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.

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.

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.

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.

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.

[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.

The Role of the Anesthesiologist during Magnetic Resonance-Guided Focused Ultrasound Thalamotomy for Tremor: A Single-Center Experience.

Ablative incisionless neurosurgery has become possible through advances in focused ultrasound and magnetic resonance imaging (MRI). The great advantage of MRI-guided focused ultrasound (MRgFUS) is that the ablation is performed through an intact skull without surgery. Here, we review the new modality of MRgFUS for treating tremor and enlighten the role of the anesthesiologist in the unique procedural setting of the MRI suite. During the MRgFUS process, the patients should be awake and are required to cooperate with the medical staff to allow assessment of tremor reduction and potential occurrence of adverse effects. In addition, the patient's head is immobilized inside the MRI tunnel for hours. This combination presents major challenges for the attending anesthesiologist, who is required to try to prevent pain and nausea and when present, to treat these symptoms. Anxiety, vertigo, and vomiting may occur during treatment and require urgent treatment. Here, we review the literature available on anesthetic management during the procedure and our own experience and provide recommendations based on our collected knowledge.

Magnetic resonance-guided focused ultrasound thalamotomy for tremor: a report of 30 Parkinson's disease and essential tremor cases.

OBJECTIVE Thalamotomy of the ventral intermediate nucleus (VIM) is effective in alleviating medication-resistant tremor in patients with essential tremor (ET) and Parkinson's disease (PD). MR-guided focused ultrasound (MRgFUS) is an innovative technology that enables noninvasive thalamotomy via thermal ablation. METHODS Patients with severe medication-resistant tremor underwent unilateral VIM thalamotomy using MRgFUS. Effects on tremor were evaluated using the Clinical Rating Scale for Tremor (CRST) in patients with ET and by the motor part of the Unified Parkinson's Disease Rating Scale (UPDRS) in patients with PD and ET-PD (defined as patients with ET who developed PD many years later). Quality of life in ET was measured by the Quality of Life in Essential Tremor (QUEST) questionnaire and in PD by the PD Questionnaire (PDQ-39). RESULTS Thirty patients underwent MRgFUS, including 18 with ET, 9 with PD, and 3 with ET-PD. The mean age of the study population was 68.9 ± 8.3 years (range 46-87 years) with a mean disease duration of 12.1 ± 8.9 years (range 2-30 years). MRgFUS created a lesion at the planned target in all patients, resulting in cessation of tremor in the treated hand immediately following treatment. At 1 month posttreatment, the mean CRST score of the patients with ET decreased from 40.7 ± 11.6 to 9.3 ± 7.1 (p < 0.001) and was 8.2 ± 5.0 six months after treatment (p < 0.001, compared with baseline). Average QUEST scores decreased from 44.8 ± 12.9 to 13.1 ± 13.2 (p < 0.001) and was 12.3 ± 7.2 six months after treatment (p < 0.001). In patients with PD, the mean score of the motor part of the UPDRS decreased from 24.9 ± 8.0 to 16.4 ± 11.1 (p = 0.042) at 1 month and was 13.4 ± 9.2 six months after treatment (p = 0.009, compared with baseline). The mean PDQ-39 score decreased from 38.6 ± 16.8 to 26.1 ± 7.2 (p = 0.036) and was 20.6 ± 8.8 six months after treatment (p = 0.008). During follow-up of 6-24 months (mean 11.5 ± 7.2 months, median 12.0 months), tremor reappeared in 6 of the patients (2 with ET, 2 with PD, and 2 with ET-PD), to a lesser degree than before the procedure in 5. Adverse events that transiently occurred during sonication included headache (n = 11), short-lasting vertigo (n = 14) and dizziness (n = 4), nausea (n = 3), burning scalp sensation (n = 3), vomiting (n = 2) and lip paresthesia (n = 2). Adverse events that lasted after the procedure included gait ataxia (n = 5), unsteady feeling (n = 4), taste disturbances (n = 4), asthenia (n = 4), and hand ataxia (n = 3). No adverse event lasted beyond 3 months. Patients underwent on average 21.0 ± 6.9 sonications (range 14-45 sonications) with an average maximal sonication time of 16.0 ± 3.0 seconds (range 13-24 seconds). The mean maximal energy reached was 12,500 ± 4274 J (range 5850-23,040 J) with a mean maximal temperature of 56.5° ± 2.2°C (range 55°-60°C). CONCLUSIONS MRgFUS VIM thalamotomy to relieve medication-resistant tremor was safe and effective in patients with ET, PD, and ET-PD. Current results emphasize the superior adverse events profile of MRgFUS over other surgical approaches for treating tremor with similar efficacy. Large randomized studies are needed to assess prolonged efficacy and safety.

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.

MRI-Guided Focused Ultrasound in Parkinson's Disease: A Review.

MRI-guided focused ultrasound is a new technology that enables intracranial ablation. Since lesioning ameliorates some of the symptoms of PD, this technology is being explored as a possible treatment for medication resistant symptoms in PD patients. The purpose of this paper is to review the clinical use and treatment outcomes of PD patients treated to date with this technology.

Vaccination as primary prevention? The effect of anti-pneumococcal vaccination on the outcome of patients suffering traumatic skull base fractures.

