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Vascular malformations are thought to be monogenic disorders that result in dysregulated growth of blood vessels. In the brain, cerebral cavernous malformations (CCMs) arise owing to inactivation of the endothelial CCM protein complex, which is required to dampen the activity of the kinase MEKK3 1 – 4 . Environmental factors can explain differences in the natural history of CCMs between individuals 5 , but why single CCMs often exhibit sudden, rapid growth, culminating in strokes or seizures, is unknown. Here we show that growth of CCMs requires increased signalling through the phosphatidylinositol-3-kinase (PI3K)–mTOR pathway as well as loss of function of the CCM complex. We identify somatic gain-of-function mutations in PIK3CA and loss-of-function mutations in the CCM complex in the same cells in a majority of human CCMs. Using mouse models, we show that growth of CCMs requires both PI3K gain of function and CCM loss of function in endothelial cells, and that both CCM loss of function and increased expression of the transcription factor KLF4 (a downstream effector of MEKK3) augment mTOR signalling in endothelial cells. Consistent with these findings, the mTORC1 inhibitor rapamycin effectively blocks the formation of CCMs in mouse models. We establish a three-hit mechanism analogous to cancer, in which aggressive vascular malformations arise through the loss of vascular ‘suppressor genes’ that constrain vessel growth and gain of a vascular ‘oncogene’ that stimulates excess vessel growth. These findings suggest that aggressive CCMs could be treated using clinically approved mTORC1 inhibitors. Aggressive cerebral cavernous malformations (CCMs) are found to grow through a three-hit cancer-like mechanism, involving gain of function of a gene that promotes vascular growth, and loss of function of genes that suppress it.

Abstract BACKGROUND: Blister aneurysms of the supraclinoid internal carotid artery (ICA) are challenging lesions with high intraoperative rupture rates and significant morbidity. An optimal treatment strategy for these aneurysms has not been established. OBJECTIVE: To analyze treatment strategy, operative techniques, and outcomes in a consecutive 17-year series of ICA blister aneurysms treated microsurgically. METHODS: Seventeen patients underwent blister aneurysm treatment with direct clipping, bypass and trapping, or clip-reinforced wrapping. RESULTS: Twelve aneurysms (71%) were treated with direct surgical clipping. Three patients required bypass: 1 superficial temporal artery to middle cerebral artery bypass, 1 external carotid artery to middle cerebral artery bypass, and 1 ICA to middle cerebral artery bypass. One patient was treated with clip-reinforced wrapping. Initial treatment strategy was enacted 71% of the time. Intraoperative rupture occurred in 7 patients (41%), doubling the rate of a poor outcome (57% vs 30% for patients with and without intraoperative rupture, respectively). Severe vasospasm developed in 9 of 16 patients (56%). Twelve patients (65%) were improved or unchanged after treatment, and 10 patients (59%) had good outcomes (modified Rankin Scale scores of 1 or 2). CONCLUSION: ICA blister aneurysms can be cautiously explored and treated with direct clipping as the first-line technique in the majority of cases. Complete trapping of the parent artery with temporary clips and placing permanent clip blades along normal arterial walls enables clipping that avoids intraoperative aneurysm rupture. Trapping/bypass is used as the second-line treatment, maintaining a low threshold for bypass with extensive or friable pathology of the carotid wall and in patients with incomplete circles of Willis.

Aneurysmal subarachnoid hemorrhage (aSAH) is a highly fatal and morbid type of hemorrhagic strokes. Intracranial aneurysms (ICAs) rupture cause subarachnoid hemorrhage. ICAs formation, growth and rupture involves cellular and molecular inflammation. Macrophages orchestrate inflammation in the wall of ICAs. Macrophages generally polarize either into classical inflammatory (M1) or alternatively-activated anti-inflammatory (M2)-phenotype. Macrophage infiltration and polarization toward M1-phenotype increases the risk of aneurysm rupture. Strategies that deplete, inhibit infiltration, ameliorate macrophage inflammation or polarize to M2-type protect against ICAs rupture. However, clinical translational data is still lacking. This review summarizes the contribution of macrophage led inflammation in the aneurysm wall and discuss pharmacological strategies to modulate the macrophageal response during ICAs formation and rupture.

