A taxonomy for cerebellar cavernous malformations: subtypes of cerebellar lesions.

OBJECTIVE: An anatomical taxonomy has been established to guide surgical approach selection for resecting brainstem and deep and superficial cerebral cavernous malformations (CMs). The authors propose a novel taxonomy for cerebellar CMs, introduce 6 distinct neuroanatomical subtypes, and assess their clinical outcomes. METHODS: This bi-institutional, 2-surgeon cohort study included 143 cerebellar CMs that were microsurgically treated over a 25-year period. The proposed taxonomy classifies cerebellar CMs into 6 subtypes on the basis of anatomical location as identified on preoperative MR imaging. Neurological outcomes were assessed using the modified Rankin Scale (mRS), and outcomes were compared among the subtypes, with favorable outcomes defined as mRS scores ≤ 2. RESULTS: A total of 143 cerebellar CMs were resected in 140 patients. The mean (SD) age was 42.3 (15.2) years; 86 (60%) of the cerebellar CMs were in women, and 57 (40%) were in men. Cerebellar subtypes were suboccipital (17%, 25/143); tentorial (9%, 13/143); petrosal (43%, 62/143); vermian (13%, 18/143); tonsillar (2%, 3/143); and deep nuclear (15%, 22/143). Overall, 78 of 143 (55%) cerebellar CMs presenting to a cerebellar surface were resected without tissue transgression, and the remaining CMs (65/143, 45%) required translobular or transsulcal approaches. Complete resection was achieved in 134 of 143 cases (94%). Favorable outcomes were achieved in 91% (129/141) of cases with follow-up at a mean (SD) follow-up duration of 37.4 (53.8) months. Relative outcomes were unchanged or improved relative to the preoperative baseline in 93% (131/141) of cases with follow-up, without differences between subtypes. CONCLUSIONS: Most cerebellar CMs are convexity lesions that do not require deep dissection. However, transsulcal and fissural approaches are used for those beneath the cerebellar surface to minimize tissue transgression and preserve associated function. Complete resection without any new deficit is accomplished in most patients. The proposed taxonomy for cerebellar CMs (suboccipital, tentorial, petrosal, vermian, tonsillar, and deep nuclear) guides the selection of craniotomy and approach to enhance patient safety and optimize neurological outcomes.

Predictors of Neurological Outcomes in Patients with Poor Glasgow Coma Scale Scores 1 Week After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: This study assessed neurological outcomes and variables associated with favorable outcomes in aneurysmal subarachnoid hemorrhage patients with low functional status (Glasgow Coma Scale [GCS] score ≤8) on postbleed day 7 (PBD7). METHODS: A retrospective analysis was conducted of all patients in the Barrow Ruptured Aneurysm Trial (January 1, 2014-July 31, 2019) treated for a ruptured aneurysm and who had a GCS score ≤8 on PBD7. The primary outcome was a favorable neurological outcome (modified Rankin Scale score ≤2) at last follow-up. RESULTS: Of 312 patients, 63 had low GCS scores at PBD7. These patients had a significantly greater proportion of poor Hunt and Hess scale grades (≥4) (44/63 [70%] vs. 49/249 [19.7%], P < 0.001) and poor Fisher grades (grade = 4) (58/63 [92%] vs. 174/249 [69.9%], P < 0.001) compared to patients who did not have low GCS scores on PBD7, but no differences were found in age, sex, anterior location, aneurysm size, or type of treatment. Of the 63 patients, 7 (11%) experienced a favorable neurological outcome. On univariate analysis, none of the physical examination reflexes predicted a favorable neurological outcome. The middle cerebral artery aneurysm territory was the only significant predictor of a favorable neurological outcome by multivariate analysis (odds ratio, 10.8; 95% confidence interval, 1.16-100], P = 0.04). CONCLUSIONS: This study yielded no significant physical examination findings that predict a favorable outcome in patients with a GCS score ≤8 on PBD7. This finding may inform the decision of whether to prolong hospital management or arrange for end-of-life care.

A single-cell atlas deconstructs heterogeneity across multiple models in murine traumatic brain injury and identifies novel cell-specific targets.

Traumatic brain injury (TBI) heterogeneity remains a critical barrier to translating therapies. Identifying final common pathways/molecular signatures that integrate this heterogeneity informs biomarker and therapeutic-target development. We present the first large-scale murine single-cell atlas of the transcriptomic response to TBI (334,376 cells) across clinically relevant models, sex, brain region, and time as a foundational step in molecularly deconstructing TBI heterogeneity. Results were unique to cell populations, injury models, sex, brain regions, and time, highlighting the importance of cell-level resolution. We identify cell-specific targets and previously unrecognized roles for microglial and ependymal subtypes. Ependymal-4 was a hub of neuroinflammatory signaling. A distinct microglial lineage shared features with disease-associated microglia at 24 h, with persistent gene-expression changes in microglia-4 even 6 months after contusional TBI, contrasting all other cell types that mostly returned to naive levels. Regional and sexual dimorphism were noted. CEREBRI, our searchable atlas (https://shiny.crc.pitt.edu/cerebri/), identifies previously unrecognized cell subtypes/molecular targets and is a leverageable platform for future efforts in TBI and other diseases with overlapping pathophysiology.

