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Aneurysmal subarachnoid hemorrhage is a devastating condition causing significant morbidity and mortality. While outcomes from subarachnoid hemorrhage have improved in recent years, there continues to be significant interest in identifying therapeutic targets for this disease. In particular, there has been a shift in emphasis toward secondary brain injury that develops in the first 72 hours after subarachnoid hemorrhage. This time period of interest is referred to as the early brain injury period and comprises processes including microcirculatory dysfunction, blood-brain-barrier breakdown, neuroinflammation, cerebral edema, oxidative cascades, and neuronal death. Advances in our understanding of the mechanisms defining the early brain injury period have been accompanied by improved imaging and nonimaging biomarkers for identifying early brain injury, leading to the recognition of an elevated clinical incidence of early brain injury compared with prior estimates. With the frequency, impact, and mechanisms of early brain injury better defined, there is a need to review the literature in this area to guide preclinical and clinical study.

Background: Inhalational anesthetics were associated with reduced incidence of angiographic vasospasm and delayed cerebral ischemia (DCI) in patients with aneurysmal subarachnoid hemorrhage (SAH). Whether intravenous anesthetics provide similar level of protection is not known. Methods: Anesthetic data were collected retrospectively for patients with SAH who received general anesthesia for aneurysm repair between January 1, 2014 and May 31, 2018, at 2 academic centers in the United States (one employing primarily inhalational and the other primarily intravenous anesthesia with propofol). We compared the outcomes of angiographic vasospasm, DCI, and neurological outcome (measured by disposition at hospital discharge), between the 2 sites, adjusting for potential confounders. Results: We compared 179 patients with SAH receiving inhalational anesthetics at one institution to 206 patients with SAH receiving intravenous anesthetics at the second institution. The rates of angiographic vasospasm between inhalational versus intravenous anesthetic groups were 32% versus 52% (odds ratio, 0.49 [CI, 0.32–0.75]; P =0.001) and DCI were 21% versus 40% (odds ratio, 0.47 [CI, 0.29–0.74]; P =0.001), adjusting for imbalances between sites/groups, Hunt-Hess and Fisher grades, type of aneurysm treatment, and American Society of Anesthesiology status. No impact of anesthetics on neurological outcome at time of discharge was noted with rates of good discharge outcome between inhalational versus intravenous anesthetic groups at (78% versus 72%, P =0.23). ConclusionS: Our data suggest that those who received inhalational versus intravenous anesthetic for ruptured aneurysm repair had significant protection against SAH-induced angiographic vasospasm and DCI. Although we cannot fully disentangle site-specific versus anesthetic effects in this comparative study, these results, when coupled with preclinical data demonstrating a similar protective effect of inhalational anesthetics on vasospasm and DCI, suggest that inhalational anesthetics may be preferable for patients with SAH undergoing aneurysm repair. Additional investigations examining the effect of inhalational anesthetics on other SAH outcomes such as early brain injury and long-term neurological outcomes are warranted.

Functional connectivity (FC) is a sensitive metric that provides a readout of whole cortex coordinate neural activity in a mouse model. We examine the impact of experimental SAH modeled through endovascular perforation, and the effectiveness of subsequent treatment on FC, through three key questions: 1) Does the endovascular perforation model of SAH induce deficits in FC; 2) Does exposure to hypoxic conditioning provide protection against these FC deficits and, if so, is this neurovascular protection SIRT1-mediated; and 3) does treatment with the SIRT1 activator resveratrol alone provide protection against these FC deficits? Cranial windows were adhered on skull-intact mice that were then subjected to either sham or SAH surgery and either left untreated or treated with hypoxic post-conditioning (with or without EX527) or resveratrol for 3 days. Mice were imaged 3 days post-SAH/sham surgery, temporally aligned with the onset of major SAH sequela in mice. Here we show that the endovascular perforation model of SAH induces global and network-specific deficits in FC by day 3, corresponding with the time frame of DCI in mice. Hypoxic conditioning provides SIRT1-mediated protection against these network-specific FC deficits post-SAH, as does treatment with resveratrol. Conditioning-based strategies provide multifaceted neurovascular protection in experimental SAH.

In the USA, around 30% of 795,000 strokes per year are due to proximal large-vessel occlusion, and these are a major cause of death and disability. We review the most recent advances regarding treatment of ischemic stroke amenable to mechanical thrombectomy.In the last four years, clinical trial evidence has expanded the time window for successful endovascular treatment to 24 h. Current research is aimed at expanding patient selection to mild strokes, large ischemic cores and occlusions of smaller, more distal blood vessels. Further, we have developed understanding of how to manage blood pressure after thrombectomy and even had promising results for a neuroprotective agent in these patients. Thrombectomy has transformed the treatment of ischemic stroke due to large-vessel occlusion. Recent research has focused on expanding patient candidacy for endovascular treatment and improving medical management to support better neurologic outcomes.

Many groups have reported lymphatic and glymphatic structures in animal and human brains, but tracer injection into the human brain to demonstrate real-time lymphatic drainage and mapping has not been described. We enrolled patients undergoing standard-of-care resection or stereotactic biopsy for suspected intracranial tumors. Patients received peritumoral injections of 99mTc-tilmanocept followed by planar or tomographic imaging. Fourteen patients with suspected brain tumors were enrolled. One was excluded from analysis because of tracer leakage during injection. There was no drainage of 99mTc-tilmanocept to regional lymph nodes in any of the patients. On average, after correcting for radioactive decay, 70.7% (95% CI: 59.9%, 81.6%) of the tracer in the injection site and 78.1% (95% CI: 71.1%, 85.1%) in the whole-head on the day of surgery remained the morning after, with variable radioactivity in the subarachnoid space. The retained fraction was much greater than expected based on the clearance rate from non-brain injection sites. In this pilot study, the lymphatic tracer 99mTc-tilmanocept was injected into the brain parenchyma, and there was no drainage outside the brain to the cervical lymph nodes. Our work demonstrates an inefficiency of drainage from peritumoral brain parenchyma and highlights a therapeutic opportunity to improve immunosurveillance of the brain.

