Tremor Relief and Structural Integrity after MRI-guided Focused US Thalamotomy in Tremor Disorders.

Background MRI-guided focused US thalamotomy of ventral intermediate nucleus of the thalamus is a treatment for tremor disorders. Purpose To evaluate white matter integrity before and after thalamotomy and its correlation with clinical outcome. Materials and Methods Participants with essential tremor (ET) or Parkinson disease (PD) undergoing thalamotomy were prospectively recruited between March 2016 and October 2018. Tremor and quality of life were assessed before, 1 month after, and 6 months after thalamotomy. Participants underwent T1-weighted, T2-weighted fluid-attenuated image recovery, and diffusion-tensor MRI before and 1 day, 7-10 days, 1-3 months, and 6 months or longer after treatment. Diffusivity and fiber tractography measures were calculated. Repeated measures analysis of variance with post hoc paired t test and Skillings-Mack test with post hoc Wilcoxon signed-rank test were used for normally and nonnormally distributed data, respectively, and Bonferroni method corrected for multiple comparisons. Results Twenty-two study participants with ET (mean age, 72 years ± 6 [standard deviation]; 14 men), 17 participants with PD (mean age, 65 years ± 8; 13 men), and a replication set of 17 participants with ET (mean age, 73 years ± 6; 10 men) were evaluated. Long-term damage was found in the ablated core (mean fractional anisotropy [FA] at baseline, 0.41 ± 0.10, and at ≥6 months, 0.23 ± 0.09; P < .001) and thalamus to red nucleus tract (mean number of tracts at baseline, 1663, and at ≥6 months, 1070; P = .003). Negative correlation was observed between motor thalamus FA 1 day after ablation and tremor improvement (ET: R = -0.52 [P = .03]; PD: R = -0.61 [P = .003]). Better tremor relief in ET was associated with lower fractional anisotropy before treatment (R = -0.5; P = .02). Conclusion MRI-guided focused US thalamotomy resulted in short- and long-term white-matter changes. Diffusion-tensor imaging provided evidence for long-term damage in the ablation core and in the thalamus and red nucleus tract, and a correlation between preablation fractional anisotropy in the motor thalamus and clinical outcome. © RSNA, 2020 Online supplemental material is available for this article.

[EFFECT OF GENDER ON OUTCOME OF TREATMENT FOR TREMOR WITH MRI GUIDED FOCUSED ULTRASOUND].

INTRODUCTION: Thalamotomy is an effective treatment for medication-resistant tremor. MRI-guided focused ultrasound (MRgFUS) has been shown to be an effective and safe treatment for alleviating tremor. OBJECTIVES: We examined whether there is a gender difference in the efficacy and safety of thalamotomy using MRgFUS. METHODS: Seventy patients with moderate to severe medication-resistant tremor were treated with MRgFUS at Rambam Medical Center. Thermal ablation with ultrasound waves was carried out in the MRI suite while real-time monitoring of treatment efficacy and adverse events were recorded. A comparison was made between outcomes in men and women. RESULTS: Seventy patients, 47 men and 23 women with essential tremor, Parkinson's disease, paraneoplastic syndrome, and multiple system atrophy were treated. Both men and women reported the disappearance of tremor after MRgFUS with the exception of one patient with a paraneoplastic syndrome. In all patients, there was a significant decrease in the tremor scores (p <0.001), with no gender difference, and all patients reported a significant improvement in quality of life (p<0.001) regardless of gender. In ten patients, 8 men and 2 women, the tremor returned, but was bothersome in only 4, all men. This gender difference was not statistically significant. Transient adverse events were observed in the same frequency in men and women. The most common adverse event was transient gait instability and ataxia. CONCLUSIONS: In this series of patients, MRgFUS was an effective and safe treatment for both sexes with no significant difference in efficacy or adverse events.

Optimization of Endotracheal Tube Cuff Pressure by Monitoring CO2 Levels in the Subglottic Space in Mechanically Ventilated Patients: A Randomized Controlled Trial.

