS CLT for refractory NP. METHODS: In this prospective, nonrandomized, single-arm, investigator-initiated phase I trial, patients with NP for more than 6 months related to phantom limb pain, spinal cord injury, or radiculopathy/radicular injury and who had undergone at least one previous failed intervention were eligible. The main outcomes were safety profile and pain as assessed using the brief pain inventory, the pain disability index, and the numeric rating scale. Medication use and the functional connectivity of the default mode network (DMN) were also assessed. RESULTS: Ten patients were enrolled, with nine achieving successful ablation. There were no serious adverse events and 12 mild/moderate severity events. The mean age was 50.9 years (SD: 12.7), and the mean symptom duration was 12.3 years (SD: 9.7). Among eight patients with a 1-year follow-up, the brief pain inventory decreased from 7.6 (SD: 1.1) to 3.8 (SD: 2.8), with a mean percent decrease of 46.3 (SD: 40.6) (paired t -test, P = .017). The mean pain disability index decreased from 43.0 (SD: 7.5) to 25.8 (SD: 16.8), with a mean percent decrease of 39.3 (SD: 41.6) ( P = .034). Numeric rating scale scores decreased from a mean of 7.2 (SD: 1.8) to 4.0 (SD: 2.8), with a mean percent decrease of 42.8 (SD: 37.8) ( P = .024). Patients with predominantly intermittent pain or with allodynia responded better than patients with continuous pain or without allodynia, respectively. Some patients decreased medication use. Resting-state functional connectivity changes were noted, from disruption of the DMN at baseline to reactivation of connectivity between DMN nodes at 3 months. CONCLUSION: MRgFUS CLT is feasible and safe for refractory NP and has potential utility in reducing symptoms as measured by validated pain scales.

Clinical safety and feasibility of a novel implantable neuroimmune modulation device for the treatment of rheumatoid arthritis: initial results from the randomized, double-blind, sham-controlled RESET-RA study.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes persistent synovitis, bone damage, and progressive joint destruction. Neuroimmune modulation through electrical stimulation of the vagus nerve activates the inflammatory reflex and has been shown to inhibit the production and release of inflammatory cytokines and decrease clinical signs and symptoms in RA. The RESET-RA study was designed to determine the safety and efficacy of an active implantable device for treating RA. METHODS: The RESET-RA study is a randomized, double-blind, sham-controlled, multi-center, two-stage pivotal trial that enrolled patients with moderate-to-severe RA who were incomplete responders or intolerant to at least one biologic or targeted synthetic disease-modifying anti-rheumatic drug. A neuroimmune modulation device (SetPoint Medical, Valencia, CA) was implanted on the left cervical vagus nerve within the carotid sheath in all patients. Following post-surgical clearance, patients were randomly assigned (1:1) to active stimulation or non-active (control) stimulation for 1 min once per day. A predefined blinded interim analysis was performed in patients enrolled in the study's initial stage (Stage 1) that included demographics, enrollment rates, device implantation rates, and safety of the surgical procedure, device, and stimulation over 12 weeks of treatment. RESULTS: Sixty patients were implanted during Stage 1 of the study. All device implant procedures were completed without intraoperative complications, infections, or surgical revisions. No unanticipated adverse events were reported during the perioperative period and at the end of 12 weeks of follow-up. No study discontinuations were due to adverse events, and no serious adverse events were related to the device or stimulation. Two serious adverse events were related to the implantation procedure: vocal cord paresis and prolonged hoarseness. These were reported in two patients and are known complications of surgical implantation procedures with vagus nerve stimulation devices. The adverse event of vocal cord paresis resolved after vocal cord augmentation injections with filler and speech therapy. The prolonged hoarseness had improved with speech therapy, but mild hoarseness persists. CONCLUSIONS: The surgical procedures for implantation of the novel neuroimmune modulation device for the treatment of RA were safe, and the device and its use were well tolerated. TRIAL REGISTRATION: NCT04539964; August 31, 2020.

Variability in the Arterial Supply of Intracranial Meningiomas: An Anatomic Study.