OBJECTIVEIntraoperative MRI (iMRI) is used in the surgical treatment of glioblastoma, with uncertain effects on outcomes. The authors evaluated the impact of iMRI on extent of resection (EOR) and overall survival (OS) while controlling for other known and suspected predictors.METHODSA multicenter retrospective cohort of 640 adult patients with newly diagnosed supratentorial glioblastoma who underwent resection was evaluated. iMRI was performed in 332/640 cases (51.9%). Reviews of MRI features and tumor volumetric analysis were performed on a subsample of cases (n = 286; 110 non-iMRI, 176 iMRI) from a single institution.RESULTSThe median age was 60.0 years (mean 58.5 years, range 20.5–86.3 years). The median OS was 17.0 months (95% CI 15.6–18.4 months). Gross-total resection (GTR) was achieved in 403/640 cases (63.0%). Kaplan-Meier analysis of 286 cases with volumetric analysis for EOR (grouped into 100%, 95%–99%, 80%–94%, and 50%–79%) showed longer OS for 100% EOR compared to all other groups (p < 0.01). Additional resection after iMRI was performed in 104/122 cases (85.2%) with initial subtotal resection (STR), leading to a 6.3% mean increase in EOR and a 2.2-cm3 mean decrease in tumor volume. For iMRI cases with volumetric analysis, the GTR rate increased from 54/176 (30.7%) on iMRI to 126/176 (71.5%) postoperatively. The EOR was significantly higher in the iMRI group for intended GTR and STR groups (p = 0.02 and p < 0.01, respectively). Predictors of GTR on multivariate logistic regression included iMRI use and intended GTR. Predictors of shorter OS on multivariate Cox regression included older age, STR, isocitrate dehydrogenase 1 (IDH1) wild type, no O6-methylguanine DNA methyltransferase (MGMT) methylation, and no Stupp therapy. iMRI was a significant predictor of OS on univariate (HR 0.82, 95% CI 0.69–0.98; p = 0.03) but not multivariate analyses. Use of iMRI was not associated with an increased rate of new permanent neurological deficits.CONCLUSIONSGTR increased OS for patients with newly diagnosed glioblastoma after adjusting for other prognostic factors. iMRI increased EOR and GTR rate and was a significant predictor of GTR on multivariate analysis; however, iMRI was not an independent predictor of OS. Additional supporting evidence is needed to determine the clinical benefit of iMRI in the management of glioblastoma.

OBJECTIVEDelayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (SAH) is characterized by large-artery vasospasm, distal autoregulatory dysfunction, cortical spreading depression, and microvessel thrombi. Large-artery vasospasm has been identified as an independent predictor of poor outcome in numerous studies. Recently, several animal studies have identified a strong protective role for inhalational anesthetics against secondary brain injury after SAH including DCI—a phenomenon referred to as anesthetic conditioning. The aim of the present study was to assess the potential role of inhalational anesthetics against cerebral vasospasm and DCI in patients suffering from an SAH.METHODSAfter IRB approval, data were collected retrospectively for all SAH patients admitted to the authors’ hospital between January 1, 2010, and December 31, 2013, who received general anesthesia with either inhalational anesthetics only (sevoflurane or desflurane) or combined inhalational (sevoflurane or desflurane) and intravenous (propofol) anesthetics during aneurysm treatment. The primary outcomes were development of angiographic vasospasm and development of DCI during hospitalization. Univariate and logistic regression analyses were performed to identify independent predictors of these endpoints.RESULTSThe cohort included 157 SAH patients whose mean age was 56 ± 14 (± SD). An inhalational anesthetic–only technique was employed in 119 patients (76%), while a combination of inhalational and intravenous anesthetics was employed in 34 patients (22%). As expected, patients in the inhalational anesthetic–only group were exposed to significantly more inhalational agent than patients in the combination anesthetic group (p < 0.05). Multivariate logistic regression analysis identified inhalational anesthetic–only technique (OR 0.35, 95% CI 0.14–0.89), Hunt and Hess grade (OR 1.51, 95% CI 1.03–2.22), and diabetes (OR 0.19, 95% CI 0.06–0.55) as significant predictors of angiographic vasospasm. In contradistinction, the inhalational anesthetic–only technique had no significant impact on the incidence of DCI or functional outcome at discharge, though greater exposure to desflurane (as measured by end-tidal concentration) was associated with a lower incidence of DCI.CONCLUSIONSThese data represent the first evidence in humans that inhalational anesthetics may exert a conditioning protective effect against angiographic vasospasm in SAH patients. Future studies will be needed to determine whether optimized inhalational anesthetic paradigms produce definitive protection against angiographic vasospasm; whether they protect against other events leading to secondary brain injury after SAH, including microvascular thrombi, autoregulatory dysfunction, blood-brain barrier breakdown, neuroinflammation, and neuronal cell death; and, if so, whether this protection ultimately improves patient outcome.

Delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (SAH) has been associated with numerous pathophysiological sequelae, including large artery vasospasm and microvascular thrombosis. The focus of this review is to provide an overview of experimental animal model studies and human autopsy studies that explore the temporal-spatial characterization and mechanism of microvascular platelet aggregation and thrombosis following SAH, as well as to critically assess experimental studies and clinical trials highlighting preventative therapeutic options against this highly morbid pathophysiological process. Upon review of the literature, we discovered that microvascular platelet aggregation and thrombosis occur after experimental SAH across multiple species and SAH induction techniques in a similar time frame to other components of DCI, occurring in the cerebral cortex and hippocampus across both hemispheres. We discuss the relationship of these findings to human autopsy studies. In the final section of this review, we highlight the important therapeutic options for targeting microvascular platelet aggregation and thrombosis, and emphasize why therapeutic targeting of this neurovascular pathology may improve patient care. We encourage ongoing research into the pathophysiology of SAH and DCI, especially in regard to microvascular platelet aggregation and thrombosis and the translation to randomized clinical trials.

Background Many therapies designed to prevent delayed cerebral ischemia (DCI) and improve neurological outcome in aneurysmal subarachnoid hemorrhage (SAH) have failed, likely because of targeting only one element of what has proven to be a multifactorial disease. We previously demonstrated that initiating hypoxic conditioning before SAH (hypoxic preconditioning) provides powerful protection against DCI. Here, we expanded upon these findings to determine whether hypoxic conditioning delivered at clinically relevant time points after SAH (hypoxic postconditioning) provides similarly robust DCI protection. Methods and Results In this study, we found that hypoxic postconditioning (8% O 2 for 2 hours) initiated 3 hours after SAH provides strong protection against cerebral vasospasm, microvessel thrombi, and neurological deficits. By pharmacologic and genetic inhibition of SIRT1 (sirtuin 1) using EX527 and global Sirt1 −/− mice, respectively, we demonstrated that this multifaceted DCI protection is SIRT1 mediated. Moreover, genetic overexpression of SIRT1 using Sirt1‐Tg mice, mimicked the DCI protection afforded by hypoxic postconditioning. Finally, we found that post‐SAH administration of resveratrol attenuated cerebral vasospasm, microvessel thrombi, and neurological deficits, and did so in a SIRT1‐dependent fashion. Conclusions The present study indicates that hypoxic postconditioning provides powerful DCI protection when initiated at clinically relevant time points, and that pharmacologic augmentation of SIRT1 activity after SAH can mimic this beneficial effect. We conclude that conditioning‐based therapies administered after SAH hold translational promise for patients with SAH and warrant further investigation.