BACKGROUND: Many of the complications of mechanical ventilation are related to inappropriate endotracheal tube (ETT) cuff pressure. The aim of the current study was to evaluate the effectiveness of automatic cuff pressure closed-loop control in patients under prolonged intubation, where presence of carbon dioxide (CO2) in the subglottic space is used as an indicator for leaks. The primary outcome of the study is leakage around the cuff quantified using the area under the curve (AUC) of CO2 leakage over time. METHODS: This was a multicenter, prospective, randomized controlled, noninferiority trial including intensive care unit patients. All patients were intubated with the AnapnoGuard ETT, which has an extra lumen used to monitor CO2 levels in the subglottic space.The study group was connected to the AnapnoGuard system operating with cuff control adjusted automatically based on subglottic CO2 (automatic group). The control group was connected to the AnapnoGuard system, while cuff pressure was managed manually using a manometer 3 times/d (manual group). The system recorded around cuff CO2 leakage in both groups. RESULTS: Seventy-two patients were recruited and 64 included in the final analysis. The mean hourly around cuff CO2 leak (mm Hg AUC/h) was 0.22 ± 0.32 in the manual group and 0.09 ± 0.04 in the automatic group (P = .01) where the lower bound of the 1-sided 95% confidence interval was 0.05, demonstrating noninferiority (>-0.033). Additionally, the 2-sided 95% confidence interval was 0.010 to 0.196, showing superiority (>0.0) as well. Significant CO2 leakage (CO2 >2 mm Hg) was 0.027 ± 0.057 (mm Hg AUC/h) in the automatic group versus 0.296 ± 0.784 (mm Hg AUC/h) in the manual group (P = .025). In addition, cuff pressures were in the predefined safety range 97.6% of the time in the automatic group compared to 48.2% in the automatic group (P < .001). CONCLUSIONS: This study shows that the automatic cuff pressure group is not only noninferior but also superior compared to the manual cuff pressure group. Thus, the use of automatic cuff pressure control based on subglottic measurements of CO2 levels is an effective method for ETT cuff pressure optimization. The method is safe and can be easily utilized with any intubated patient.

Immunological Aspects of Malignant Gliomas.

Glioblastoma Multiforme (GBM) is the most common malignant primary brain neoplasm having a mean survival time of <24 months. This figure remains constant, despite significant progress in medical research and treatment. The lack of an efficient anti-tumor immune response and the micro-invasive nature of the glioma malignant cells have been explained by a multitude of immune-suppressive mechanisms, proven in different models. These immune-resistant capabilities of the tumor result in a complex interplay this tumor shares with the immune system. We present a short review on the immunology of GBM, discussing the different unique pathological and molecular features of GBM, current treatment modalities, the principles of cancer immunotherapy and the link between GBM and melanoma. Current knowledge on immunological features of GBM, as well as immunotherapy past and current clinical trials, is discussed in an attempt to broadly present the complex and formidable challenges posed by GBM.

Uncal herniation in a fully conscious patient-The sliding uncus syndrome.

Uncal herniation is accompanied by a decreased level of consciousness. We describe a patient who remained fully alert despite the uncal herniation. The computed tomography (CT) scans allowed us to visualize the uncus and its spatial relation to the cerebral peduncle. We describe the sliding uncus syndrome.

Focused Ultrasound Thalamotomy for Tremor Relief in Atypical Parkisnsonism.

Background: Magnetic resonance imaging (MRI)-guided focused ultrasound (FUS) VIM-thalamotomy has established efficacy and safety in tremor relief in patients with essential tremor and Parkinson's disease. The efficacy and safety in patients with atypical parkinsonism have not been reported. Objective: To report on the efficacy and safety of FUS VIM-thalamotomy in 8 patients with parkinsonism, multiple system atrophy-Parkinsonian type (MSA-P) (n = 5), and dementia with Lewy bodies (DLB) (n = 3). Methods: Tremor was assessed in the treated hemibody using the Clinical Rating Scale for Tremor (CRST). The motor Unified MSA Rating Scale (UMSAR) was used in the MSA-P and motor sections of the Unified Parkinson's Disease Rating Scale (UPDRS-III) in DLB patients. Cognition was measured using the Montreal Cognitive Assessment (MoCA). Results: In MSA-P and DLB patients, there was immediate tremor relief. CRST scores measured on the treated side improved compared to baseline. During the follow-up of up to 1 year tremor reduction persisted. The change in CRST scores at different time points did not reach statistical significance, probably due to the small sample size. Adverse events were transient and resolved within a year. Conclusions: In our experience, FUS VIM-thalamotomy was effective in patients with MSA-P and DLB. Larger, controlled studies are needed to verify our preliminary observations.

