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OBJECTIVE MRI-guided low-intensity focused ultrasound (FUS) has been shown to reversibly open the blood-brain barrier (BBB), with the potential to deliver therapeutic agents noninvasively to target brain regions in patients with Alzheimer’s disease (AD) and other neurodegenerative conditions. Previously, the authors reported the short-term safety and feasibility of FUS BBB opening of the hippocampus and entorhinal cortex (EC) in patients with AD. Given the need to treat larger brain regions beyond the hippocampus and EC, brain volumes and locations treated with FUS have now expanded. To evaluate any potential adverse consequences of BBB opening on disease progression, the authors report safety, imaging, and clinical outcomes among participants with mild AD at 6–12 months after FUS treatment targeted to the hippocampus, frontal lobe, and parietal lobe. METHODS In this open-label trial, participants with mild AD underwent MRI-guided FUS sonication to open the BBB in β-amyloid positive regions of the hippocampus, EC, frontal lobe, and parietal lobe. Participants underwent 3 separate FUS treatment sessions performed 2 weeks apart. Outcome assessments included safety, imaging, neurological, cognitive, and florbetaben β-amyloid PET. RESULTS Ten participants (range 55–76 years old) completed 30 separate FUS treatments at 2 participating institutions, with 6–12 months of follow-up. All participants had immediate BBB opening after FUS and BBB closure within 24–48 hours. All FUS treatments were well tolerated, with no serious adverse events related to the procedure. All 10 participants had a minimum of 6 months of follow-up, and 7 participants had a follow-up out to 1 year. Changes in the Alzheimer’s Disease Assessment Scale–cognitive and Mini-Mental State Examination scores were comparable to those in controls from the Alzheimer’s Disease Neuroimaging Initiative. PET scans demonstrated an average β-amyloid plaque of 14% in the Centiloid scale in the FUS-treated regions. CONCLUSIONS This study is the largest cohort of participants with mild AD who received FUS treatment, and has the longest follow-up to date. Safety was demonstrated in conjunction with reversible and repeated BBB opening in multiple cortical and deep brain locations, with a concomitant reduction of β-amyloid. There was no apparent cognitive worsening beyond expectations up to 1 year after FUS treatment, suggesting that the BBB opening treatment in multiple brain regions did not adversely influence AD progression. Further studies are needed to determine the clinical significance of these findings. FUS offers a unique opportunity to decrease amyloid plaque burden as well as the potential to deliver targeted therapeutics to multiple brain regions in patients with neurodegenerative disorders.

Surgical targeting of the ventral intermediate nucleus of the thalamus (VIM) has been historically done using indirect strategies. Here we depict the cerebello-thalamo-cortical tract (CTCT) through 3 T proton density (PD) in a cohort of patients who underwent high-intensity focus ultrasound (HIFUS) thalamotomy. Forty-seven patients treated in our institution with MR-guided HIFUS VIM thalamotomy were included in this study. PD weighted 3 T MRI used for presurgical planning was compared with postoperative MRI obtained 1 month after surgery. Images were processed with ISTX software (Brain lab, Munich, Germany). The coordinates of the VIM lesion concerning the inter-commissural line (ICL) were annotated. Deterministic tractographies using three ROIs were used to verify the different tracts. The triangle seen in the 3 T PD sequence at the level of the mesencephalic-diencephalic junction was systematically recognized. The posterior angle of this triangle at the junction of the CTCT and the ZI was denominated as "point P." The area of this triangle corresponds to the posterior subthalamic area (PSA) harboring the Raprl fibers. The CTCT was visible from 1 to 2.5 mm below the ICL. The average center of the final HIFUS lesion (point F) was 11 mm from the medial thalamic border of the thalamus (14.9 mm from the midline), 6.4 mm anterior to PC, and 0.6 mm above the ICL. The FUS point was consistently 1-2 mm directly above point P. The anterior border of the external angle of this triangle (point P) can be used as an intraparenchymal point for targeting the ventral border of the VIM. Three ROIs placed in a single slice around this triangle are a fast way to originate tractography of the CTCT, lemniscus medialis, and pyramidal tract.

Background. To determine the utility of an intraoperative magnetic resonance imaging (iMRI) system, the Polestar N30, for enhancing the resection control of non-enhancing intra-axial brain lesions. Materials and methods. Seventy-three patients (60 males [83.3%], mean age 37 years) with intra-axial brain lesions underwent resection at Sheba Medical Centre using the Polestar between February 2012 and the end of August 2018. Demographic and imaging data were retrospectively analysed. Thirty-five patients had a non-enhancing lesion (48%). Results. Complete resection was planned for 60/73 cases after preoperative imaging. Complete resection was achieved in 59/60 (98.3%) cases. After iMRI, additional resection was performed in 24/73 (32.8%) cases, and complete resection was performed in 17/60 (28.8%) cases in which a complete resection was intended. In 6/13 (46%) patients for whom incomplete resection was intended, further resection was performed. The extent of resection was extended mainly for non-enhancing lesions: 16/35 (46%) as opposed to only 8/38 (21%) for enhancing lesions. Further resection was not significantly associated with sex, age, intended resection, recurrence, or affected side. Univariate analysis revealed non-eloquent area, intended complete resection, and enhancing lesions to be predictive factors for complete resection, and non-enhancing lesions and scan time to be predictive factors for an extended resection. Non-enhancement was the only independent factor for extended resection. Conclusions. The Polestar N30 is useful for evaluating residual non-enhancing intra-axial brain lesions and achieving maximal resection.

Hemangioblastomas (HB) are benign low grade vascular tumors most frequently occurring in the cerebellum, brain stem, and spinal cord. Often associated with Von Hippel Lindau disease (VHL), the lesions are often multifocal requiring complex resection and are difficult to control. Linear Accelerator (LINAC) Stereotactic Radiosurgery (SRS) has been demonstrated to provide additional tumor control. In this case series, we present our multi-center experience utilizing LINAC SRS in fourteen patients with 23 lesions. We observed a tumor control rate of 87% and found interval changes in the peritumoral enhancement to correlate with treatment outcome. In our study, SRS treatment was also well-tolerated in both cystic and noncystic patients with multifocal disease. Disease control was achieved in all but three patients post-resection and no longitudinal radiation-induced secondary malignancy was observed. SRS response correlated highly with lesion size and radiation dose. We conclude that LINAC SRS is safe and effective for patients with HB and should be considered in addition to surgery in asymptomatic, VHL patients, deep seated lesions and isolated lesions.