Tremendous advancements in the treatment of acute ischemic stroke in the last 25 years have been based on the principle of reperfusion in early time windows and identification of small core infarct for intravenous thrombolysis and mechanical thrombectomy. Advances in neuroimaging have made possible the safe treatment of patients with acute ischemic stroke in longer time windows and with more specific selection of patients with salvageable brain tissue. In this review, we discuss the history of endovascular stroke thrombectomy trials and highlight the neuroimaging-based trials that validated mechanical thrombectomy techniques in the extended time window with assessment of penumbral tissue. We conclude with a survey of currently open trials that seek to safely expand eligibility for this highly efficacious treatment.

Primary intraosseous meningiomas (PIMs) are an infrequent variant of meningiomas characterized by hyperostosis and brain compression. En bloc surgical resection of giant PIMs involving critical structures such as venous sinuses or cranial nerves could be associated with significant morbidity. The objective of this report is to demonstrate the safety and feasibility of piecemeal resection of PIMs involving the superior sagittal sinus and frontal sinus. A 54-year-old female with a large 5 cm thick bifrontal primary intra-osseous meningioma encasing the anterior segment of the superior sagittal sinus and frontal sinus underwent a bifrontal craniotomy with piecemeal microsurgical resection of the lesion, complete frontal sinus exoneration, and a synthetic cranioplasty. Clinical outcome was measured by extent of resection, preservation of cortical draining veins and postoperative course. A Simpson grade I resection of the lesion was achieved following piecemeal resection of the giant PIM without clinical or radiographic evidence of venous infarct or injury. The postoperative course was uncomplicated, and the patient was discharged home 3 days after cranioplasty. A complete resection of a giant bifrontal PIM with superior sagittal sinus encasement and frontal sinus involvement can be achieved safely via a piecemeal approach without significant intra-operative morbidity.

OBJECTIVE Brain arteriovenous malformations (AVMs) carry a risk of rupture and subsequent morbidity or mortality unless fully treated. AVMs in pediatric patients are known to occasionally recur after obliteration. The objective of this study was to characterize the risk of AVM recurrence following angiographically confirmed obliteration in children. METHODS Consecutive pediatric AVMs treated at a single center were identified from a prospective database. Patients with angiographically confirmed AVM obliteration following treatment were included in this study. Associations between AVM recurrence and patient or procedural factors were characterized using the two-tailed Fisher exact test or Mann-Whitney U-test. A literature search was conducted using PubMed, Scopus, Embase, and the Clarivate Web of Science with defined search criteria, and eligible studies were included alongside this study cohort in a meta-analysis. Rates of AVM recurrence following obliteration were pooled across studies with a random-effects model and reported with 95% confidence intervals (CIs). RESULTS Recurrence after angiographic confirmation of AVM obliteration was observed in 10.4% (7/67) of pediatric AVMs treated at the authors’ center. Patients with recurrent AVMs were significantly younger than those without recurrence (p = 0.002). In the meta-analysis, which included 1134 patients across 24 studies, the rate of recurrence was 4.8% (95% CI 3.0%–6.7%). The rate of AVM recurrence following radiosurgery was 0.7% (95% CI 0%–1.6%), which was significantly lower than the 8.5% rate (95% CI 5.0%–12.0%) following microsurgery. CONCLUSIONS Recurrence of obliterated brain AVMs is common in children. Recurrence is more common in young children and following microsurgery.

Cervical carotid and vertebral artery traumatic injuries can have a devastating natural history. This article reviews the epidemiology, mechanisms of injury, clinical presentation, and classification systems pertinent to consideration of endovascular treatment. The growing role of modern endovascular techniques for the treatment of these diseases is presented to equip endovascular surgeons with a framework for critically assessing patients presenting with traumatic cervical cerebrovascular injury.

Basilar tip aneurysm clipping is technically challenging because of the depth of operative corridor, rarity in presentation, and important perforators supplying deep, critical structures. Two major approaches to basilar tip aneurysms include (1) a frontotemporal (transorbital) trans-sylvian approach for most aneurysms and (2) a modified subtemporal approach for aneurysms with low-lying necks. A 53-yr-old woman presented to our institution with a large unruptured basilar tip aneurysm notable for a low, broad neck (6.4 mm). After discussion of risks and benefits of endovascular vs surgical options, the patient consented to operative intervention. She underwent a right frontotemporal craniotomy with zygomatic osteotomy, intradural petrous apicectomy, elective sectioning of the fourth cranial nerve (CN IV), and intracavernous removal of the dorsum sellae and posterior clinoid process to provide more space for aneurysm dissection. After temporary clipping of the basilar artery, the perforating arteries were dissected free from the aneurysm and the aneurysm occluded with 2 fenestrated clips. Important technical nuances of the approach include (1) achieving ample working room for temporary occlusion aneurysm dissection, (2) careful dissection of the perforators and contralateral P1, and (3) utilization of 2 fenestrated clips to accommodate and preserve the ipsilateral P1 segment. Postoperative angiogram showed complete aneur-ysmal occlusion. Postoperatively, the patient demonstrated mild cognitive impairment and a right CN IV palsy. At 6-wk follow-up, cognition recovered to normalcy. More recently, at 12-mo follow-up, the patient noted intermittent diplopia. Formal neuro-ophthalmologic assessment confirmed persistence of a CN IV palsy treated with prism lenses but no other neurological deficits.

Supplemental material, sj-pdf-1-jcb-10.1177_0271678X20921974 for Microvascular platelet aggregation and thrombosis after subarachnoid hemorrhage: A review and synthesis by Julian V Clarke, Julia M Suggs, Deepti Diwan, Jin V Lee, Kim Lipsey, Ananth K Vellimana and Gregory J Zipfel in Journal of Cerebral Blood Flow & Metabolism

Background Diagnostic workflows for glioblastoma (GBM) patients increasingly include DNA sequencing-based analysis of a single tumor site following biopsy or resection. We hypothesized that sequencing of multiple sectors within a given tumor would provide a more comprehensive representation of the molecular landscape and potentially inform therapeutic strategies. Methods Ten newly diagnosed, isocitrate dehydrogenase 1 (IDH1) wildtype GBM tumor samples were obtained from 2 (n = 9) or 4 (n = 1) spatially distinct tumor regions. Tumor and matched blood DNA samples underwent whole-exome sequencing. Results Across all 10 tumors, 51% of mutations were clonal and 3% were subclonal and shared in different sectors, whereas 46% of mutations were subclonal and private. Two of the 10 tumors exhibited a regional hypermutator state despite being treatment naive, and remarkably, the high mutational load was predominantly limited to one sector in each tumor. Among the canonical cancer-associated genes, only telomerase reverse transcriptase (TERT) promoter mutations were observed in the founding clone in all tumors. Reconstruction of the clonal architecture in different sectors revealed regionally divergent evolution, and integration of data from 2 sectors increased the resolution of inferred clonal architecture in a given tumor. Predicted therapeutic mutations differed in presence and frequency between tumor regions. Similarly, different sectors exhibited significant divergence in the predicted neoantigen landscape. Conclusions The substantial spatial heterogeneity observed in different GBM tumor sectors, especially in spatially restricted hypermutator cases, raises important caveats to our current dependence on single-sector molecular information to guide either targeted or immune-based treatments.