Real-time change detection of steady-state evoked potentials.

Steady-state evoked potentials (SSEP) are the electrical activity recorded from the scalp in response to high-rate sensory stimulation. SSEP consist of a constituent frequency component matching the stimulation rate, whose amplitude and phase remain constant with time and are sensitive to functional changes in the stimulated sensory system. Monitoring SSEP during neurosurgical procedures allows identification of an emerging impairment early enough before the damage becomes permanent. In routine practice, SSEP are extracted by averaging of the EEG recordings, allowing detection of neurological changes within approximately a minute. As an alternative to the relatively slow-responding empirical averaging, we present an algorithm that detects changes in the SSEP within seconds. Our system alerts when changes in the SSEP are detected by applying a two-step Generalized Likelihood Ratio Test (GLRT) on the unaveraged EEG recordings. This approach outperforms conventional detection and provides the monitor with a statistical measure of the likelihood that a change occurred, thus enhancing its sensitivity and reliability. The system's performance is analyzed using Monte Carlo simulations and tested on real EEG data recorded under coma.

Why mortality is still high with modern care of 613 evacuated mass lesions presented as severe head injuries 1999-2009.

Of 1,949 successive acute severe head injuries (SHI) over a period of 11 years 1999-2009, 613 (31.5%) underwent evacuation of mass lesions. Mortality at 3 months of evacuated mass (EM) lesions was higher over 10 years compared with that of non-EM lesions (it was overall 22%). The reduction of mortality was significantly less in EM compared with that for non-surgical cases (14.4-9.4% recently) and for the cases that were operated but not for mass evacuation (18.1-12.1%). A few explanations are: first, more SDH (60.5% of the EM recently compared with 45.9% in the first few years); second, more severe cases and older patients with co-morbidities were treated surgically; third, advances in prehospital care brought more severe patients to operative care - the rate of referrals decreased from 61.5% to 52.8% recently; fourth, part of the significant shortening of the injury to NT admission time (163-141 min) vanished owing to the parallel elongation of admission to operation time (95-100 min), thus, the threshold recommendation of 4 h to mass evacuation was achieved in only 52%; fifth, introducing decompressive craniectomy was not associated with outcome improvement.

Focused Ultrasound Thalamotomy in Tremor Dominant Parkinson's Disease: Long-Term Results.

BACKGROUND: MRI-guided focused ultrasound (FUS) has established short-term efficacy in tremor relief. OBJECTIVE: We report our long-term experience of treating tremor with unilateral FUS unilateral VIM-thalamotomy in tremor dominant Parkinson's disease (TDPD) patients. METHODS: We report outcome of FUS thalamotomy in TDPD patients with 1-5 years of follow-up. OUTCOMES: tremor reduction assessed with Clinical Rating Scale for Tremor (CRST) and Unified Parkinson's Disease Rating Scale (UPDRS part III) overall and in the treated hemibody and safety. RESULTS: Twenty-six TDPD patients completed 1-5 years of follow-up (median follow-up 36 months, range 12-60 months). Median age was 60 years (range 46-79), with median disease duration of 6 years (range 2-16). Immediately, treatment resulted in 100%improvement in tremor in the treated arm in 23 patients and 90%improvement in 3 patients. In 15 patients with leg tremor, 2 patients with chin tremor and 1 patient with head tremor, tremor was significantly improved. Up to 5 years, median CRST score, median UPDRS score, overall and in treated hemibody, decreased significantly as compared with baseline (p < 0.0001). In 2 patients tremor returned completely and in 8 patients there was partial return of tremor. Adverse events were mild and resolved within 3 months. At baseline 4 patients were not receiving any medication vs. 3 at last follow-up and 15 were not taking levodopa vs.9 at last follow-up. CONCLUSION: Unilateral FUS VIM-thalamotomy in TDPD patients was effective and safe and provided long-term tremor relief in most patients. FUS thalamotomy for tremor may delay initiation of levodopa treatment.