Background Most anterior visual pathway meningiomas (AVPM) are benign and slow-growing, but these tumors may affect visual functions, including visual acuity (VA) and visual field (VF). Due to location, most are treated non-surgically by fractionated stereotactic radiotherapy (FSRT), aiming to prevent tumor progression and visual functions deterioration. Unfortunately, FSRT in itself may affect visual functions. The current preferred treatment regimen (in terms of safety and effectiveness) is undetermined. While most cases are treated with conventional fractionation (cFSRT)—50.4–54 Gy in 28–30 fractions of 1.8–2 Gy, advances in technology have allowed shortening of total treatment length to hypofractionation (hSRT)—25-27 Gy in 3–5 fractions of 5–9 Gy. Our aim was to evaluate the association of radiotherapy regimen for treating AVPM (cFSRT vs. hSRT) with visual function outcomes (VA, VF) at the last neuro-ophthalmologic evaluation. Methods We conducted a retrospective cohort study of AVPM cases treated at Sheba Medical Center during 2004–2015. We compared cFSRT and hSRT regimens regarding visual function (VA, VF) outcomes at the last neuro-ophthalmologic evaluation. VA was determined by the logarithm of the minimum angle of resolution (LogMAR). VF was determined by the mean deviation (MD). A clinically relevant change in VA was defined as 0.2 LogMAR. Results 48 patients (13 receiving hSRT, 35 receiving cFSRT) were included, with a median follow-up of 55 months. No significant difference was evident regarding LogMAR or MD of involved eyes at the last evaluation. Six (17%) patients in the cFSRT group experienced clinically relevant VA deterioration in the involved eye, compared with six (46%) in hSRT (p = 0.06). Conclusion Our findings, using comprehensive and meticulous investigation of visual outcomes, suggest that hSRT may be associated with higher risk for VA and VF deterioration in AVPM especially in ONSM. We recommend the use of cFSRT for ONSM.

Background A definitive diagnosis of brain lesions not amenable to surgery is mainly made by stereotactic needle biopsy. The diagnostic yield and safety of the frameless versus frame-based image-guided stereotactic techniques is unclear. Our objective was to evaluate the safety and accuracy of frameless versus frame-based stereotactic brain biopsy techniques. Methods A total of 278 patients (153 men; mean age: 65.5 years) with intra-axial brain lesions underwent frame-based (n = 148) or frameless image-guided stereotactic brain biopsy (n = 130) using a minimally invasive twist drill technique during 2010–2016 at Sheba Medical Center. Demographic, imaging, and clinical data were retrospectively analyzed. Results The diagnostic yield (>90%) did not differ significantly between groups. Overall morbidity (6.8% vs. 8.5%), incidence of permanent neurologic deficits (2.1% vs. 1.6%), mortality rate (0.7% vs. 0.8%), and postoperative computed tomography–detected asymptomatic (14.2% vs. 16.1%) and symptomatic (2.0% vs. 1.6%) bleeding also did not differ significantly between the frame-based and frameless cohorts, respectively. The diagnostic yield and complication rates related to the biopsy technique were not significantly associated with sex, age, entry angle to the skull and skull thickness, lesion location or depth, or radiologic characteristics. Diagnostic yield was significantly associated with the mean lesion volume. Smaller lesions were less diagnostic than larger lesions in both techniques (P = 0.043 frame-based and P = 0.048 frameless). Conclusions The frameless biopsy technique is as efficient as the frame-based brain biopsy technique with a low complication rate. Lesion volume was the only predictive factor of diagnostic yield. The minimally invasive twist drill technique is safe and efficient.

BACKGROUND Most anterior visual pathway meningiomas (AVPM) are benign and slow-growing, but these tumors may affect visual functions, including visual acuity (VA) and visual field (VF). Due to location, most are treated non-surgically by fractionated stereotactic radiotherapy (FSRT), aiming to prevent tumor progression and visual functions deterioration. Unfortunately, FSRT in itself may affect visual functions. The current preferred treatment regimen (in terms of safety and effectiveness) is undetermined. While most cases are treated with conventional fractionation (cFSRT) – 50.4–54 Gy in 28–30 fractions of 1.8-2 Gy, advances in technology have allowed shortening of total treatment length to hypofractionation (hSRT) – 25-27Gy in 3–5 fractions of 5–9 Gy. Our aim was to evaluate the association of radiotherapy regimen for treating AVPM (cFSRT vs. hSRT) with visual function outcomes (VA, VF) at the last neuro-ophthalmologic evaluation. METHODS We conducted a retrospective cohort study of AVPM cases treated at Sheba Medical Center during 2004–2015. We compared cFSRT and hSRT regimens regarding visual function (VA, VF) outcomes at the last neuro-ophthalmologic evaluation. VA was determined by the logarithm of the minimum angle of resolution (LogMAR). VF was determined by the mean deviation (MD). A clinically relevant change in VA was defined as 0.2 LogMAR. RESULTS 48 patients (13 receiving hSRT, 35 receiving cFSRT) were included, with a median follow-up of 55 months. No significant difference was evident regarding LogMAR or MD of involved eyes at the last evaluation. Six (17%) patients in the cFSRT group experienced clinically relevant VA deterioration in the involved eye, compared with six (46%) in hSRT (p = 0.06). CONCLUSION Our findings, using comprehensive and meticulous investigation of visual outcomes, suggest that hSRT may be associated with higher risk for VA and VF deterioration in AVPM especially in ONSM. We recommend the use of cFSRT for ONSM.

The blood–brain barrier (BBB) presents a significant challenge for treating brain disorders. The hippocampus is a key target for novel therapeutics, playing an important role in Alzheimer’s disease (AD), epilepsy, and depression. Preclinical studies have shown that magnetic resonance (MR)-guided low-intensity focused ultrasound (FUS) can reversibly open the BBB and facilitate delivery of targeted brain therapeutics. We report initial clinical trial results evaluating the safety, feasibility, and reversibility of BBB opening with FUS treatment of the hippocampus and entorhinal cortex (EC) in patients with early AD. Six subjects tolerated a total of 17 FUS treatments with no adverse events and neither cognitive nor neurological worsening. Post-FUS contrast MRI revealed immediate and sizable hippocampal parenchymal enhancement indicating BBB opening, followed by BBB closure within 24 h. The average opening was 95% of the targeted FUS volume, which corresponds to 29% of the overall hippocampus volume. We demonstrate that FUS can safely, noninvasively, transiently, reproducibly, and focally mediate BBB opening in the hippocampus/EC in humans. This provides a unique translational opportunity to investigate therapeutic delivery in AD and other conditions.