BACKGROUND AND OBJECTIVES: Intracranial meningiomas are a diverse group of tumors, which vary by grade, genetic composition, location, and vasculature. Expanding the understanding of the supply of skull base (SBMs) and non-skull base meningiomas (NSBMs) will serve to further inform resection strategies. We sought to delineate the vascular supply of a series of intracranial meningiomas by tumor location. METHODS: A retrospective study of intracranial meningiomas that were studied using preoperative digital subtraction angiograms before surgical resection at a tertiary referral center was performed. Patient, tumor, radiologic, and treatment data were collected, and regression models were developed. RESULTS: One hundred sixty-five patients met inclusion criteria. The mean age was 57.1 years (SD: 12.6). The mean tumor diameter was 4.9 cm (SD: 1.5). One hundred twenty-six were World Health Organization Grade I, 37 Grade II, and 2 Grade III. Arterial feeders were tabulated by Al-Mefty's anatomic designations. SBMs were more likely to derive arterial supply from the anterior circulation, whereas NSBMs were supplied by external carotid branches. NSBMs were larger (5.61 cm vs 4.45 cm, P = <.001), were more often presented with seizure (20% vs 8%, P = .03), were higher grade ( P = <.001) had more frequent peritumoral brain edema (84.6% vs 66%, P = .04), and had more bilateral feeders (47.7% vs 28%, P = .01) compared with SBMs. More arterial feeders were significantly associated with lower tumor grade ( P = .023, OR = 0.59). Higher tumor grade (Grade II/III) was associated with fewer arterial feeders ( P = .017, RR = 0.74). CONCLUSION: Meningioma location is associated with specific vascular supply patterns, grade, and patient outcomes. This information suggests that grade I tumors, especially larger tumors, are more likely to have diverse vascular supply patterns, including internal carotid branches. This study may inform preoperative embolization and surgical considerations, particularly for large skull base tumors.

Magnetic resonance imaging-guided focused ultrasound thalamotomy for essential tremor: 5-year follow-up results.

OBJECTIVE: The objective of this study was to evaluate, at 4 and 5 years posttreatment, the long-term safety and efficacy of unilateral MRI-guided focused ultrasound (MRgFUS) thalamotomy for medication-refractory essential tremor in a cohort of patients from a prospective, controlled, multicenter clinical trial. METHODS: Outcomes per the Clinical Rating Scale for Tremor (CRST), including postural tremor scores (CRST Part A), combined hand tremor/motor scores (CRST Parts A and B), and functional disability scores (CRST Part C), were measured by a qualified neurologist. The Quality of Life in Essential Tremor Questionnaire (QUEST) was used to assess quality of life. CRST and QUEST scores at 48 and 60 months post-MRgFUS were compared to those at baseline to assess treatment efficacy and durability. All adverse events (AEs) were reported. RESULTS: Forty-five and 40 patients completed the 4- and 5-year follow-ups, respectively. CRST scores for postural tremor (Part A) for the treated hand remained significantly improved by 73.3% and 73.1% from baseline at both 48 and 60 months posttreatment, respectively (both p < 0.0001). Combined hand tremor/motor scores (Parts A and B) also improved by 49.5% and 40.4% (p < 0.0001) at each respective time point. Functional disability scores (Part C) increased slightly over time but remained significantly improved through the 5 years (p < 0.0001). Similarly, QUEST scores remained significantly improved from baseline at year 4 (p < 0.0001) and year 5 (p < 0.0003). All previously reported AEs remained mild or moderate, and no new AEs were reported. CONCLUSIONS: Unilateral MRgFUS thalamotomy demonstrates sustained and significant tremor improvement at 5 years with an overall improvement in quality-of-life measures and without any progressive or delayed complications. Clinical trial registration no.: NCT01827904 (ClinicalTrials.gov).

Effect of citicoline on functional and cognitive status among patients with traumatic brain injury: Citicoline Brain Injury Treatment Trial (COBRIT).

CONTEXT: Traumatic brain injury (TBI) is a serious public health problem in the United States, yet no treatment is currently available to improve outcome after TBI. Approved for use in TBI in 59 countries, citicoline is an endogenous substance offering potential neuroprotective properties as well as facilitated neurorepair post injury. OBJECTIVE: To determine the ability of citicoline to positively affect functional and cognitive status in persons with complicated mild, moderate, and severe TBI. DESIGN, SETTING, AND PATIENTS: The Citicoline Brain Injury Treatment Trial (COBRIT), a phase 3, double-blind randomized clinical trial conducted between July 20, 2007, and February 4, 2011, among 1213 patients at 8 US level 1 trauma centers to investigate effects of citicoline vs placebo in patients with TBI classified as complicated mild, moderate, or severe. INTERVENTION: Ninety-day regimen of daily enteral or oral citicoline (2000 mg) or placebo. MAIN OUTCOME MEASURES: Functional and cognitive status, assessed at 90 days using the TBI-Clinical Trials Network Core Battery. A global statistical test was used to analyze the 9 scales of the core battery. Secondary outcomes were functional and cognitive improvement, assessed at 30, 90, and 180 days, and examination of the long-term maintenance of treatment effects. RESULTS: Rates of favorable improvement for the Glasgow Outcome Scale-Extended were 35.4% in the citicoline group and 35.6% in the placebo group. For all other scales the rate of improvement ranged from 37.3% to 86.5% in the citicoline group and from 42.7% to 84.0% in the placebo group. The citicoline and placebo groups did not differ significantly at the 90-day evaluation (global odds ratio [OR], 0.98 [95% CI, 0.83-1.15]); in addition, there was no significant treatment effect in the 2 severity subgroups (global OR, 1.14 [95% CI, 0.88-1.49] and 0.89 [95% CI, 0.72-1.49] for moderate/severe and complicated mild TBI, respectively). At the 180-day evaluation, the citicoline and placebo groups did not differ significantly with respect to the primary outcome (global OR, 0.87 [95% CI, 0.72-1.04]). CONCLUSION: Among patients with traumatic brain injury, the use of citicoline compared with placebo for 90 days did not result in improvement in functional and cognitive status. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00545662.