Mice ( Mus musculus ) are one of the most commonly used animal species in basic science and translational research worldwide. Ovariectomy and hysterectomy are frequently employed to explore the systemic effects of the sex-hormone axis and other pathological conditions. While several surgical protocols exist for dorsal ovariectomy in rodents, very few address a ventral midline technique, and none are specific to the mouse model. Historically, ventral midline approaches have been considered technically challenging due to unique anatomical features, including long, thin uterine horns, fragile salpinges, short ovarian suspensory ligaments, and small animal size. This protocol provides a detailed guide for performing ovariectomy, hysterectomy, or ovariohysterectomy in mice, including the microsurgical steps required. All procedures were performed using an operative stereomicroscope under 3-5x magnification. The mean weight of the mice was 24 g (SD = 2 g), with ages ranging from 19 to 21 weeks. Of the 255 surgeries performed, 3 post-operative deaths occurred, resulting in an attrition rate of 1.18%. Post-operatively, all mice were housed in groups with fresh, paddy husk bedding, and no infections or wound breakdown were observed. Despite their small size and the manipulation of several vital anatomical structures, this procedure is easily reproducible and well-tolerated in mice.

Abstract BACKGROUND: The supplementary grading system for brain arteriovenous malformations (AVMs) was introduced in 2010 as a tool for improving preoperative risk prediction and selecting surgical patients. OBJECTIVE: To demonstrate in this multicenter validation study that supplemented Spetzler-Martin (SM-Supp) grades have greater predictive accuracy than Spetzler-Martin (SM) grades alone. METHODS: Data collected from 1009 AVM patients who underwent AVM resection were used to compare the predictive powers of SM and SM-Supp grades. Patients included the original 300 University of California, San Francisco patients plus those treated thereafter (n = 117) and an additional 592 patients from 3 other centers. RESULTS: In the combined cohort, the SM-Supp system performed better than SM system alone: area under the receiver-operating characteristics curve (AUROC) = 0.75 (95% confidence interval, 0.71–0.78) for SM-Supp and AUROC = 0.69 (95% confidence interval, 0.65-0.73) for SM (P < .001). Stratified analysis fitting models within 3 different follow-up groupings (<6 months, 6 months-2 years, and >2 years) demonstrated that the SM-Supp system performed better than SM system for both medium (AUROC = 0.71 vs 0.62; P = .003) and long (AUROC = 0.69 vs 0.58; P = .001) follow-up. Patients with SM-Supp grades ⩽6 had acceptably low surgical risks (0%-24%), with a significant increase in risk for grades >6 (39%-63%). CONCLUSION: This study validates the predictive accuracy of the SM-Supp system in a multicenter cohort. An SM-Supp grade of 6 is a cutoff or boundary for AVM operability. Supplemented grading is currently the best method of estimating neurological outcomes after AVM surgery, and we recommend it as a starting point in the evaluation of AVM operability.

Abstract BACKGROUND Ruptured wide-neck aneurysms (WNAs) are difficult to treat and few publications have compared clipping to coiling. OBJECTIVE To determine, using Barrow Ruptured Aneurysm Trial (BRAT) data: (1) How many aneurysms had a wide neck? (2) Did wide-neck status influence treatment? (3) How did clipping compare to coiling for WNAs? METHODS A post hoc analysis was conducted of saccular WNAs in the BRAT. A WNA was defined as maximum neck width ≥ 4 mm or maximum aneurysm dome-diameter–to–neck-width ratio < 2. Both intent-to-treat and as-treated analyses were performed. RESULTS Of the 327 patients analyzed, 177 (54.1%) had a WNA. WNAs were more likely to occur in older patients (P = .03) with worse presenting clinical grade (P = .02), were more likely to arise from the middle cerebral artery, basilar tip, or internal carotid artery other than the junction with the posterior communicating artery (P = .001) and were associated with worse clinical outcomes at all time points (P ≤ .01). WNAs were equally distributed in assigned treatment groups (clip 56.6% vs coil 51.8%; P = .38), but were overrepresented in the actual clipping group (clip 62.4% vs coil 37.6%, P < .001). Most patients (76.7%) in the coil-to-clip crossover group had a WNA. Comparing clipping to coiling, there was no difference in clinical outcomes at any time point in either analysis (P ≥ .33). The aneurysm obliteration rate was lower (P < .001) and the retreatment rate higher (P < .001) in the actual coiling group. CONCLUSION Wide-neck status significantly impacted treatment strategy in the BRAT, favoring clipping. Clipping and coiling of ruptured WNAs resulted in statistically similar long-term clinical outcomes. 10.1093/neuros/nyy439 Video Abstract 10.1093.neuros.nyy439 5850292551001

Abstract BACKGROUND The advent of the operating microscope (OM) revolutionized the field of neurosurgery. It allowed surgeons to operate on and effectively treat diseases previously inaccessible with conventional eyesight because of magnification and illumination. Improvements in the essential methods of visualization and the quality of the optics have plateaued. Another main limitation of the OM remains its ergonomics because of the need of the surgeon and assistant to directly interface with the OM objective. Recently, exoscopes have been introduced to overcome some shortcomings of the conventional OM. OBJECTIVE To subjectively review the individual authors experience with the current exoscope platforms in an attempt to provide a resource to the neurosurgeon when considering imaging options. METHODS Experts with previous use of each individual platform were contacted and asked to contribute their experiences. RESULTS In total, 4 systems are discussed. They include the VITOM (Karl Storz, Tuttlingen, Germany), the Olympus ORBEYE (Olympus, Tokyo, Japan), the Synaptive Modus V (Synaptive Medical, Toronto, Canada), and the Zeiss KINEVO (Carl Zeiss AG, Oberkochen, Germany). CONCLUSION The advent of exoscopes has the potential to begin to allow surgeons to move beyond solely the microscope for intraoperative visualization while improving upon its ergonomic disadvantages.