Background: People with Parkinson's disease (PD) treated with deep brain stimulation (DBS) with non-rechargeable implantable pulse generators (IPGs) require elective IPG replacement operations involving surgical and anesthesiologic risk. Life expectancy and the number of replacements per patient with DBS are increasing. Objective: To determine whether IPG longevity is influenced by stimulation parameters alone or whether there is an independent effect of the number of battery replacements and IPG model. Methods: PD patients treated with bilateral subthalamic DBS were included if there was at least one IPG replacement due to battery end of life. Fifty-five patients had one or two IPG replacements and seven had three or four replacements, (80 Kinetra® and 23 Activa-PC®). We calculated longevity corrected for total electrical energy delivered (TEED) and tested for the effect of IPG model and number of previous battery replacements on this measure. Results: TEED-corrected IPG longevity for the 1st implanted IPG was 51.3 months for Kinetra® and 35.6 months for Activa-PC®, which dropped by 5.9 months and 2.8 months, respectively with each subsequent IPG replacement (p

Recent reports indicate that Parkinson's disease (PD) involves specific functional abnormalities in residual neurons – decreased vesicular sequestration of cytoplasmic catecholamines via the vesicular monoamine transporter (VMAT) and decreased aldehyde dehydrogenase (ALDH) activity. This double hit builds up the autotoxic metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), the focus of the catecholaldehyde hypothesis for the pathogenesis of PD. An animal model is needed that reproduces this abnormal catecholamine neurochemical pattern. Adult rats received subcutaneous vehicle or the mitochondrial complex 1 inhibitor rotenone (2 mg/kg/day via a minipump) for 10 days. Locomotor activity was recorded, and striatal tissue sampled for catechol contents and catechol ratios that indicate the above abnormalities. Compared to vehicle, rotenone reduced locomotor activity (P=0.002), decreased tissue dopamine concentrations (P=0.00001), reduced indices of vesicular sequestration (3,4-dihydroxyphenylacetic acid (DOPAC)/dopamine) and ALDH activity (DOPAC/DOPAL) (P=0.0025, P=0.036), and increased DOPAL levels (P=0.04). The rat rotenone model involves functional abnormalities in catecholaminergic neurons that replicate the pattern found in PD putamen. These include a vesicular storage defect, decreased ALDH activity and DOPAL build-up. The rat rotenone model provides a suitable in vivo platform for studying the catecholaldehyde hypothesis., Summary: This study presents an animal model that reflects the neurochemical pattern found in Parkinson's patients, the basis of the new and evolving catecholaldehyde hypothesis for the disease.

BACKGROUND Meningiomas are the most common primary CNS tumor in adults, with a median age at diagnosis of 65 years and a female to male ratio of 2–3:1 (except in grade II, III meningiomas). Younger patients usually have a genetic background or history of prior radiation exposure. Based on population-level studies, approximately 80–85% of meningiomas are WHO grade I (benign), 15–18% grade II (atypical), and 1–3% grade III (anaplastic). This case series describes a single center experience of the presentation and pathology of meningiomas in patients under the age of 40. MATERIALS AND METHODS We reviewed the Sheba Medical Center Neurosurgery and radiotherapy databases containing patients who were operated on for meningioma between the years 2011–2020. Patients under 40 were selected and information from digital medical records was gathered on these patients, including pathology reports, surgical reports, clinical and radiological data, and the use of radiotherapy or medical treatments. RESULTS Of 600 patients in the database, 49 patients under 40 (8.3%) were identified and 54 tumors were reviewed (five patients were operated on for multiple meningiomas). 31 patients were female (63%); 2 were under 20 years old, 15 were age 20–29 and 32 were age 30–39 at first presentation. Seven patients had received prior radiation therapy for a childhood malignancy. 28 meningiomas were histology confirmed grade I (52%), 22 were grade II (41%), 2 were grade III (4%), and 2 (4%) were grade undetermined. 22 tumors were located in the skull base (41%) and 32 (59%) in the brain convexity. Of the skull base tumors, 16 were grade I, 5 were grade II, and one was grade III. Of the convexity tumors, 12 were grade I, 16 were grade II, and 2 were grade III. Median follow-up was 35 months, and longest follow-up time was 98 months. Six patients were treated with additional radiotherapy after surgery. CONCLUSION Our experience with meningioma patients under 40 revealed a different grade segregation than the older population, with younger patients showing a higher incidence of grade II tumors. These tumors are generally more aggressive, and require careful resection and consideration for post-surgical radiotherapy. Further validation with population based databases is required.

Use of spinal cord stimulation (SCS) has expanded beyond pain control. There are increasing indications in which SCS is being used. The understanding of central and peripheral neural pathways and their controlling influences on peripheral organs is better understood now. The concept of stimulating the spinal cord and modulating central pathways with SCS is already established. Different studies have shown the benefit with SCS on visceral pain control, improving quality of live in severe peripheral vascular disease and even assist in controlling the vago-sympathetic balance. We will discuss the art of implantation. Patient selection and stimulation with respect to current clinical data.

Magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU) is a well-established technology that has been developed during the last decade and is currently used in the treatment of a diverse range of neurodegenerative brain disorders and neuropsychiatric diseases. This innovative noninvasive technology uses nonionizing ultrasound waves to heat and thus ablate brain tissue in selected targets. In comparison with other lesioning and surgical techniques, MRgHIFU has the following advantages: noninvasive, an immediate clinical outcome with no risk of long-standing ionizing radiation injury, no need for general anesthesia, and no device implantation.