Age dependency of inhibition of alpha7 nicotinic receptors and tonically active N-methyl-D-aspartate receptors by endogenously produced kynurenic acid in the brain.

In the mouse hippocampus normal levels of kynurenic acid (KYNA), a neuroactive metabolite synthesized in astrocytes primarily by kynurenine aminotransferase II (KAT II)-catalyzed transamination of L-kynurenine, maintain a degree of tonic inhibition of α7 nicotinic acetylcholine receptors (nAChRs). The present in vitro study was designed to test the hypothesis that α7 nAChR activity decreases when endogenous production of KYNA increases. Incubation (2-7 h) of rat hippocampal slices with kynurenine (200 µM) resulted in continuous de novo synthesis of KYNA. Kynurenine conversion to KYNA was significantly decreased by the KAT II inhibitor (S)-(-)-9-(4-aminopiperazine-1-yl)-8-fluoro-3-methyl-6-oxo-2,3,5,6-tetrahydro-4H-1-oxa-3a-azaphenalene-5carboxylic acid (BFF122) (100 µM) and was more effective in slices from postweaned than preweaned rats. Incubation of slices from postweaned rats with kynurenine inhibited α7 nAChRs and extrasynaptic N-methyl-D-aspartate receptors (NMDARs) on CA1 stratum radiatum interneurons. These effects were attenuated by BFF122 and mimicked by exogenously applied KYNA (200 µM). Exposure of human cerebral cortical slices to kynurenine also inhibited α7 nAChRs. The α7 nAChR sensitivity to KYNA is age-dependent, because neither endogenously produced nor exogenously applied KYNA inhibited α7 nAChRs in slices from preweaned rats. In these slices, kynurenine-derived KYNA also failed to inhibit extrasynaptic NMDARs, which could, however, be inhibited by exogenously applied KYNA. In slices from preweaned and postweaned rats, glutamatergic synaptic currents were not affected by endogenously produced KYNA, but were inhibited by exogenously applied KYNA. These results suggest that in the mature brain α7 nAChRs and extrasynaptic NMDARs are in close apposition to KYNA release sites and, thereby, readily accessible to inhibition by endogenously produced KYNA.

Technical Comparison of Treatment Efficiency of Magnetic Resonance-Guided Focused Ultrasound Thalamotomy and Pallidotomy in Skull Density Ratio-Matched Patient Cohorts.

OBJECTIVE: MR-guided focused ultrasound (MRgFUS) is increasingly being used to treat patients with essential tremor (ET) and Parkinson's disease (PD) with thalamotomy and pallidotomy, respectively. Pallidotomy is performed off-center within the cranium compared to thalamotomy and may present challenges to therapeutic lesioning due to this location. However, the impact of target location on treatment efficiency and ability to create therapeutic lesions has not been studied. This study aimed to compare the physical efficiency of MRgFUS thalamotomy and pallidotomy. METHODS: Treatment characteristics were compared between patients treated with thalamotomy (n = 20) or pallidotomy (n = 20), matched by skull density ratios (SDR). Aspects of treatment efficiency were compared between these groups. Demographic and comparative statistics were conducted to assess these differences. Acoustic field simulations were performed to compare and validate the simulated temperature profile for VIM and GPi ablation. RESULTS: Lower SDR values were associated with greater energy requirement for thalamotomy (R2 = 0.197, p = 0.049) and pallidotomy (R2 = 0.342, p = 0.007). The impact of low SDR on efficiency reduction was greater for pallidotomy, approaching significance (p = 0.061). A nearly two-fold increase in energy was needed to reach 50°C in pallidotomy (10.9kJ) than in thalamotomy (5.7kJ), (p = 0.002). Despite lower energy requirement, the maximum average temperature reached was higher in thalamotomy (56.7°C) than in pallidotomy (55.0°C), (p = 0.017). Mean incident angle of acoustic beams was lesser in thalamotomy (12.7°) than in pallidotomy (18.6°), (p < 0.001). For all patients, a lesser mean incident angle correlated with a higher maximum average temperature reached (R2 = 0.124, p = 0.026), and less energy needed to reach 50°C (R2=0.134, p = 0.020). Greater skull thickness was associated with a higher maximum energy for a single sonication for thalamotomy (R2 = 0.206, p = 0.045) and pallidotomy (R2 = 0.403, p = 0.003). An acoustic and temperature field simulation validated similar findings for thalamotomy and pallidotomy in a single patient. CONCLUSION: The centrally located VIM offers a more efficient location for therapeutic lesioning compared to GPi pallidotomy in SDR matched cohort of patients. The impact on therapeutic lesioning with lower SDR may be greater for pallidotomy patients. As newer off-center targets are investigated, these findings can inform patient selection and treatment requirements for lesion production.