Arteriovenous malformations in the cerebellopontine angle: assessment of the "backdoor resection" technique and microsurgical results in 38 patients.

OBJECTIVE: Posterior fossa arteriovenous malformations (AVMs) represent 7% to 15% of all intracranial AVMs and are associated with an increased risk of hemorrhage, morbidity, and mortality compared with supratentorial AVMs, thus prompting urgent and definitive treatment. Cerebellopontine angle (CPA) AVMs are a unique group of posterior fossa AVMs incorporating characteristics of brainstem and cerebellar lesions, which are particularly amenable to microsurgical resection. This study reports the clinical, radiological, operative, and outcome features of patients with CPA AVMs in a large cohort. METHODS: The authors conducted a single-surgeon, 2-institution retrospective cohort study of all consecutive patients with CPA AVMs treated with microsurgical resection during a 25-year period. RESULTS: CPA AVMs represented 22% (38 of 176) of all infratentorial AVMs resected by the senior author. Overall, 38 patients (22 [58%] male and 16 [42%] female) met the study inclusion criteria and were analyzed. Most patients presented with hemorrhage (n = 29, 76%). The median age at surgery was 56 (range 6-82) years. Subtypes included 22 (58%) petrosal cerebellar AVMs, 11 (29%) lateral pontine AVMs, and 5 (13%) AVMs involving both the brainstem and cerebellum. Most AVM niduses were small (< 3 cm; n = 35, 92%) and compact (n = 31, 82%). Fourteen (37%) patients harbored flow-related aneurysms. Twenty (53%) patients underwent preoperative embolization. Complete angiographic obliteration was achieved with microsurgery in 35 (92%) patients. Five (13%) patients with poor neurological conditions at presentation died before hospital discharge. Of the 7 (18%) patients with new postoperative neurological deficits, 5 had transient deficits. The median (interquartile range) follow-up was 1.7 (0.5-3.2) years; 32 (84%) patients were alive at last follow-up, and 30 (79%) had achieved a favorable neurological outcome (modified Rankin Scale [mRS] score 0-2). The only independent predictor of unfavorable postoperative outcome (mRS score 3-6) was the preoperative mRS score (p = 0.002). CONCLUSIONS: CPA AVMs are unique posterior fossa lesions, including petrosal cerebellar and lateral pontine AVMs. The "backdoor resection" technique provides a safe and efficient strategy with high obliteration rates and a low risk of treatment-related morbidity. Microsurgical resection should be considered the frontline treatment for most CPA AVMs, except for those with a significant diffuse brainstem component.

Transcirculation retrograde placement of a Pipeline embolization device for treatment of a vertebrobasilar junction aneurysm.

Transcirculation catheterization, also known as the retrograde approach, involves the navigation of a catheter or other endovascular device from one arterial circulation to the other (right to left, or anterior to posterior).1-4 We present a case of a complex vertebrobasilar junction aneurysm previously treated by bilateral vertebral artery deconstruction, precluding antegrade access (video 1). Following the creation of a protective occipital artery to posterior inferior cerebellar artery (PICA) bypass, the patient was treated with transcirculation placement of a Pipeline embolization device (PED).5-9 The right internal carotid artery was accessed with a guide catheter using a transradial approach. The microwire-microcatheter combination was then tracked through the right posterior communicating artery, down the basilar trunk, and to the left PICA. The PED was successfully deployed from the left vertebral artery to the mid-basilar artery. At 3-month follow-up, the aneurysm was completely obliterated. The nuances of transcirculation technique, especially for flow diversion, are discussed. (Used with permission from Barrow Neurological Institute, Phoenix, Arizona, USA.)neurintsurg;jnis-2023-021363v1/V1F1V1Video 1Transcirculation retrograde placement of a Pipeline embolization device for treatment of a vertebrobasilar junction aneurysm previously treated by bilateral vertebral artery deconstruction, precluding antegrade access.

Assessing the Relationship between Surgical Timing and Postoperative Seizure Outcomes in Cavernoma-Related Epilepsy: A Single-Institution Retrospective Analysis of 63 Patients with a Review of the Literature.