Aims and Objectives: To review a series of patients with brain metastases from ovarian cancer at a single institution. To describe treatment modalities, their outcomes and to determine prognostic factors. Patients and Methods: Between January 1995 and December 2014, 25 patients with ovarian cancer brain metastases were treated at The Sheba Medical Center. The medical records were retrospectively reviewed to collect demographic, clinical, and imaging data as well as the information on the treatment modalities used and their outcomes. Results: Mean patient age at the time of brain metastasis diagnosis was 62.7 years. The median interval between the diagnosis of primary cancer and brain metastasis was 42.3 months. Neurologic deficits, headache, and seizure were the most common symptoms. The brain was the only site of metastasis in 20% of the patients. Active ovarian cancer at the time of diagnosis of brain metastasis was observed in half of the patients with systemic disease. Multiple brain metastases were observed in 25% of the patients. We treated 11 patients with surgery plus radiation therapy protocols in various orders: surgery followed by complementary whole-brain radiation therapy (WBRT), surgery followed by stereotactic radiosurgery (SRS), and surgery followed by WBRT and then by adjuvant SRS. Five patients underwent surgery alone and nine patients were treated with radiation alone (WBRT, SRS, or both). Univariate analysis for predictors of survival demonstrated that age above 62.7 years at the time of central nervous system involvement was a significant risk factor and leptomeningeal disease was a poor prognostic factor in reference to supra-tentorial lesions. Multivariate analysis for predictors of survival, however, showed that multiple brain lesions (>4) were a poor prognostic factor, and multivariate analysis of the time to progression revealed that combined treatments of surgery and radiation resulted in longer median periods of progression-free survival than each modality alone. Conclusion: We conclude that the only significant predictors of survival or progression-free survival in our cohort were the number of brain metastases and the treatment modality.

BACKGROUND Meningiomas are the most common primary CNS tumor in adults, with a median age at diagnosis of 65 years. Younger patients usually have a genetic background or history of prior radiation exposure. Population-level studies suggest 80-85% of meningiomas are WHO grade I (benign), 15-18% grade II (atypical), and 1-3% grade III (anaplastic). This case series describes a single center experience of meningiomas in patients under 40. METHODS We reviewed the Sheba Medical Center Neurosurgery and radiotherapy databases containing patients operated on for meningioma between 2011-2020. Digital medical records were retrieved, including pathology reports, surgical reports, clinical and radiological data, and use of radiotherapy or medical treatments. RESULTS Of 600 patients in the database, 47 patients under 40 (7.8%) were identified and 54 tumors were reviewed (five patients had multiple operation). 32 patients were female (68%) ; 2 were under 20 years old, 17 were age 20-30 and 28 were age 31-39 at first presentation. Seven patients had received prior radiation therapy for a childhood malignancy. 28 meningiomas were histology confirmed grade I (52%), 22 were grade II (41%), 2 were grade III (4%), and 2 (4%) were grade undetermined. 22 tumors were located in the skull base (41%) and 32 (59%) in the brain convexity. 16 skull base tumors were grade I, five were grade II, and one was grade III. 12 convexity tumors were grade I, 16 were grade II, and two were grade III. Median follow-up was 35 months (range 1 - 98 months). CONCLUSION Our experience with meningioma patients under 40 revealed a different grade segregation than the older population, with younger patients showing a higher incidence of grade II tumors. These tumors are generally more aggressive, and require careful resection and consideration for post-surgical radiotherapy. Further validation with population based databases is required.

Altering the enormous complex connectivity and output of the central nervous system is one of the most fascinating development in medical technologies. It harbors the ability to treat and modulate different neurological disorders and diseases such as Parkinson's disease, Alzheimer's disease and even help with drug delivery to treat unreachable areas of brain via opening of the blood brain barrier. Evolution of neuromodulation techniques has been significant in last few years. They have become less invasive and more focused. Newer neuromodulation techniques consist of invasive, minimally invasive and non-invasive technologies. The decision to use one of these technologies depends on the indication and the targeted area within the central or peripheral nervous system. In the last decade technological advances and the urge to minimize the surgical and the long term complications of hardware implantation, have pushed the neurosurgical community to increase the use of non-invasive neuromodulation technics. In this article, we will discuss the different emerging technologies in neuromodulation and the increasing role of non-invasive neuromodulation.

Introduction The field of neuromodulation continues to grow, especially in the area of pain management. Percutaneous nerve field stimulation continues to gain significant popularity for chronic, focal, and intractable neuropathic pain. Materials and Methods Tuohy needles have been traditionally used as the instrument of choice for subcutaneous implantation of peripheral field stimulators. The ON-Q® Tunneling System (Braun Melsungen AG, Melsungen, Germany) provides an adaptable option for subcutaneous implantation of electrodes, with a variety of lengths and gauges available. This system uses a disposable blunt needle and a peel-away sheath and is firm but malleable. Gentle curves can be applied to the stylet prior to implantation. The blunt, malleable nature of the needle and the soft Silastic sheath allow for applications in areas with greater curvature, such as the face, and ensure a subcutaneous placement. Conclusions The great adaptability of this system allows for implantation of electrodes subcutaneously with efficacy and ease. Here we present a technical note on the use of this system for subcutaneous implantation of peripheral nerve field stimulators.

The objective of this study was to assess reduction in cerebral edema following linear accelerator radiosurgery (LINAC) as first line therapy for brain metastasis. We reviewed the medical records of all patients who underwent LINAC radiosurgery for brain metastasis at our institution during 2010-2012, and who had not previously undergone either surgery or whole brain radiotherapy. Data were analyzed for 55 brain metastases from 46 patients (24 males), mean age 59.9 years. During the 2 months following LINAC radiosurgery, the mean steroid dose decreased from 4.8 to 2.6 mg/day, the mean metastasis volume decreased from 3.79±4.12 cc to 2.8±4.48 cc (p=0.001), and the mean edema volume decreased from 16.91±30.15 cc to 12.85±24.47 cc (p=0.23). The 17 patients with reductions of more than 50% in brain edema volume had single metastases. Edema volume in the nine patients with two brain metastases remained stable in five patients (volume change10%, 0-2 cc) and increased in four patients (by10%, 2-14 cc). In a subanalysis of eight metastases with baseline edema volume greater than 40 cc, edema volume decreased from 77.27±37.21 cc to 24.84±35.6 cc (p=0.034). Reductions in brain edema were greater in metastases for which non-small-cell lung carcinoma and breast cancers were the primary diseases. Overall, symptoms improved in most patients. No patients who were without symptoms or who had no signs of increased intracranial pressure at baseline developed signs of intracranial pressure following LINAC radiosurgery. In this series, LINAC stereotactic radiosurgery for metastatic brain lesions resulted in early reduction in brain edema volume in single metastasis patients and those with large edema volumes, and reduced the need for steroids.