MR-guided focused ultrasound pallidotomy for Parkinson's disease: safety and feasibility.

OBJECTIVE: Stereotactic radiofrequency pallidotomy has demonstrated improvement in motor fluctuations in patients with Parkinson's disease (PD), particularly levodopa (L-dopa)-induced dyskinesias. The authors aimed to determine whether or not unilateral pallidotomy with MR-guided focused ultrasound (MRgFUS) could safely improve Unified Dyskinesia Rating Scale (UDysRS; the primary outcome measure) scores over baseline scores in patients with PD. METHODS: Twenty patients with PD and L-dopa responsiveness, asymmetrical motor signs, and motor fluctuations, including dyskinesias, participated in a 1-year multicenter open-label trial of unilateral MRgFUS ablation of the globus pallidus internus. RESULTS: The sonication procedure was successfully completed in all 20 enrolled patients. MRgFUS-related adverse neurological events were generally mild and transient, including visual field deficit (n = 1), dysarthria (n = 4, 2 mild and 2 moderate), cognitive disturbance (n = 1), fine motor deficit (n = 2), and facial weakness (n = 1). Although 3 adverse events (AEs) were rated as severe (transient sonication-related pain in 2, nausea/vomiting in 1), no AE fulfilled US FDA criteria for a Serious Adverse Effect. Total UDysRS, the primary outcome measure, improved 59% after treatment (baseline mean score 36.1, 95% CI 4.88; at 3 months 14.2, 95% CI 5.72, p < 0.0001), which was sustained throughout the study (at 12 months 20.5, 95% CI 7.39, 43% improvement, p < 0.0001). The severity of motor signs on the treated side (Movement Disorder Society version of the United Parkinson's Disease Rating Scale [MDS-UPDRS] part III) in the "off" medication state also significantly improved (baseline mean score 20.0, 95% CI 2.4; at 3 months 10.6, 95% CI 1.86, 44.5% improvement, p < 0.0001; at 12 months 10.4, 95% CI 2.11, 45.2% improvement, p > 0.0001). The vast majority of patients showed a clinically meaningful level of improvement on the impairment component of the UDysRS or the motor component of the UPDRS, while 1 patient showed clinically meaningful worsening on the UPDRS at month 3. CONCLUSIONS: This study supports the feasibility and preliminary efficacy of MRgFUS pallidotomy in the treatment of patients with PD and motor fluctuations, including dyskinesias. These preliminary data support continued investigation, and a placebo-controlled, blinded trial is in progress. Clinical trial registration no.: NCT02263885 (clinicaltrials.gov).

Predicting final lesion characteristics during MR-guided focused ultrasound pallidotomy for treatment of Parkinson's disease.