Improvement of cerebral metabolism mediated by Ro5-4864 is associated with relief of intracranial pressure and mitochondrial protective effect in experimental brain injury.

PURPOSE: To investigate the possible impact of reduction of mitochondrial membrane permeabilization by modulation of the 18 kDa translocator protein mediated by Ro5-4864 over post-traumatic cerebral edema and metabolic crisis. METHODS: Cerebral microdialysis and intracranial pressure (ICP) monitoring were performed in Sprague-Dawley rats treated by intraperitoneal injection of either dimethylsulfoxide (vehicle) or Ro5-4864 following cortical contusion and further correlated with quantitative assessment of mitochondrial damage, water content in the injured tissue, modified neurological severity score, and lesion size. RESULTS: Ro5-4864 resulted in a profound decrease in ICP that correlated with improved cerebral metabolism characterized by significantly higher glucose and pyruvate and lower lactate concentrations in the pericontusional area in comparison with vehicle-treated animals. Reduced ICP correlated with reduced water content in the injured tissue; improved metabolism was associated with reduced mitochondrial damage evidenced by electron microscopy. Both effects were associated with a profound and significant reduction in glycerol release and lesion size, and correlated with improved neurological recovery. CONCLUSIONS: The present study shows that Ro5-4864 has a favorable effect on the fate of injured brain, presumably mediated by improvement of metabolism. It further suggests that improvement of metabolism may contribute to ICP relief.

The Geriatric Scoring System (GSS) in meningioma patients--validation.

BACKGROUND: Meningiomas are the most common primary brain tumor, the incidence of which rises with age. The Geriatric Scoring System (GSS) was constructed in an attempt to answer which elderly subpopulation will benefit from a surgical intervention in terms of their overall physical and functional state of health. The GSS incorporates different prognostic indicators, both clinical and radiological, for risk stratification. OBJECTIVE: The purpose of the study was to validate the previously defined GSS for the evaluation and risk stratification of elderly patients suffering from intracranial meningioma. METHODS: One hundred and twenty patients aged over 65 years admitted to the RAMBAM Medical Center with meningiomas during the years 2005-2010 were characterized, forming an independent cohort. We report the presenting symptoms, chronic illness and radiological features, as well as perioperative and long-term follow-up results up to 5 years after the surgery. RESULTS: Nine outcome parameters were tested against the GSS score on admission. Survival, Barthel Index, Karnofsky Performance Scale (KPS), consciousness expressed by the Glasgow Coma Scale (GCS) [14] score 5 years after surgery, recurrence within and beyond 12 months of surgery, the length of hospitalization both overall and in a neurosurgical intensive care unit. A GSS score higher than 16 was associated with a significantly more favorable outcome. CONCLUSION: The present results suggest that common experience-based considerations may be optimized and implemented into a simple scoring system that in turn may allow for outcome prediction and evidence-based decision making.

Safety, tolerability and preliminary evidence for antidepressant efficacy of theta-burst transcranial magnetic stimulation in patients with major depression.

The aim of this open study was to evaluate the safety and tolerability of theta-burst transcranial magnetic stimulation (TBS) and to assess preliminarily its therapeutic efficacy in patients with major depression. A total of 33 patients were assigned to receive one of four TBS protocols for 10 consecutive work days. TBS consisted of triple-pulse 50-Hz bursts given at a rate of 5 Hz to the left or right dorsolateral prefrontal cortex at different stimulation parameters. Severity of depression was assessed by the Hamilton Depression Rating Scale. Our results indicate that TBS as applied in this study is safe and well tolerated in depressed patients and seems to have antidepressant properties. Increase of stimulation parameters is not associated with more side-effects and adds to its therapeutic effect.

Ethnic disparities in first primary intracerebral hemorrhage in northern Israel.