OBJECTIVECerebral mapping for surgical planning and operative guidance is a challenging task in neurosurgery. Pediatric patients are often poor candidates for many modern mapping techniques because of inability to cooperate due to their immature age, cognitive deficits, or other factors. Resting-state functional MRI (rs-fMRI) is uniquely suited to benefit pediatric patients because it is inherently noninvasive and does not require task performance or significant cooperation. Recent advances in the field have made mapping cerebral networks possible on an individual basis for use in clinical decision making. The authors present their initial experience translating rs-fMRI into clinical practice for surgical planning in pediatric patients.METHODSThe authors retrospectively reviewed cases in which the rs-fMRI analysis technique was used prior to craniotomy in pediatric patients undergoing surgery in their institution. Resting-state analysis was performed using a previously trained machine-learning algorithm for identification of resting-state networks on an individual basis. Network maps were uploaded to the clinical imaging and surgical navigation systems. Patient demographic and clinical characteristics, including need for sedation during imaging and use of task-based fMRI, were also recorded.RESULTSTwenty patients underwent rs-fMRI prior to craniotomy between December 2013 and June 2016. Their ages ranged from 1.9 to 18.4 years, and 12 were male. Five of the 20 patients also underwent task-based fMRI and one underwent awake craniotomy. Six patients required sedation to tolerate MRI acquisition, including resting-state sequences. Exemplar cases are presented including anatomical and resting-state functional imaging.CONCLUSIONSResting-state fMRI is a rapidly advancing field of study allowing for whole brain analysis by a noninvasive modality. It is applicable to a wide range of patients and effective even under general anesthesia. The nature of resting-state analysis precludes any need for task cooperation. These features make rs-fMRI an ideal technology for cerebral mapping in pediatric neurosurgical patients. This review of the use of rs-fMRI mapping in an initial pediatric case series demonstrates the feasibility of utilizing this technique in pediatric neurosurgical patients. The preliminary experience presented here is a first step in translating this technique to a broader clinical practice.

Objective Delayed cerebral ischemia (DCI) is an independent risk factor for poor outcome after aneurysmal subarachnoid hemorrhage (SAH) and is multifactorial in etiology. While prior studies have suggested a role for matrix metalloproteinase-9 (MMP-9) in early brain injury after SAH, its contribution to the pathophysiology of DCI is unclear. Methods In the first experiment, wild-type (WT) and MMP-9−/− mice were subjected to sham or endovascular perforation SAH surgery. In separate experiments, WT and MMP-9−/−mice were administered vehicle or minocycline either pre- or post-SAH. All mice underwent assessment of multiple components of DCI including vasospasm, neurobehavioral function, and microvessel thrombosis. In another experiment, rabbits were subjected to sham or cisterna magna injection SAH surgery, and administered vehicle or minocycline followed by vasospasm assessment. Results MMP-9 expression and activity was increased after SAH. Genetic (MMP-9−/− mice) and pharmacological (pre-SAH minocycline administration) inhibition of MMP-9 resulted in decreased vasospasm and neurobehavioral deficits. A therapeutically feasible strategy of post-SAH administration of minocycline resulted in attenuation of multiple components of DCI. Minocycline administration to MMP-9−/− mice did not yield additional protection. Consistent with experiments in mice, both pre- and post-SAH administration of minocycline attenuated SAH-induced vasospasm in rabbits. Interpretation MMP-9 is a key player in the pathogenesis of DCI. The consistent attenuation of multiple components of DCI with both pre- and post-SAH administration of minocycline across different species and experimental models of SAH, combined with the excellent safety profile of minocycline in humans suggest that a clinical trial in SAH patients is warranted.

Various techniques have been developed to study changes in the cerebral vasculature in numerous neuropathological processes including subarachnoid hemorrhage (SAH). One of the most widely employed techniques uses India ink-gelatin casting, which presents numerous challenges due to its high viscosity, rapid solidification, and its impact on immunohistochemical analysis. To overcome these limitations, we developed a novel technique for assessing cerebral vasospasm using cerebrovascular perfusion with ROX, SE (5-Carboxy-X-Rhodamine, Succinimidyl Ester), a fluorescent labeling dye. We found that ROX SE perfusion achieves excellent delineation of the cerebral vasculature, was qualitatively and quantitatively superior to India ink-gelatin casting for the assessment of cerebral vasospasm, permits outstanding immunohistochemical examination of non-vasospasm components of secondary brain injury, and is a more efficient and cost-effective experimental technique. ROX SE perfusion is therefore a novel and highly useful technique for studying cerebrovascular pathology following experimental SAH.

Corpus callosotomy is a palliative surgical procedure for patients with refractory epilepsy. It can be performed through an open approach via a standard craniotomy and the aid of an operating microscope, or alternatively via a mini-craniotomy with endoscope assistance. The extent of callosal disconnection performed varies according to indications and surgeon preference. In this article, we describe both open and endoscopic surgical techniques for anterior and complete corpus callosotomy.

OBJECTIVE Electrical status epilepticus of sleep (ESES) is a rare electrographic pattern associated with global regression, which is often poorly responsive to traditional epilepsy treatments and can have a devastating and permanent neurocognitive outcome. The authors analyzed clinical, electroencephalographic, and neuropsychological outcomes in 9 patients with refractory ESES treated with functional hemispherotomy to illustrate the wide clinical spectrum associated with the disease and explore the role of hemispherotomy in its treatment. METHODS During the period between 2003 and 2015, 80 patients underwent hemispherotomy at the authors' institution. Video electroencephalography (EEG) reports were reviewed for ESES or continuous spikes and waves during sleep (CSWS). Patients with preoperative ESES (> 85% slow-wave sleep occupied by spike waves), a unilateral structural lesion amenable to surgery, and more than 6 months of follow-up data were included in the analysis. Clinical data, EEG recordings, neuropsychological testing, and parental and clinician reports were retrospectively reviewed. RESULTS Nine patients were eligible for study inclusion. Age at seizure onset ranged from birth to 4.2 years (mean 1.9 years), age at ESES diagnosis ranged from 3.5 to 8.8 years (mean 6.0 years), and age at hemispherotomy ranged from 3.7 to 11.5 years (mean 6.8 years). All patients had drug-resistant epilepsy. The duration of epilepsy prior to hemispherotomy ranged from 2.7 to 8.9 years (mean ± SD, 5.0 ± 2.2 years). Engel Class I seizure outcome was observed in all 9 children, with a mean follow-up of 3.0 years (range 0.5–6.1 years). Hemispherotomy terminated ESES in 6 of 6 patients with available postoperative sleep EEG. All children had preoperative neuropsychological impairments. Developmental regression was halted postoperatively, but none of the children returned to their original pre-ESES baseline. Four children demonstrated academic gains, 2 of whom transitioned to mainstream classes. CONCLUSIONS Children with drug-resistant ESES and a unilateral structural lesion should be evaluated for hemispherotomy as they may experience the cessation of seizures, termination of ESES, and improvement in neuropsychological status.