High-grade gliomas constitute a group of aggressive CNS cancers that have high morbidity and mortality rates. Despite extensive research, current therapeutic approaches enable survival beyond 2 years in rare cases only. Thrombin and its main CNS target, protease-activated receptor-1, have been implicated in tumor progression and brain edema. Our aim was to study protease-activated receptor-1 (PAR-1) protein expression and thrombin-like activity levels in both in vitro and in vivo models of glioblastoma and correlate them with the volume of the surrounding edema. We measured the presence of PAR-1 protein using fluorescence immunohistochemistry and assessed thrombin activity in various glial and non-glial cell lines and in a CNS-1 glioma rat model using a thrombin-specific fluorescent assay. Thrombin activity was found to be highly elevated in various high-grade glioma cell lines as well as in non-glial malignant cell lines. In the CNS-1 glioma model, the level of PAR-1 fluorescence in the tumor was significantly elevated compared to adjacent regions of reactive gliosis or distant brain areas. The elevated level of thrombin activity observed in the high-grade glioma positively correlated with tumor-induced brain edema. In conclusion, thrombin is secreted from glioma cells and PAR-1 may be a new biological marker for high-grade gliomas.

Synovial chondromatosis is a benign condition characterized by metaplastic changes of the synovial membrane typically affecting large joints. Cervical spine involvement is rare and has not been reported in a teenager. The authors report a case of cervical synovial chondromatosis in a 19-year-old male presenting with left-sided weakness and numbness from spinal cord compression. After gross total resection was accomplished via laminoplasty, the patient's presenting symptoms improved and continued to do so over the follow-up period. The likely cause of the synovial chondromatosis in this patient was repetitive neck trauma as a child from a motor vehicle accident and football. This case demonstrates that the pathophysiology of this rare entity can initiate in the pediatric population. Although rare, synovial chondromatosis should be considered in the differential diagnosis of calcified extradural masses in the teenage population.

Multiple studies have shown proved efficacy of spinal cord stimulation (SCS) in peripheral vascular disease (PVD). The exact mechanism by which SCS acts in the treatment of PVD is not completely understood, and may include stimulating the release of nitric oxide, modulation of the sympathetic nervous system, or modulation of prostaglandin production. Patient selection criteria have been well defined and SCS should be reserved for patients with end-stage lower limb PVD unresponsive to medical therapy and not amenable to surgical reconstruction but in whom disease has not caused inevitable limb loss. This article reviews the outcomes, techniques, patient selection criteria, and putative mechanisms of SCS for PVD.

Ilioinguinal neuralgia (IG) and genitofemoral (GF) neuralgia following inguinal hernia repair is a chronic and debilitating neuropathic condition. Recently, peripheral nerve stimulation has become an effective and minimally invasive option for the treatment of refractory pain. Here we present a retrospective case series of six patients who underwent placement of peripheral nerve stimulation electrodes using various techniques for treatment of refractory post-intervention inguinal region pain.Six patients with post-intervention inguinal, femoral or GF neuropathic pain were evaluated for surgery. Either octopolar percutaneous electrodes or combination of paddle and percutaneous electrodes were implanted in the area of their pain. Pain visual analog scores (VAS), surgical complication rate, preoperative symptom duration, degree of pain relief, preoperative and postoperative work status, postoperative changes in medication usage, and overall degree of satisfaction with this therapy was assessed.All six patients had an average improvement of 62% in the immediate post-operative follow-up. Four patients underwent stimulation for IG, one for femoral neuralgia, and another for GF neuralgia. Peripheral nerve stimulation provided at least 50% pain relief in all the six patients with post-intervention inguinal region pain. 85% of patients indicated they were completely satisfied with the therapy overall. There was one treatment failure with an acceptable complication rate.Peripheral nerve or field stimulation for post-intervention inguinal region pain is a safe and effective treatment for this refractory and complex problem for patients who have exhausted other management options.

Future clinical applications of magnetic resonance imaging-guided high-intensity focused ultrasound (MRgHIFU) are moving toward the management of different intracranial pathologies. We sought to validate the production, safety, and efficacy of thermal injury to cranial nerves generated by MRgHIFU. In this study, five female domestic pigs underwent a standard bifrontal craniectomy under general anesthesia. Treatment was then given using an MRgHIFU system to induce hyperthermic ablative sonication (6 to 10 s; 50 to 2000 J.) Histological analyses were done to confirm nerve damage; temperature measured on the optic nerve was approximately 53.4°C (range: 39°C to 70°C.) Histology demonstrated a clear definition between a necrotic, transitional zone, and normal tissue. MRgHIFU induces targeted thermal injury to nervous tissue within a specific threshold of 50°C to 60°C with the tissue near the sonication center yielding the greatest effect; adjacent tissue showed minimal changes. Additional studies utilizing this technology are required to further establish accurate threshold parameters for optic nerve thermo-ablation.

The success of deep brain stimulation (DBS) surgery for movement disorders over the past 20 years with over 100,000 patient implants has revived the interest in neurosurgical treatment of refractory psychiatric disorders. The introduction of stereotaxis in the second half of the twentieth century aided with the technological evolutions enabled neurosurgeons to interrupt the white matter tracts while minimizing the cortical damage and thereby the side effects associated with leucotomies/lobotomies. Moreover, the integration of functional imaging, microelectrode recordings and computer based data with stereotaxis made it a robust technique to target the subcortical structures more precisely. With better understanding of the pathophysiology and neural circuits involved in these disorders, it may be possible to delineate the anatomical “target” or “targets” for neuromodulation. The role of cortico-striato-thalamo-cortical (CSTC) loops in the pathophysiology of these psychiatric disorders is well established. Preliminary results suggested the efficacy of this treatment modality in the management of refractory psychiatric disorders such as OCD and MDD and neurostimulation therapy may be an option in the management of these disorders. There are several advantages of neurostimulation therapy over ablation therapy such as reversibility and adjustability according to the patient’s symptoms and disease progression and the ability to switch the stimulation without patient’s awareness, thereby providing an opportunity for blinding in crossover research studies. The opportunity for surgical intervention is of importance given the large prevalence and the socioeconomic impact of psychiatric disorders, the presence of many refractory and disabled patients, improved understanding of the neural circuitry underlying these conditions, and increasing safety, precision, and technological innovations in the neurosurgical interventions. This chapter focuses on neurosurgery for severe and treatment-refractory psychiatric disorders including history of psychosurgery, ethical considerations, current concepts, and future goals.