BACKGROUND: As many as 360,000 people suffer yearly from skull base fractures (SBF). These may be associated with a dural tear, hemosinus, otorrhea or rhinorrhea. The most common causative agent of post-traumatic meningitis is Streptococcus Pneumonia (Pneumococcus). PNEUMOVAX 23 is a potent vaccine against Pneumococcus, but head trauma involving any skull fractures are not defined indications for its use. Our aim was to identify the effect of PNEUMOVAX on the natural course and incidence of infections and infectious prognosis following SBF. METHODS: A retrospective review of patients suffering a traumatic SBF who were admitted to the Department of Neurosurgery at a single tertiary hospital referred from the entire north of Israel during 2002-2009 were characterized. Six hundred and two patients patients were included in the study; 99 patients received the PNEUMOVAX in the first few days of hospitalization, while 503 patients did not. Demographic data, presenting symptoms, chronic illnesses and radiologic features were logged. Treatment regimens were logged as well, including the use of PNEUMOVAX vaccine. Outcome parameters including infectious complications and functional state were logged at different set time points after admission. RESULTS: The group receiving the vaccine had a significantly older mean age, higher incidence of obesity, higher rate of headache or confusion on presentation, and a significantly higher incidence of additional cranial injuries. All these factors, known to worsen the outcome of SBF patients did not manifest in the vaccinated group. There was no statistically significant differences between the groups in the outcome parameters measured (fever, meningitis, mortality or length of hospitalization). CONCLUSIONS: We suggest that patients with a more severe status upon admission may benefit from a prophylactic treatment with the PNEUMOVAX vaccine.

Major-histocompatibility complex harnessing and lymphocytic recruitment: a new tool for glioblastoma multiforme immunotherapy.

Glioblastoma multiforme (GBM) is the most common malignant primary brain neoplasm, notorious for being able to evade and suppress the immune-system. We present a new immunotherapeutic approach that can potentially overcome or circumvent many of the GBM laden obstacles for an efficient antitumor immune response. In this molecular construct, a soluble major-histocompatibility complex (MHC), presenting an immunogenic peptide is directed towards GBM cells. This soluble complex is known to be able to activate relevant cytotoxic T-lymphocyte (CTL's) populations, mounting an effective local immune response. The chimeric protein consists of a targeting domain, a function that can be fulfilled by an antibody or other small molecule that binds tumor associated antigens, and an effector domain. A single chain MHC directly linked to an immunogenic Cytomegalovirus derived peptide (phosphoprotein 65) can be used as such an effector domain. Targeting MHC complexes to the tumor enables to recruit different lymphocyte populations using MHC-molecules bearing a single, highly antigenic peptide derived from immunogenic T cell epitopes. Moreover, the recruited potent memory CTL's at the tumor's milieu may prove resistant to the previously described local immunosuppressive environment, and may enable the shift to TH1 cytokine profile resulting in specific massive tumor destruction.

Glioblastoma multiforme targeted therapy: The Chlorotoxin story.

Glioblastoma multiforme (GBM) is the most common malignant primary brain neoplasm having a mean survival of <24months. Scorpion toxins are considered promising cancer drug candidates, primarily due to the discovery of hlorotoxin, derived from the venom of the Israeli yellow scorpion. This intriguing short peptide of only 36 amino-acids length and tight configuration, possess the ability to bind to GBM cells in a grade-related manner with ∼100% of GBM cells staining positive and no cross reactivity to normal brain. Chlorotoxin has an anti-angiogenic effect as well. Molecular targets for Chlorotoxin include voltage gated chloride channels (GCC), calcium-dependent phospholipid-binding protein Annexin-2, and the inducible extracellular enzyme Matrix Metalloproteinase-2 (MMP-2). Of all its targets, MMP-2 seems to bear the most anti-neoplastic potential. Chlorotoxin is a promising tumortargeting peptide. Its small size and compact shape are convenient for intracranial delivery. We present a short discussion on Chlorotoxin. The structure, biological activity, molecular targets and possible clinical role of Chlorotoxin are discussed. Chlorotoxin can be utilized as a targeting domain as well, attaching different effector functions to it. Clinical applications in GBM therapy, intraoperative imaging, nano-probes and nano-vectors based technology; targeted chemotherapy and immunotherapy are discussed as well. Chlorotoxin is likely to play a significant role in effective GBM immunotherapy in the future.

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.

MRI Guided Focused Ultrasound Thalamotomy for Moderate-to-Severe Tremor in Parkinson's Disease.

Background. Thalamotomy is effective in alleviating tremor in Parkinson's disease (PD). Methods. Seven PD patients, mean age 59.4 ± 9.8 years (range, 46-74) with a mean disease duration of 5.4 ± 2.8 years (range, 2-10) suffering from severe refractory tremor, underwent ventral intermediate nucleus thalamotomy using MRI guided focused ultrasound (MRgFUS), an innovative technology that enables noninvasive surgery. Results. Tremor stopped in the contralateral upper extremity in all patients immediately following treatment. Total UPDRS decreased from 37.4 ± 12.2 to 18.8 ± 11.1 (p = 0.007) and PDQ-39 decreased from 42.3 ± 16.4 to 21.6 ± 10.8 (p = 0.008) following MRgFUS. These effects were sustained (mean follow-up 7.3 months). Adverse events during MRgFUS included headache (n = 3), dizziness (n = 2), vertigo (n = 4), and lip paresthesia (n = 1) and following MRgFUS were hypogeusia (n = 1), unsteady feeling when walking (n = 1, resolved), and disturbance when walking tandem (n = 1, resolved). Conclusions. Thalamotomy using MRgFUS is safe and effective in PD patients. Large randomized studies are needed to assess prolonged efficacy and safety.