Background and purpose Vasospasm and delayed cerebral ischemia (DCI) contribute significantly to the morbidity/mortality associated with aneurysmal subarachnoid hemorrhage (SAH). While considerable research effort has focused on preventing or reversing vasospasm, SAH-induced brain injury occurs in response to a multitude of concomitantly acting pathophysiologic mechanisms. In this regard, the pleiotropic epigenetic responses to conditioning-based therapeutics may provide an ideal SAH therapeutic strategy. We previously documented the ability of hypoxic preconditioning (PC) to attenuate vasospasm and neurological deficits after SAH, in a manner that depends on the activity of endothelial nitric oxide synthase. The present study was undertaken to elucidate whether the NAD-dependent protein deacetylase sirtuin isoform SIRT1 is an upstream mediator of hypoxic PC-induced protection, and to assess the efficacy of the SIRT1-activating polyphenol Resveratrol as a pharmacologic preconditioning therapy. Methods Wild-type C57BL/6J mice were utilized in the study and subjected to normoxia or hypoxic PC. Surgical procedures included induction of SAH via endovascular perforation or sham surgery. Multiple endpoints were assessed including cerebral vasospasm, neurobehavioral deficits, SIRT1 expression via quantitative real-time PCR for mRNA, and western blot for protein quantification. Pharmacological agents utilized in the study include EX-527 (SIRT1 inhibitor), and Resveratrol (SIRT1 activator). Results Hypoxic PC leads to rapid and sustained increase in cerebral SIRT1 mRNA and protein expression. SIRT1 inhibition blocks the protective effects of hypoxic PC on vasospasm and neurological deficits. Resveratrol pretreatment dose-dependently abrogates vasospasm and attenuates neurological deficits following SAH – beneficial effects that were similarly blocked by pharmacologic inhibition of SIRT1. Conclusion SIRT1 mediates hypoxic preconditioning-induced protection against neurovascular dysfunction after SAH. Resveratrol mimics this neurovascular protection, at least in part, via SIRT1. Activation of SIRT1 is a promising, novel, pleiotropic therapeutic strategy to combat DCI after SAH.

Background and importance Antiphospholipid syndrome (APS) is an autoimmune disorder associated with a hypercoagulable state and increased risk of intraoperative and postoperative thrombosis. Few neurosurgical studies have examined the management of these patients, though the standard of care in most other disciplines involves the use of anticoagulation therapy. However, this is associated with risks such as hemorrhage, thrombosis due to warfarin withdrawal, and is not compatible with operative intervention. Clinical presentation We report the cases of 2 antiphospholipid positive patients who were on anticoagulant therapy and underwent surgical bypasses and received perioperative management with plasmapheresis. The first was a 44-yr-old woman who presented with worsening vision, recurring headaches, and a known left internal carotid artery aneurysm that was unsuccessfully treated twice via extracranial to intracranial (ECIC) bypass at another institution. Preoperative tests at our institution revealed elevated beta 2 glycoprotein 1 IgA autoantibodies. The second case was a 24-yr-old woman with previously diagnosed APS, who presented for surgical evaluation of moyamoya disease after sustaining recurrent left hemispheric strokes. Both cases were managed with perioperative plasmapheresis to avoid the need for anticoagulation during the perioperative period, and both underwent successful ECIC bypass procedures without perioperative ischemic or hemorrhagic complications. Conclusion Management of neurosurgical patients with APS can be a precarious proposition. We describe the successful use of plasmapheresis and antiplatelet therapy to better manage patients undergoing neurosurgical procedures, specifically ECIC bypass, and feel this approach can be considered in future cases.

Functional magnetic resonance imaging (fMRI) is an important tool for pre-surgical evaluation of eloquent cortex. Classic task-based paradigms require patient participation and individual imaging sequence acquisitions for each functional domain that is being assessed. Resting state fMRI (rs-fMRI), however, enables functional localization without patient participation and can evaluate numerous functional domains with a single imaging session. To date, post-processing of this resting state data has been resource intensive, which limits its widespread application for routine clinical use. Through a novel automated algorithm and advanced imaging IT structure, we report the clinical application and the large-scale integration of rs-fMRI into routine neurosurgical practice. One hundred and ninety one consecutive patients underwent a 3T rs-fMRI, 83 of whom also underwent both motor and language task-based fMRI. Data were processed using a novel, automated, multi-layer perceptron algorithm and integrated into stereotactic navigation using a streamlined IT imaging pipeline. One hundred eighty-five studies were performed for intracranial neoplasm, 14 for refractory epilepsy and 33 for vascular malformations or other neurological disorders. Failure rate of rs-fMRI of 13% was significantly better than that for task-based fMRI (38.5%,) (p

BACKGROUND AND IMPORTANCE: Gamma Knife radiosurgery is an established technique for non-urgent treatment of various intracranial pathologies. Intra-procedural dislodgement of the stereotactic frame is an uncommon occurrence that could lead to abortion of ongoing treatment and necessitate more invasive treatment strategies. CLINICAL PRESENTATION: In this case report we describe a novel method for resumption of Gamma Knife treatment after an unplanned intra-procedural interruption. The case example involves a radiosurgical treatment of a Spetzler-Martin Grade I arteriovenous malformation. CONCLUSION: Our technique involves integration of scans and coordinate systems from two imaging sessions using the composite isodose line to resolve translational differences, thereby limiting delivery of remaining shots to the untreated region of the lesion. MRI follow-up at 13 months showed a reduction in the nidus size with no evidence of any radiation injury to the surrounding brain parenchyma. We believe this technique will allow care teams to effectively salvage interrupted gamma knife procedures and reduce progression to more invasive treatment options.