Glioblastoma multiforme (GBM) is one of the most infiltrating, aggressive, and poorly treated brain tumors. Progress in genomics and proteomics has paved the way for identifying potential therapeutic targets for treating GBM, yet the vast majority of these leading drug candidates for the treatment of GBM are ineffective, mainly due to restricted passages across the blood-brain barrier. Nanoparticles have been emerged as a promising platform to treat different types of tumors due to their ability to transport drugs to target sites while minimizing adverse effects. Herein, we devised a localized strategy to deliver RNA interference (RNAi) directly to the GBM site using hyaluronan (HA)-grafted lipid-based nanoparticles (LNPs). These LNPs having an ionized lipid were previously shown to be highly effective in delivering small interfering RNAs (siRNAs) into various cell types. LNP's surface was functionalized with hyaluronan (HA), a naturally occurring glycosaminoglycan that specifically binds the CD44 receptor expressed on GBM cells. We found that HA-LNPs can successfully bind to GBM cell lines and primary neurosphers of GBM patients. HA-LNPs loaded with Polo-Like Kinase 1 (PLK1) siRNAs (siPLK1) dramatically reduced the expression of PLK1 mRNA and cumulated in cell death even under shear flow that simulate the flow of the cerebrospinal fluid compared with control groups. Next, a human GBM U87MG orthotopic xenograft model was established by intracranial injection of U87MG cells into nude mice. Convection of Cy3-siRNA entrapped in HA-LNPs was performed, and specific Cy3 uptake was observed in U87MG cells. Moreover, convection of siPLK1 entrapped in HA-LNPs reduced mRNA levels by more than 80% and significantly prolonged survival of treated mice in the orthotopic model. Taken together, our results suggest that RNAi therapeutics could effectively be delivered in a localized manner with HA-coated LNPs and ultimately may become a therapeutic modality for GBM.

Movement disorders have a long history of treatment with ablative or destructive procedures dating back to 1890 when Sir Victor Horsley performed an extirpation of the motor cortex for the treatment of athetosis. There was a great decline in the number of surgical cases when carbidopa/levodopa became popularized in 1968. Over time, we have discovered that medications have their limitations resulting in the resurgence of surgery for movement disorders. There are several surgical options available including high-intensity focused ultrasound, Gamma Knife, radiofrequency ablation, and deep brain stimulation. All but deep brain stimulation result in irreversible destruction of tissue. Deep brain stimulation has been proven to be a safe, efficient, and reversible tool to help movement neurologists optimize their patients’ quality of life. Currently, it is the therapeutic treatment of choice for refractory disorders. There are essential differences between deep brain stimulation and the ablative modalities, and each has its pros and cons. It this chapter, we will try to precis each modality and compare in between. We will also review the evidence for both deep brain stimulation and radiosurgery. We hope that the readers of this chapter will be able to use it as a tool in making better treatment decisions for their patients.

Objective: One of the most serious complications following subarachnoid hemorrhage (SAH) is delayed cerebral ischemia (DCI) secondary to symptomatic vasospasm. An animal model mimicking post SAH vasospasm is essential for enabling the translation of newer technologies from the conceptual phase to animal studies, and eventually to clinical trials. Various animal models of DCI following SAH have been reported, with canine models being the most common. Due to the similarity of the swine cardiovascular system and its dimensions to the human's system, the main objective of this study was to establish a consistent and quantitatively representative model of SAH-induced vasospasm in swine. Materials and Methods: Twelve female swines (57 ± 3 kg) were injected twice (with a 2-day interval between injections) with autologous blood into the subarachnoid space at the level of C2-3 vertebrae. Different volumes were injected to identify clinical and radiological changes. The effect of volume variations on hematoma size and vasospasm intensity in the circle of Willis arteries were studied 7–14 days after the first injection using ascending pharyngeal angiographic measurements of vessel diameter. Neurological outcome using a modified scoring table based on clinical parameters (e.g., appetite, behavior, walking, posture, and eye movement) was recorded. Results: Our results demonstrate that between volume combinations, intrathecal injection of 12 ml followed by 15 ml, with a 2-day interval in between, resulted in the most extensive angiographically-assessed vasospasm 12 ± 2 days following the first injection. The degree of vasospasm in the intracranial internal carotid artery was 22% and 16% for the left and right sides, respectively. Vasoconstriction of the anterior cerebral artery was 34% and 27% for the left and right sides, respectively. The vasoconstriction was not associated with either overt clinical signs or clinical outcome, which is indicative of an ischemic event. Conclusions: The relative scarcity of swine models for SAH-induced vasospasm motivated us to develop and quantify a straightforward protocol for producing consistent mild-to-moderate vasospasm following SAH. As swine is commonly used in translational cardiovascular research, we believe that this study constitutes an important phase in the study of SAH and in developing pharmacological agents and medical devices for interventions.

Objective Post herpetic neuralgia is a chronic, debilitating pain with very few management options and is often refractory to treatment. We present our experience with a series of 4 patients who underwent subcutaneous peripheral field stimulation for treatment of thoracic post herpetic neuropathic pain. Methods Four patients with intractable thoracic post herpetic neuropathic pain were operated after maximum medical treatment and a neuropsychological evaluation. Multiple percutaneous electrodes were placed in the subcutaneous plane in the region of pain for a 7-day trial. Following a successful trial (more than 50% reduction of pain), the electrodes were then internalized and attached to a pulse generator. Visual analog scores (VAS) were studied during the preoperative, immediate postoperative and last follow-up visits. Long-term treatment results were determined by retrospective review of medical records. Average follow-up period was 28.2 months. Results All 4 patients showed persistent improvement in their VAS pain scores with an average improvement of more than 75%. There were no treatment failures and no complication requiring re-operation was reported. Conclusion Peripheral field stimulation for the treatment of post herpetic neuropathic pain is a safe and effective method for pain relief for an extremely complex problem with very few solutions. Patient selection and proper lead placement is most important for the success of treatment.