Abstract BACKGROUND Spetzler-Martin (SM) grade III arteriovenous malformations (AVMs) are at the boundary of safe operability, and preoperative embolization may reduce surgical risks. OBJECTIVE To evaluate the benefits of preoperative AVM embolization by comparing neurological outcomes in patients with grade III AVMs treated with or without preoperative embolization. METHODS All microsurgically treated grade III AVMs were identified from 2011 to 2018 at 2 medical centers. Neurological outcomes, measured as final modified Rankin Scale scores (mRS) and changes in mRS from preoperative baseline to last follow-up evaluation, were compared in patients with and without preoperative embolization. RESULTS Of the 102 patients with grade III AVMs who were treated microsurgically, 57 (56%) underwent preoperative embolization. Significant differences were found between the patients with and without embolization in AVM eloquence (74% vs 93%, P = .02), size ≥ 3 cm (47% vs 73%, P = .01), diffuseness (7% vs 22%, P = .04), and mean final mRS (1.1 vs 2.0, P = .005). Poor outcomes were more frequent in patients without embolization (38%) than with embolization (7%) (final mRS > 2; P < .001). Propensity-adjusted analysis revealed AVM resection without embolization was a risk factor for poor outcome (mRS score > 2; odds ratio, 4.2; 95% CI, 1.1-16; P = .03). CONCLUSION Nonembolization of SM grade III AVMs is associated with an increased risk of poor neurological outcomes after microsurgical resection. Preoperative embolization of intermediate-grade AVMs selected because of large AVM size, surgical inaccessibility of feeding arteries, and high flow should be employed more often than anticipated, even in the context of increasing microsurgical experience with AVMs.

In recent years, there has been a significant surge in discussions surrounding artificial intelligence (AI), along with a corresponding increase in its practical applications in various facets of everyday life, including the medical industry. Notably, even in the highly specialized realm of neurosurgery, AI has been utilized for differential diagnosis, pre-operative evaluation, and improving surgical precision. Many of these applications have begun to mitigate risks of intraoperative and postoperative complications and post-operative care. This article aims to present an overview of the principal published papers on the significant themes of tumor, spine, epilepsy, and vascular issues, wherein AI has been applied to assess its potential applications within neurosurgery. The method involved identifying high-cited seminal papers using PubMed and Google Scholar, conducting a comprehensive review of various study types, and summarizing machine learning applications to enhance understanding among clinicians for future utilization. Recent studies demonstrate that machine learning (ML) holds significant potential in neuro-oncological care, spine surgery, epilepsy management, and other neurosurgical applications. ML techniques have proven effective in tumor identification, surgical outcomes prediction, seizure outcome prediction, aneurysm prediction, and more, highlighting its broad impact and potential in improving patient management and outcomes in neurosurgery. This review will encompass the current state of research, as well as predictions for the future of AI within neurosurgery.

The anatomy of the perisylvian component of the superior longitudinal fasciculus (SLF) has recently been reviewed by numerous diffusion tensor imaging tractography (DTI) studies. However, little is known about the exact cortical terminations of this tract. The aim of the present work is to isolate the different subcomponents of this tract with fiber dissection and DTI tractography, and to identify the exact cortical connections. Twelve postmortem human hemispheres (6 right and 6 left) were dissected using the cortex-sparing fiber dissection. In addition, three healthy brains were analyzed using DTI-based tractography software. The different components of the perisylvian SLF were isolated and the fibers were followed until the cortical terminations. Three segments of the perisylvian SLF were identified: (1) anterior segment, connecting the supramarginal gyrus and superior temporal gyrus with the precentral gyrus, (2) posterior segment, connecting the posterior portion of the middle temporal gyrus with the angular gyrus, and (3) long segment of the arcuate fasciculus that connects the middle and inferior temporal gyri with the precentral gyrus and posterior portion of the inferior and middle frontal gyri. In the present study, three different components of the perisylvian SLF were identified. For the first time, our dissections revealed that each component was connected to a specific cortical area within the frontal, parietal and temporal lobes. By accurately depicting not only the trajectory but also cortical connections of this bundle, it is possible to develop new insights into the putative functional role of this tract.