OBJECTIVEMany patients with medically intractable epilepsy have mesial temporal sclerosis (MTS), which significantly affects their quality of life. The surgical excision of MTS lesions can result in marked improvement or even complete resolution of the epileptic episodes. Reliable radiological diagnosis of MTS is a clinical challenge. The purpose of this study was to evaluate the utility of volumetric mapping of the hippocampi for the identification of MTS in a case-controlled series of pediatric patients who underwent resection for medically refractory epilepsy, using pathology as a gold standard.METHODSA cohort of 57 pediatric patients who underwent resection for medically intractable epilepsy between 2005 and 2015 was evaluated. On pathological investigation, this group included 24 patients with MTS and 33 patients with non-MTS findings. Retrospective quantitative volumetric measurements of the hippocampi were acquired for 37 of these 57 patients. Two neuroradiologists with more than 10 years of experience who were blinded to the patients' MTS status performed the retrospective review of MR images. To produce the volumetric data, MR scans were parcellated and segmented using the FreeSurfer software suite. Hippocampal regions of interest were compared against an age-weighted local regression curve generated with data from the pediatric normal cohort. Standard deviations and percentiles of specific subjects were calculated. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were determined for the original clinical read and the expert readers. Receiver operating characteristic curves were generated for the methods of classification to compare results from the readers with the authors' results, and an optimal threshold was determined. From that threshold the sensitivity, specificity, PPV, and NPV were calculated for the volumetric analysis.RESULTSWith the use of quantitative volumetry, a sensitivity of 72%, a specificity of 95%, a PPV of 93%, an NPV of 78%, and an area under the curve of 0.84 were obtained using a percentage difference of normalized hippocampal volume. The resulting specificity (95%) and PPV (93%) are superior to the original clinical read and to Reader A and Reader B's findings (range for specificity 74%–86% and for PPV 64%–71%). The sensitivity (72%) and NPV (78%) are comparable to Reader A's findings (73% and 81%, respectively) and are better than those of the original clinical read and of Reader B (sensitivity 45% and 63% and NPV 71% and 70%, respectively).CONCLUSIONSVolumetric measurement of the hippocampi outperforms expert readers in specificity and PPV, and it demonstrates comparable to superior sensitivity and NPV. Volumetric measurements can complement anatomical imaging for the identification of MTS, much like a computer-aided detection tool would. The implementation of this approach in the daily clinical workflow could significantly improve diagnostic accuracy.

Background and Purpose— We and others have shown that soluble amyloid β-peptide (Aβ) and cerebral amyloid angiopathy (CAA) cause significant cerebrovascular dysfunction in mutant amyloid precursor protein (APP) mice, and that these deficits are greater in aged APP mice having CAA compared with young APP mice lacking CAA. Amyloid β-peptide in young APP mice also increases infarction after focal cerebral ischemia, but the impact of CAA on ischemic brain injury is unknown. Methods— To determine this, we assessed cerebrovascular reactivity, cerebral blood flow (CBF), and extent of infarction and neurological deficits after transient middle cerebral artery occlusion in aged APP mice having extensive CAA versus young APP mice lacking CAA (and aged-matched littermate controls). Results— We found that aged APP mice have more severe cerebrovascular dysfunction that is CAA dependent, have greater CBF compromise during and immediately after middle cerebral artery occlusion, and develop larger infarctions after middle cerebral artery occlusion. Conclusions— These data indicate CAA induces a more severe form of cerebrovascular dysfunction than amyloid β-peptide alone, leading to intra- and postischemic CBF deficits that ultimately exacerbate cerebral infarction. Our results shed mechanistic light on human studies identifying CAA as an independent risk factor for ischemic brain injury.

BACKGROUND Carotid endarterectomy (CEA) for symptomatic carotid artery stenosis and intravenous tissue-type plasminogen activator (IV-tPA) for acute ischemic stroke are proven therapies; however, the safety of CEA in stroke patients who recently received IV-tPA has not been established. OBJECTIVE To evaluate the safety of CEA in stroke patients who recently received IV-tPA. METHODS A retrospective review of patients who underwent CEA for symptomatic carotid artery stenosis was performed. The primary end point was postoperative symptomatic intracerebral hemorrhage (sICH). A univariate analysis of potential risk factors for sICH, including IV-tPA therapy, timing of CEA, degree of stenosis, and stroke severity, was performed. Factors with a value of P < .1 on univariate analysis were tested further. RESULTS Among 142 patients, 3 suffered sICH after CEA: 2 of 11 patients treated with IV-tPA (18.2%) and 1 of 131 patients not treated with IV-tPA (0.8%). Both IV-tPA patients suffering sICH underwent CEA within 3 days of tPA administration. On univariate analysis, IV-tPA (P = .02), female sex (P = .09), shorter time between ischemic event and CEA (P = .06), and lower mean arterial pressure during the first 48 hours of admission (P = .08) were identified as risk factors for sICH. On multivariate analysis, IV-tPA was the only significant risk factor (P = .002 by stepwise logistic regression; P = .03 by nominal logistic regression). CONCLUSION This study indicates that IV-tPA is an independent risk factor for sICH after CEA. This suggests that CEA should be pursued cautiously in patients who recently received IV-tPA. Early surgery may be associated with an increased risk for sICH. ABBREVIATIONS CEA, carotid endarterectomyIV-tPA, intravenous recombinant tissue-type plasminogen activatorMAP, mean arterial pressureNASCET, North American Symptomatic Carotid Endarterectomy TrialNIHSS, National Institutes of Health Stroke ScaleNINDS, National Institute of Neurological Disorders and StrokesICH, symptomatic intracerebral hemorrhageTIA, transient ischemic attack.

Object The aim of this study was to define the optimal treatment for patients with symptomatic intraluminal carotid artery thrombus (ICAT). Methods The authors performed a retrospective chart review of patients who had presented with symptomatic ICAT at their institution between 2001 and 2011. Results Twenty-four patients (16 males and 8 females) with ICAT presented with ischemic stroke (18 patients) or transient ischemic attack ([TIA], 6 patients). All were initially treated using anticoagulation with or without antiplatelet drugs. Eight of these patients had no or only mild carotid artery stenosis on initial angiography and were treated with medical management alone. The remaining 16 patients had moderate or severe carotid stenosis on initial angiography; of these, 10 underwent delayed revascularization (8 patients, carotid endarterectomy [CEA]; 2 patients, angioplasty and stenting), 2 refused revascularization, and 4 were treated with medical therapy alone. One patient had multiple TIAs despite medical therapy and eventually underwent CEA; the remaining 23 patients had no TIAs after treatment. No patient suffered ischemic or hemorrhagic stroke while on anticoagulation therapy, either during the perioperative period or in the long-term follow-up; 1 patient died of an unrelated condition. The mean follow-up was 16.4 months. Conclusions Results of this study suggest that initial anticoagulation for symptomatic ICAT leads to a low rate of recurrent ischemic events and that carotid revascularization, if indicated, can be safely performed in a delayed manner.

Background Cerebral vasospasm is an independent predictor of poor outcome after subarachnoid hemorrhage (SAH). The nitric oxide-cyclic guanosine monophosphate (NO-cGMP) vasodilatory pathway is strongly implicated in its pathophysiology. Preliminary studies suggest that phosphodiesterase 5 (PDE5), an enzyme that degrades cGMP, may play a role because the PDE5 inhibitor sildenafil was found to reduce vasospasm after SAH. However, several questions that are critical when considering translational studies remain unanswered. Objective To elucidate the mechanism of action of sildenafil against vasospasm and to assess whether sildenafil attenuates SAH-induced neuronal cell death, improves functional outcome after SAH, or causes significant physiological side effects when administered at therapeutically relevant doses. Methods SAH was induced via endovascular perforation in male C57BL6 mice. Beginning 2 hours later, mice received sildenafil citrate (0.7, 2 or 5 mg/kg orally twice daily) or vehicle. Neurological outcome was assessed daily. Vasospasm was determined on post-SAH day 3. Brain PDE5 expression and activity, cGMP content, neuronal cell death, arterial blood pressure, and intracranial pressure were examined. Results We found that PDE5 activity (but not expression) is increased after SAH, leading to decreased cGMP levels. Sildenafil attenuates this increase in PDE5 activity and restores cGMP levels after SAH. Post-SAH initiation of sildenafil was found to decrease vasospasm and neuronal cell death and markedly improve neurological outcome without causing significant physiological side effects. Conclusion Sildenafil, a US Food and Drug Administration-approved drug with a proven track record of safety in humans, is a promising new therapy for vasospasm and neurological deficits after SAH.