BACKGROUND: Ethnic differences among first primary intracerebral hemorrhage (PICH) patients in an Israeli biethnic population have not yet been studied. PATIENTS AND METHODS: We included in the study 546 patients (counting warfarin-related hemorrhages) hospitalized during the period from December 1999 through June 2008. RESULTS: The mean age was 71.1 +/- 14 years for the Jewish patients and 63.3 +/- 13.9 years for the Arab patients (p < 0.0001). Diabetes and smoking were significantly more frequent among the Arab patients. No difference was found between groups by location, extent, or ventricular involvement of PICH. Although the in-hospital mortality rate was significantly higher among the Jewish patients, adjustment of the model combining multiple risk factors for PICH eliminated this difference. CONCLUSIONS: There are differences in the demographic and vascular risk factor profiles between Arab and Jewish PICH patients, with the Arabs found to be younger and to suffer more from diabetes. The location and extent of intracerebral hemorrhage as well as functional outcome were similar between the two groups. The apparent higher in-hospital mortality in the group of Jewish patients was eliminated when the influence of multiple covariates other than ethnicity, main vascular risk factors and international normalized ratio level were taken into consideration.

Meningiomas in the elderly, the surgical benefit and a new scoring system.

OBJECTIVE: The purpose of the study was to define and identify prognostic indicators within an elderly population of patients suffering from intracranial meningiomas. The clinical presentation of the patient with meningioma is diverse, manifesting as a different clinical entity in the elderly patient compared to a similar type of tumor in a young patient. METHODS: Two hundred fifty patients aged over 65 years admitted to RAMBAM Medical Center with meningiomas from 1995-2005 were characterized. We report the presenting symptoms, chronic illnesses, perioperative and longterm follow-up results for a 5-year period. RESULTS: Based on univariate and multivariate analysis,significant prognostic indicators were identified and were implemented into a new geriatric scoring system (GSS)including tumor size and location, peritumoral edema,neurological deficits, Karnofsky score (Clancey J Neurosci Nurs 27:220, 1995; Crooks et al. J Gerontol 46:M139-M144, 1991), and associated diabetes, hypertension or lung disease. Seven outcome parameters were retrospectively tested using the scoring system, namely mortality,Barthel Index score (Mahoney and Barthel Md State Med J 14:61-65, 1965), Karnofsky score and consciousness expressed by the Glasgow Coma Scale score (Jennett and Bond Lancet 1:480-484, 1975) 5 years after surgery, as well as recurrence within and beyond 12 months. Age proved to inversely correlate with outcome. Morbidity and mortality were significantly lower in women. The extent of surgical resection (Simpson J Neurol Neurosurg Psychiatry 20:22-39, 1957) had no influence on functional outcome, although radical resection was associated with significantly lower mortality. Generally, a GSS score higher than 14 was associated with a significantly more favorable outcome. CONCLUSION: The present results suggest that common experience-based considerations may be optimized and implemented into a simple scoring system that in turn may allow for outcome prediction and evidence-based decision making

New US device versus imaging US to assess tumor-in-brain.

BACKGROUND: Applying ultrasonic imaging system during surgery requires the poring of saline, performing the measurement, and acquiring data from its display-which requires time and is highly "performer dependent," i.e., the measure is of a subjective nature. A new ultrasonic device was recently developed that overcomes most of these drawbacks and was successfully applied during tumor-in-brain neurosurgeries. The purpose of this study was to compare the two types of US devices and demonstrate their properties. METHODS: The study was performed in the following stages: (i) an ex vivo experiment, where slices of the muscle and brain of a young porcine were laid one on top the other. Thicknesses and border depths were measured and compared, using the two types of US instruments. (ii) During human clinical neurosurgeries, tumor depth was compared by measuring it with both devices. (iii) Following the success of stages (i) and (ii), using solely the new US device, the tumor thickness was monitored while its resection.Correlation, Pearson's coefficient, average, mean, and standard deviation were applied for statistical tests. RESULTS: A high correlation was obtained for the distances of tissue borders and for their respective thicknesses. Applying these ultrasonic devices during neurosurgeries, tumor depths were monitored with high similarity (87%), which was also obtained by Pearson's correlation coefficient (0.44). The new US device, thanks to its small footprint, its remote measurement, and the capability of monitoring intraoperatively and in real-time, provides the approach to tumor's border before its complete resection. CONCLUSIONS: The new US device provides better accuracy than an ultrasonic imaging system; its data is objective; it enables to control the residual tumor thickness during its resection, and it is especially useful in restricted areas. These features were found of great help during a tumor-in-brain surgery and especially in the final stages of tumor's resection.