Stereotaxic sonoablative surgery by MRI guided high intensity focused ultrasound (FUS) holds great potential in disorders of the central nervous system (CNS). We previously described the ExAblate 2000 system (InSightec, Tirat Carmel, Israel), currently in use for various pathologies including uterine, liver, and, breast tumors, and referred to as the "body" system. Using a porcine model we have previously demonstrated, using the body system, the ablative capacity and thermal transfer in the cortex; developed a reproducible and translational model of craniectomy and post-operative recovery in FUS; and determined a grouping strategy based on thermal ablation and pathologic incremental changes in the cortex. Here we describe a novel ExAblate 4000 system that is designed specifically to treat CNS disorders ("head" system). Twenty-two swine underwent an improved wide craniectomy for positioning of the ExAblate 4000 containing 1024 elements arrayed with MRI guidance. Further neurologic and pathological analysis was performed 1 week post-operatively. Subjects underwent a wide craniectomy followed by high intensity MR guided focused ultrasound (MRgHIFU) sonoablation. Thermal ultrasonic ablative lesions were achieved in all subjects (n=22) ranging from 52-65°C following ∼70 consecutive sonications at 80 watts. These subjects were grouped based on thermal ablative lesions and post-operative staging (MRI, gross and microscopic pathology). Our results indicate the reproducibility of a porcine model for cerebral ablation, achieved across a dynamic temperature range, and well tolerated in this cohort. The ExAblate 4000 system is efficient through a wide craniectomy as well as a closed skull and demonstrates a high safety margin. Incremental hemorrhage and necrosis were minimal and energy dependent, indicating MRgHIFU can be used for the treatment of various cerebral pathologies and movement disorders.

Objective Central nervous system involvement in AIDS patients can present at any stage of the disease. Brain lesions detected in imaging studies are usually treated empirically. A brain biopsy is indicated in the absence of clinical and radiologic improvement. In the present study, 16 AIDS patients underwent brain biopsy. We evaluated the diagnostic yield of the brain biopsy and the changes in the disease course. Materials and methods Sixteen consecutive AIDS patients (12 men, 4 women; mean age 40.8 years) underwent a brain biopsy at Sheba Medical Center between 1997 and 2009. A retrospective analysis was performed and the clinical outcome was recorded. Results Median CD4 count before biopsy was 62.6. Magnetic resonance images revealed multiple lesions in 12 patients and enhancing lesions in 12 patients. A total of 19 biopsies were performed in 16 patients. In the present series, the initial procedures provided a diagnostic yield of 81.25% (13 diagnostic cases from 16 procedures in 16 patients). Two of these patients underwent repeated biopsies that were eventually diagnostic . If repeated biopsies were taken into consideration, the diagnostic yield was 93.75% (15 diagnostic cases in 16 patients). The rate of hemorrhagic complications was 10.5% (2 hemorrhages in 19 procedures). Pathologic examination revealed parasitic and fungal infections in 6 patients (6/16; 38%), progressive multifocal leukoencephalopathy in 4 patients (4/16; 25%), AIDS encephalopathy in 4 patients (4/16; 25%), and lymphoma in 1 patient (1/16; 6%). One patient had a nonspecific inflammatory process (6%). The treatment modality was modified in 12 patients and led to clinical and radiologic improvement in 8 patients. Conclusions Brain biopsy should be considered when empiric treatment of central nervous system lesions in AIDS patients fails. Biopsy is diagnostic in the majority of patients. The diagnosis allows for treatment modifications, which lead to clinical and radiologic improvement in some patients.

Over the past decade, progress in genomics and proteomics has paved the way for identifying promising macromolecular therapeutics including small RNAs, peptides and proteins. Still, the vast majority of leading drugs candidates for the treatment of CNS diseases is ineffective, mainly due to restricted passages across the BBB. Nanoparticles packaging of therapy is of particular interest for its potential to treat brain tumors, due to their ability to transport drugs through the BBB, while improving the performance of drugs by decreasing systemic and local toxicity. We chose GBM known for its poor prognosis, as a model for brain tumors. In our model we used a novel cluster-based nanoparticles termed Gagomers (GAGs) as our delivery system. GAGs are coated with the glycosamine glycan hyaluronan and can therefore bind to a specific CD44 variants expressed on tumor cells. We found that GAGs can successfully bind to both cultured cells and neurosphers (stem cells) of GBM patients and to GBM cell lines. In vitro, GAGs loaded with Kif-11 siRNA, dramatically reduced the expression of Kif11 mRNA in GBM cell lines, suggesting it can efficiently target GBM and reduce the expression of specific genes. Additionally, GAGs loaded with Doxorubicin (DXR) induced higher rates of GBM elimination than free DXR. As a next step, we examined GAGs' ability to bind specifically and efficiently to GBM cell lines in-vivo. U87 cell lines were stereotactically injected into the brains of SCID-NOD mice. Following tumor inoculation and growth mice underwent convection with GAGs loaded with Cy5 siRNA. only U87 cells were labeled with Cy5 suggesting that local treatment with GAGs can efficiently target GBM cells in-vivo. Our future plans are to examine the activity of GAGs co-entrapping siRNA and DXR on human GBM cell lines in-vitro and in-vivo. This strategy may ultimately become a novel therapeutic modality to treat GBM.

Neuromodulation using deep brain stimulation (DBS) has become an established therapy for the treatment of certain disorders such as Parkinson’s disease and tremors. Recent advances in surgical and imaging techniques further decrease the surgical risk associated with these procedures. Symptoms such as tremor, bradykinesia, rigidity and gait disturbances can be significantly controlled with DBS. This results in an opportunity to decrease anti-parkinsonism medications, and their dyskinetic side-effects. Following the success of DBS in the management of movement disorders, the role of this therapy is being extensively studied in more complex disorders that involve cognition and behavior. The inherent complexity in cognitive circuitry makes neuromodulation using DBS more difficult than in movement disorders. The goal of DBS surgery in these diseases is not only to slow the cognitive decline, but also restoration of function and ultimately improvement in the quality of life. DBS as a treatment for patients with advanced dementia holds significant promise in delaying or reversing the progressive cognitive decline by enhancing connectivity in the memory networks. In appropriately selected patients this potentially reversible surgical therapy can lead to a significant improvement in the quality of life and reduce the burden on patients, families and the healthcare system. This review focuses on the recent and future studies involving neuromodulation for cognitive disorders such as Alzheimer’s disease and Huntington’s disease.