Rapamycin, an anti-proliferative agent, is effective in the treatment of renal cell carcinoma and recurrent breast cancers. We proposed that this potent mammalian target of rapamycin inhibitor may be useful for the treatment of gliomas as well. We examined the cytotoxicity of rapamycin against a rodent glioma cell line, determined the toxicity of rapamycin when delivered intracranially, and investigated the efficacy of local delivery of rapamycin for the treatment of experimental malignant glioma in vivo. We also examined the dose-dependent efficacy of rapamycin and the effect when locally delivered rapamycin was combined with radiation therapy. Rapamycin was cytotoxic to 9L cells, causing 34% growth inhibition at a concentration of 0.01 µg/mL. No in vivo toxicity was observed when rapamycin was incorporated into biodegradable caprolactone-glycolide (35:65) polymer beads at 0.3%, 3%, and 30% loading doses and implanted intracranially. Three separate efficacy studies were performed to test the reproducibility of the effect of the rapamycin beads as well as the validity of this treatment approach. Animals treated with the highest dose of rapamycin beads tested (30%) consistently demonstrated significantly longer survival durations than the control and placebo groups. All dose-escalating rapamycin bead treatment groups (0.3%, 3% and 30%), treated both concurrently with tumor and in a delayed manner after tumor placement, experienced a significant increase in survival, compared with controls. Radiation therapy in addition to the simultaneous treatment with 30% rapamycin beads led to significantly longer survival duration than either therapy alone. These results suggest that the local delivery of rapamycin for the treatment of gliomas should be further investigated.

Object Stabilization of the cervical spine can be challenging when instrumentation involves the axis. Fixation with C1–2 transarticular screws combined with posterior wiring and bone graft placement has yielded excellent fusion rates, but the technique is technically demanding and places the vertebral arteries (VAs) at risk. Placement of screws in the pars interarticularis of C-2 as described by Harms and Melcher has allowed rigid fixation with greater ease and theoretically decreases the risk to the VA. However, fluoroscopy is suggested to avoid penetration laterally, medially, and superiorly to avoid damage to the VA, spinal cord, and C1–2 joint, respectively. The authors describe how, after meticulous dissection of the C-2 pars interarticularis, such screws can be placed accurately and safely without the use of fluoroscopy. Methods Prospective follow-up was performed in 55 consecutive patients who underwent instrumented fusion of C-2 by a single surgeon. The causes of spinal instability and type and extent of instrumentation were documented. All patients underwent preoperative CT or MR imaging scans to determine the suitability of C-2 screw placement. Intraoperatively, screws were placed following dissection of the posterior pars interarticularis. Postoperative CT scans were performed to determine the extent of cortical breach. Patients underwent clinical follow-up, and complications were recorded as vascular or neurological. A CT-based grading system was created to characterize such breaches objectively by location and magnitude via percentage of screw diameter beyond the cortical edge (0 = none; I = < 25% of screw diameter; II = 26–50%; III = 51–75%; IV = 76–100%). Results One-hundred consecutive screws were placed in the pedicle of the axis by a single surgeon using external landmarks only. In 10 cases, only 1 screw was placed because of a preexisting VA anatomy or bone abnormality noted preoperatively. In no case was screw placement aborted because of complications noted during drilling. Early complications occurred in 2 patients and were limited to 1 wound infection and 1 transient C-2 radiculopathy. There were 15 total breaches (15%), 2 of which occurred in the same patient. Twelve breaches were lateral (80%), and 3 were superior (20%). There were no medial breaches. The magnitude of the breach was classified as I in 10 cases (66.7% of breaches), II in 3 cases (20% of breaches), III in 1 case (6.7%), and IV in 1 case (6.7%). Conclusions Free-hand placement of screws in the C-2 pedicle can be done safely and effectively without the use of intraoperative fluoroscopy or navigation when the pars interarticularis/pedicle is assessed preoperatively with CT or MR imaging and found to be suitable for screw placement. When breaches do occur, they are overwhelmingly lateral in location, breach < 50% of the screw diameter, and in the authors' experience, are not clinically significant.

Background Heat has been used to control bleeding for thousands of years. In the 1920s, this concept was applied to the development of electrosurgical instruments and was used to control hemorrhage during surgical procedures. In the time that has passed since its first use, electrosurgery has evolved into modern-day bipolar technology, involving a diverse group of coagulation instruments. Methods We review the evolution and advances in electrosurgery, specifically bipolar coagulation, and the current technologies available for intraoperative hemorrhage control. Results Electrosurgery has evolved to include highly accurate devices that deliver thermal energy via nonstick and noncontact methods. Over time, the operative range of coagulation instruments has increased dramatically with the incorporation of irrigating pathways, a wide range of instrument tips to perform various functions, and the application of bipolar technology to microforceps and microscissors for minimally invasive procedures. Conclusion Electrosurgical devices and techniques, especially bipolar coagulation, have developed significantly with the availability of new technologies. This has led to better intraoperative coagulation control while minimizing iatrogenic damage associated with heat spread and tissue adherence, thus potentially improving outcomes for neurosurgical procedures.

Object Laminar fixation of the axis with crossing bilateral screws has been shown to provide rigid fixation with a theoretically decreased risk of vertebral artery damage compared with C1–2 transarticular screw fixation and C-2 pedicle screw fixation. Some studies, however, have shown restricted rigidity of such screws compared with C-2 pedicle screws, and others note that anatomical variability exists within the posterior elements of the axis that may have an impact on successful placement. To elucidate the clinical impact of such screws, the authors report their experience in placing C-2 laminar screws in adult patients over a 2-year period, with emphasis on clinical outcome and technical placement. Methods Sixteen adult patients with cervical instability underwent posterior cervical and cervicothoracic fusion procedures at our institution with constructs involving C-2 laminar screws. Eleven patients were men and 5 were women, and they ranged in age from 28 to 84 years (mean 57 years). The reasons for fusion were degenerative disease (9 patients) and treatment of trauma (7 patients). In 14 patients (87.5%) standard translaminar screws were placed, and in 2 (12.5%) an ipsilateral trajectory was used. All patients underwent preoperative radiological evaluation of the cervical spine, including computed tomography scanning with multiplanar reconstruction to assess the posterior anatomy of C-2. Anatomical restrictions for placement of standard translaminar screws included a deeply furrowed spinous process and/or an underdeveloped midline posterior ring of the axis. In these cases, screws were placed into the corresponding lamina from the ipsilateral side, allowing bilateral screws to be oriented in a more parallel, as opposed to perpendicular, plane. All patients were followed for > 2 years to record rates of fusion, instrumentation failure, and other complications. Results Thirty-two screws were placed without neurological or vascular complications. The mean follow-up duration was 27.3 months. Complications included 2 revisions, one for pseudarthrosis and the other for screw pullout, and 3 postoperative infections. Conclusions Placement of laminar screws into the axis from the standard crossing approach or via an ipsilateral trajectory may allow a safe, effective, and durable means of including the axis in posterior cervical and cervicothoracic fusion procedures.