OBJECTIVE: Magnetic resonance-guided focused ultrasound (MRgFUS) ablation of the globus pallidus interna (GPi) is being investigated for the treatment of advanced Parkinson's disease symptoms. However, GPi lesioning presents unique challenges due to the off-midline location of the target. Furthermore, it remains uncertain whether intraprocedural MR thermometry data can predict final lesion characteristics. METHODS: The authors first performed temperature simulations of GPi pallidotomy and compared the results with those of actual cases and the results of ventral intermediate nucleus (VIM) thalamotomy performed for essential tremor treatment. Next, thermometry data from 13 MRgFUS pallidotomy procedures performed at their institution were analyzed using 46°C, 48°C, 50°C, and 52°C temperature thresholds. The resulting thermal models were compared with resulting GPi lesions noted on postprocedure days 1 and 30. Finally, the treatment efficiency (energy per temperature rise) of pallidotomy was evaluated. RESULTS: The authors' modeled acoustic intensity maps correctly demonstrate the elongated, ellipsoid lesions noted during GPi pallidotomy. In treated patients, the 48°C temperature threshold maps most accurately predicted postprocedure day 1 lesion size, while no correlation was found for day 30 lesions. The average energy/temperature rise of pallidotomy was higher (612 J/°C) than what had been noted for VIM thalamotomy and varied with the patients' skull density ratios (SDRs). CONCLUSIONS: The authors' acoustic simulations accurately depicted the characteristics of thermal lesions encountered following MRgFUS pallidotomy. MR thermometry data can predict postprocedure day 1 GPi lesion characteristics using a 48°C threshold model. Finally, the lower treatment efficiency of pallidotomy may make GPi lesioning challenging in patients with a low SDR.

Magnetic Resonance Imaging Pilot Study of Intravenous Glyburide in Traumatic Brain Injury.

Pre-clinical studies of traumatic brain injury (TBI) show that glyburide reduces edema and hemorrhagic progression of contusions. We conducted a small Phase II, three-institution, randomized placebo-controlled trial of subjects with TBI to assess the safety and efficacy of intravenous (IV) glyburide. Twenty-eight subjects were randomized and underwent a 72-h infusion of IV glyburide or placebo, beginning within 10 h of trauma. Of the 28 subjects, 25 had Glasgow Coma Scale (GCS) scores of 6-10, and 14 had contusions. There were no differences in adverse events (AEs) or severe adverse events (ASEs) between groups. The magnetic resonance imaging (MRI) percent change at 72-168 h from screening/baseline was compared between the glyburide and placebo groups. Analysis of contusions (7 per group) showed that lesion volumes (hemorrhage plus edema) increased 1036% with placebo versus 136% with glyburide (p = 0.15), and that hemorrhage volumes increased 11.6% with placebo but decreased 29.6% with glyburide (p = 0.62). Three diffusion MRI measures of edema were quantified: mean diffusivity (MD), free water (FW), and tissue MD (MDt), corresponding to overall, extracellular, and intracellular water, respectively. The percent change with time for each measure was compared in lesions (n = 14) versus uninjured white matter (n = 24) in subjects receiving placebo (n = 20) or glyburide (n = 18). For placebo, the percent change in lesions for all three measures was significantly different compared with uninjured white matter (analysis of variance [ANOVA], p < 0.02), consistent with worsening of edema in untreated contusions. In contrast, for glyburide, the percent change in lesions for all three measures was not significantly different compared with uninjured white matter. Further study of IV glyburide in contusion TBI is warranted.

Predictors of Outcomes After Focused Ultrasound Thalamotomy.

BACKGROUND: Magnetic resonance-guided focused ultrasound thalamotomy (FUS-T) is an emerging treatment for essential tremor (ET). OBJECTIVE: To determine the predictors of outcomes after FUS-T. METHODS: Two treatment groups were analyzed: 75 ET patients enrolled in the pivotal trial, between 2013 and 2015; and 114 patients enrolled in the postpivotal trials, between 2015 and 2016. All patients had medication-refractory, disabling ET, and underwent unilateral FUS-T. The primary outcome (hand tremor score, 32-point scale with higher scores indicating worse tremor) and the secondary outcome variables (Clinical Rating Scale for Tremor Part C score: 32-point scale with higher scores indicating more disability) were assessed at baseline and 1, 3, 6, and 12 mo. The operative outcome variables (ie, peak temperature, number of sonications) were analyzed. The results between the 2 treatment groups, pivotal and postpivotal, were compared with repeated measures analysis of variance and adjusted for confounding variables. RESULTS: A total of 179 patients completed the 12-mo evaluation. The significant predictors of tremor outcomes were patient age, disease duration, peak temperature, and number of sonications. A greater improvement in hand tremor scores was observed in the postpivotal group at all time points, including 12 mo (61.9% ± 24.9% vs 52.1% ± 24.9%, P = .009). In the postpivotal group, higher energy was used, resulting in higher peak temperatures (56.7 ± 2.5 vs 55.6 ± 2.8°C, P = .004). After adjusting for age, years of disease, number of sonications, and maximum temperature, the treatment group was a significant predictor of outcomes (F = 7.9 [1,165], P = .005). CONCLUSION: We observed an improvement in outcomes in the postpivotal group compared to the pivotal group potentially reflecting a learning curve with FUS-T. The other associations of tremor outcomes included patient age, disease duration, peak temperature, and number of sonications.