CoCl(2) induces apoptosis via the 18 kDa translocator protein in U118MG human glioblastoma cells.

The 18 kDa translocator protein (TSPO), formerly known as the peripheral-type benzodiazepine receptor, has been reported to be closely associated with the mitochondrial permeability transition pore (MPTP). TSPO is believed to exert pro-apoptotic functions via modulation of MPTP opening. Cobalt chloride (CoCl(2)), which is sometimes used as a hypoxia mimicking agent, is also known to be able to induce apoptosis. One of our questions was whether CoCl(2) may induce apoptosis via the TSPO. To address this question, we used the U118MG human glioblastoma cell line. We applied the specific TSPO ligand, PK 11195, as well as TSPO knockdown with siRNA and studied their influence on the effects of CoCl(2) on cell death, including activation of the mitochondrial apoptosis pathway. To assay TSPO expression, we applied binding assays and Western blotting to whole cell homogenates and mitochondrial fractions. To assay activation of the mitochondrial apoptosis pathway, including some of the cellular mechanisms involved, we determined the incidence of collapse of the mitochondrial membrane potential (Deltapsi(m)) and cardiolipin oxidation and measured the level of DNA fragmentation to assay apoptotic rates. We found that the TSPO ligand, PK 11195, significantly counteracted induction of cell death by 0.4 mM CoCl(2), including apoptosis, collapse of the Deltapsi(m), and cardiolipin oxidation. Moreover, we found that TSPO knockdown with siRNA fully protected against mentioned cell death mechanisms. Thus, we found that the TSPO is required for cell death induction by CoCl(2), including apoptosis. In conclusion, our studies show that activation of TSPO by CoCl(2) application is required for ROS generation, leading to cardiolipin oxidation, and collapse of the Deltapsi(m), as induced by CoCl(2).

Magnetic resonance-guided focused ultrasound thalamotomy for essential tremor: a 5-year single-center experience.

OBJECTIVE: The authors report their experience in treating patients suffering from medication-resistant essential tremor (ET) with MR-guided focused ultrasound (MRgFUS) thalamotomy over a 5-year period. METHODS: Forty-four ET patients treated with unilateral MRgFUS ventral intermediate nucleus (VIM) thalamotomy were assessed using the Clinical Rating Scale for Tremor (CRST) score and the Quality of Life in Essential Tremor Questionnaire (QUEST) over a 5-year span. RESULTS: Tremor was significantly improved immediately following MRgFUS in all patients and ceased completely in 24 patients. CRST scores in the treated hand at baseline (median 19; range 7-32, 44 patients) improved by a median of 16 at 1 month (44 patients; p < 0.0001), 17 at 6 months (31 patients; p < 0.0001), 15 at 1 year (24 patients; p < 0.0001), 18 at 2 years (15 patients; p < 0.0001), 19 at 3 years, (10 patients; p < 0.0001), 21 at 4 years (6 patients; p < 0.01), and 23 at 5 years (2 patients, significance not tested). Return of tremor that impacted activities of daily living was reported in 5 patients (11%). QUEST scores showed significant improvement, with median change of 35 points (p < 0.0001; 44 patients) at 1 month, 33 (p < 0.0001; 31 patients) at 6 months, 27 (p < 0.0001; 24 patients) at 1 year, 26 (p < 0.001; 15 patients) at 2 years, 25 (p < 0.001; 10 patients) at 3 years, 33 (p < 0.001; 6 patients) at 4 years, and 28 (significance not tested, 2 patients) at 5 years. Adverse events after the procedure were reversible in all but 5 patients (11%). CONCLUSIONS: MRgFUS thalamotomy for ET is an effective and safe procedure that provides long-term tremor relief and improvement in quality of life even in patients with medication-resistant disabling tremor. Additional studies with a larger group of patients is needed to substantiate these favorable results.