Background Because of the paucity of effective treatments for intracranial hemorrhage (ICH), the mortality rate remains at 40%-60%. A novel application of magnetic resonance-guided focused ultrasound (MRgFUS) for ICH may offer an alternative noninvasive treatment through the precise delivery of FUS under real-time MR imaging (MRI) guidance. The purpose of the present study was to optimize the parameters for rapid, effective, and safe trans-skull large clot liquefaction using in vivo porcine and ex vivo human skull models to provide a clinically relevant proof of concept. Methods The transcranial effectiveness of MRgFUS was tested ex vivo by introducing a porcine blood clot into a human skull, without introducing tissue plasminogen activator (tPA). We used an experimental human head device to deliver pulsed FUS sonications at an acoustic power of 600-900 W for 5-10 seconds. A 3-mL clot was also introduced in a porcine brain and sonicated in vivo with one 5-second pulse of 700 W through a bone window or with 3000 W when treated through an ex vivo human skull. Treatment targeting was guided by MRI, and the tissue temperature was monitored online. Liquefied volumes were measured as hyperintense regions on T2-weighted MR images. Results In both in vivo porcine blood clot through a craniectomy model and the porcine clot in an ex vivo human skull model targeted clot liquefaction was achieved, with only marginal increase in temperature in the surrounding tissue. Conclusions Our results demonstrate the feasibility of fast, efficient, and safe thrombolysis in an in vivo porcine model of ICH and in 2 ex vivo models using a human skull, without introducing tPA. Future studies will further optimize parameters and assess the nature of sonication-mediated versus natural clot lysis, the risk of rebleeding, the potential effect on the adjacent parenchyma, and the chemical and toxicity profiles of resulting lysate particles.

Background Spinal cord metastatic lesions affect a high number of cancer patients usually resulting in spinal cord compression syndrome. A major obstacle in the research of spinal metastatic disease is the lack of a simple reproducible animal model that mimics the natural course of the disease. In this study, we present a highly reproducible rodent model that can be used for different types of cancers while mimicking the natural course of human metastatic spinal cord compression syndrome. Results All sixteen Fisher 344 rats survived the dorsal approach intraosseous implantation of CRL-1666 adenocarcinoma cells and both rats survived the sham control surgery. By Day 13 functional analysis via the modified Basso-Beattie-Bresnahan (BBB) locomotor rating scale showed significant decrease in motor function; median functional score was 3 for the tumor group (p = 0.0011). Median time to paresis was 8.7 days post-operatively. MR imaging illustrated repeated and consistent tumor formation, furthermore, onset of neurological sequale was the result of tumor formation and cord compression as confirmed by histological examination. Conclusions Analysis of these findings demonstrates a repeatable and consistent tumor growth model for cancer spinal metastases in rats. This novel rat model requires a less intricate surgical procedure, and as a result minimizes procedure time while subsequently increasing consistency. Therefore, this model allows for the preclinical evaluation of therapeutics for spinal metastases that more closely replicates physiological findings.

Hemangioblastomas are benign vascular central nervous system (CNS) tumors. Hemangioblastoma are frequently associated with peritumoral cysts (cysts arising at tumor edge). Because resection is curative, it is the preferred therapy for symptomatic brainstem hemangioblastomas. Nevertheless, surgical removal can present a treatment challenge due to the delicate surrounding anatomic structures in this region of the CNS (Wang et al.2001; Wind et al.2011). Here, we describe the salient clinical and management features of brainstem hemangioblastomas.

Background: Perianal Pa get's disease is an uncommon intraepithelial neoplasm that involves areas affluent with apocrine glands, most frequently in the female external genitalia, but may also affect the perianal region. Objective: We present the pathologic and clinical management of a case of Paget's disease involving the perianal region, in which diagnosis was delayed for 8 years. Conclusions: The importance of a high index of suspicion for early diagnosis is emphasized, which should be followed by aggressive surgical treatment with wide excision and local reconstruction.

Study design A phantom experiment, two thermocouple experiments, three in vivo pig experiments, and a simulated treatment on a healthy human volunteer were conducted to test the feasibility, safety, and efficacy of magnetic resonance-guided focused ultrasound (MRgFUS) for treating facet joint pain. Objective The goal of the current study was to develop a novel method for accurate and safe noninvasive facet joint ablation using MRgFUS. Summary of background data Facet joints are a common source of chronic back pain. Direct facet joint interventions include medial branch nerve ablation and intra-articular injections, which are widely used, but limited in the short and long term. MRgFUS is a breakthrough technology that enables accurate delivery of high-intensity focused ultrasound energy to create a localized temperature rise for tissue ablation, using MR guidance for treatment planning and real-time feedback. Methods We validated the feasibility, safety, and efficacy of MRgFUS for facet joint ablation using the ExAblate 2000® System (InSightec Ltd., Tirat Carmel, Israel) and confirmed the system's ability to ablate the edge of the facet joint and all terminal nerves innervating the joint. A phantom experiment, two thermocouple experiments, three in vivo pig experiments, and a simulated treatment on a healthy human volunteer were conducted. Results The experiments showed that targeting the facet joint with energies of 150–450 J provides controlled and accurate heating at the facet joint edge without penetration to the vertebral body, spinal canal, or root foramina. Treating with reduced diameter of the acoustic beam is recommended since a narrower beam improves access to the targeted areas. Conclusions MRgFUS can safely and effectively target and ablate the facet joint. These results are highly significant, given that this is the first study to demonstrate the potential of MRgFUS to treat facet joint pain.

We describe surgical management of herniated coil using indocyanine green video angiography (ICGA) following failure of endovascular retrieval methods in a patient who had endovascular treatment for anterior communicating artery aneurysm. The interdisciplinary cooperation between the endovascular and neurosurgical teams proved to be crucial for obtainment of a desirable outcome in this case. ICGA technology applied in such difficult cases may improve the surgical outcome.