OBJECT Studies show that phosphodiesterase-V (PDE-V) inhibition reduces cerebral vasospasm (CVS) and improves outcomes after experimental subarachnoid hemorrhage (SAH). This study was performed to investigate the safety and effect of sildenafil (an FDA-approved PDE-V inhibitor) on angiographic CVS in SAH patients. METHODS A2-phase, prospective, nonrandomized, human trial was implemented. Subarachnoid hemorrhage patients underwent angiography on Day 7 to assess for CVS. Those with CVS were given 10 mg of intravenous sildenafil in the first phase of the study and 30 mg in the second phase. In both, angiography was repeated 30 minutes after infusion. Safety was assessed by monitoring neurological examination findings and vital signs and for the development of adverse reactions. For angiographic assessment, in a blinded fashion, pre- and post-sildenafil images were graded as “improvement” or “no improvement” in CVS. Unblinded measurements were made between pre- and post-sildenafil angiograms. RESULTS Twelve patients received sildenafil; 5 patients received 10 mg and 7 received 30 mg. There were no adverse reactions. There was no adverse effect on heart rate or intracranial pressure. Sildenafil resulted in a transient decline in mean arterial pressure, an average of 17% with a return to baseline in an average of 18 minutes. Eight patients (67%) were found to have a positive angiographic response to sildenafil, 3 (60%) in the low-dose group and 5 (71%) in the high-dose group. The largest degree of vessel dilation was an average of 0.8 mm (range 0–2.1 mm). This corresponded to an average percentage increase in vessel diameter of 62% (range 0%–200%). CONCLUSIONS The results from this Phase I safety and proof-of-concept trial assessing the use of intravenous sildenafil in patients with CVS show that sildenafil is safe and well tolerated in the setting of SAH. Furthermore, the angiographic data suggest that sildenafil has a positive impact on human CVS.

Cerebral amyloid angiopathy (CAA) is characterized by deposition of amyloid β peptide (Aβ) within walls of cerebral arteries and is an important cause of intracerebral hemorrhage, ischemic stroke, and cognitive dysfunction in elderly patients with and without Alzheimer's Disease (AD). NADPH oxidase-derived oxidative stress plays a key role in soluble Aβ-induced vessel dysfunction, but the mechanisms by which insoluble Aβ in the form of CAA causes cerebrovascular (CV) dysfunction are not clear. Here, we demonstrate evidence that reactive oxygen species (ROS) and, in particular, NADPH oxidase-derived ROS are a key mediator of CAA-induced CV deficits. First, the NADPH oxidase inhibitor, apocynin, and the nonspecific ROS scavenger, tempol, are shown to reduce oxidative stress and improve CV reactivity in aged Tg2576 mice. Second, the observed improvement in CV function is attributed both to a reduction in CAA formation and a decrease in CAA-induced vasomotor impairment. Third, anti-ROS therapy attenuates CAA-related microhemorrhage. A potential mechanism by which ROS contribute to CAA pathogenesis is also identified because apocynin substantially reduces expression levels of ApoE-a factor known to promote CAA formation. In total, these data indicate that ROS are a key contributor to CAA formation, CAA-induced vessel dysfunction, and CAA-related microhemorrhage. Thus, ROS and, in particular, NADPH oxidase-derived ROS are a promising therapeutic target for patients with CAA and AD.

Diagnostic workflows for GBM patients increasingly include DNA sequencing-based analysis of a single tumor site following tumor biopsy or resection. Recent studies have highlighted the significant intratumoral heterogeneity of both treatment naïve and recurrent tumors in glioblastoma. We hypothesized that sequencing of multiple sectors within a given tumor would provide a more comprehensive representation of the molecular landscape than data from a single site and inform therapeutic strategies. We show that across 10 tumors subjected to whole-exome sequencing of multiple tumor sectors, 54% of mutations were shared between sectors (51% clonal and 3% subclonal), while 46% were subclonal and private. Among the canonical GBM-associated genes, only TERT promoter mutations were observed in the founding clone in all tumor sectors across all cases. Despite being treatment naïve, two of the 10 tumors exhibited a hypermutator state, which has been shown to predict response to immune checkpoint inhibitor therapy. Critically, the high mutational load was predominantly limited to one sector in both cases. Analysis of clonal architecture, inferred from variant allele frequencies of single nucleotide variants in copy-number neutral regions, demonstrated significant differences between sectors in 8 of 10 cases, suggesting regionally divergent evolution. Predicted therapeutically relevant mutations, based on exploratory analysis of the Drug Gene Interaction database (DGIdb), differed in presence and frequency between tumor sectors, with 74% of mutations across all tumors being private to one region. 80% of tumors had at least one private therapeutically relevant mutation. Similarly, different sectors exhibited significant divergence in the predicted neoantigen landscape, based on the pVAC-seq pipeline, with all 10 tumors harboring private neoantigens. Overall, 55% of predicted neoantigens were subclonal and private. These results suggest that multi-site analyses may be necessary to thoroughly characterize individual GBM tumors and precisely guide personalization of molecular and immune-based therapies.

Dural arteriovenous fistulas (dAVFs) are usually idiopathic lesions. While individual case reports have documented the occurrence of dAVFs in conjunction with benign meningeal tumors, a detailed characterization of this association is lacking. The objective of this study was to critically examine the relationship between benign meningeal tumors and dAVFs.We performed a retrospective review of records at two institutions, identified patients with coexisting benign meningeal tumors and dAVFs at the time of clinical presentation, and examined various clinical, anatomical and radiographic characteristics.Ten patients (4.6%) had coexisting benign meningeal tumors and dAVFs. The most common tumor was meningioma (90%). Nine patients were symptomatic: five from tumor, three from dAVF, and one from both tumor and dAVF. All dAVFs were related to the meningeal tumor.Benign meningeal tumors may be associated with dAVFs that are either in direct anatomical relation to the tumor or in distant anatomical locations. The increased propensity for development of dAVFs in patients with benign meningeal tumors may be due to multiple factors. Due to this association, additional imaging to exclude dAVFs could be considered in patients with meningeal tumors if exuberant vessels or flow voids are identified on routinely obtained magnetic resonance imaging scans.