Background: Patients with supratentorial cavernous malformations (SCMs) commonly present with seizures. First-line treatments for cavernoma-related epilepsy (CRE) include conservative management (antiepileptic drugs (AEDs)) and surgery. We compared seizure outcomes of CRE patients after early (≤6 months) vs. delayed (>6 months) surgery. Methods: We compared outcomes of CRE patients with SCMs surgically treated at our large-volume cerebrovascular center (1 January 2010-31 July 2020). Patients with 1 sporadic SCM and ≥1-year follow-up were included. Primary outcomes were International League Against Epilepsy (ILAE) class 1 seizure freedom and AED independence. Results: Of 63 CRE patients (26 women, 37 men; mean ± SD age, 36.1 ± 14.6 years), 48 (76%) vs. 15 (24%) underwent early (mean ± SD, 2.1 ± 1.7 months) vs. delayed (mean ± SD, 6.2 ± 7.1 years) surgery. Most (32 (67%)) with early surgery presented after 1 seizure; all with delayed surgery had ≥2 seizures. Seven (47%) with delayed surgery had drug-resistant epilepsy. At follow-up (mean ± SD, 5.4 ± 3.3 years), CRE patients with early surgery were more likely to have ILAE class 1 seizure freedom and AED independence than those with delayed surgery (92% (44/48) vs. 53% (8/15), p = 0.002; and 65% (31/48) vs. 33% (5/15), p = 0.03, respectively). Conclusions: Early CRE surgery demonstrated better seizure outcomes than delayed surgery. Multicenter prospective studies are needed to validate these findings.

Strategies to Improve Drug Delivery Across the Blood-Brain Barrier for Glioblastoma.

PURPOSE OF REVIEW: Glioblastoma remains resistant to most conventional treatments. Despite scientific advances in the past three decades, there has been a dearth of effective new treatments. New approaches to drug delivery and clinical trial design are needed. RECENT FINDINGS: We discuss how the blood-brain barrier and tumor microenvironment pose challenges for development of effective therapies for glioblastoma. Next, we discuss treatments in development that aim to overcome these barriers, including novel drug designs such as nanoparticles and antibody-drug conjugates, novel methods of drug delivery, including convection-enhanced and intra-arterial delivery, and novel methods to enhance drug penetration, such as blood-brain barrier disruption by focused ultrasound and laser interstitial thermal therapy. Lastly, we address future opportunities, positing combination therapy as the best strategy for effective treatment, neoadjuvant and window-of-opportunity approaches to simultaneously enhance therapeutic effectiveness with interrogation of on-treatment biologic endpoints, and adaptive platform and basket trials as imperative for future trial design. New approaches to GBM treatment should account for the blood-brain barrier and immunosuppression by improving drug delivery, combining treatments, and integrating novel clinical trial designs.

Arteriovenous shunts of the cervical spine: patient demographics, presentation, patterns of high-risk venous drainage, and updated classification.

BACKGROUND: Intracranial dural arteriovenous (AV) fistula classifications focus on presence/absence of retrograde flow in the cortical veins of the brain as this angiographic finding portends a worse prognosis. However, prior categorization systems of AV shunts in the spine do not incorporate these features. We propose an updated classification for spinal shunting lesions that terms any shunting lesion with retrograde flow in any cortical vein of the brain or spinal cord medullary vein as "high risk". To present this classification, we analyzed our center's most recent experience with cervical spine shunting lesions. METHODS: The electronic medical record at our institution was reviewed to identify shunting lesions of the cervical spine and patient demographics/presentation. Comprehensive craniospinal digital subtraction angiograms were evaluated to classify shunt location, type (arteriovenous malformation (AVM) vs arteriovenous fistula (AVF)), and presence of high-risk venous drainage. RESULTS: Some 52 lesions were identified and categorized as pial/dural/epidural/paravertebral AVFs and intramedullary/extraspinal AVMs. Lesions were classified as high risk or not depending on the presence of retrograde flow into at least one vein that directly drains the spinal cord or brain. All patients who presented with either hemorrhage or infarct had underlying high-risk lesions. Additionally, 50% (17/34) of symptomatic patients with high-risk lesions presented with neurological extremity symptoms (OR=10.0, p=0.037) most of which fit a myelopathic pattern. CONCLUSION: We present an updated classification system for shunting lesions of the spine that focuses on high-risk retrograde flow to the brain or spine in addition to anatomical location in order to better inform patient management.

Racial and Socioeconomic Status among a Patient Population Presenting with Aneurysmal Subarachnoid Hemorrhage versus Unruptured Intracranial Aneurysm: A Single-Center Study.

Racial and socioeconomic health disparities are well documented in the literature. This study examined patient demographics, including socioeconomic status (SES), among individuals presenting with aneurysmal subarachnoid hemorrhage (aSAH) and unruptured intracranial aneurysm (UIA) to identify factors associated with aSAH presentation. A retrospective assessment was conducted of all patients with aSAH and UIA who presented to a large-volume cerebrovascular center and underwent microsurgical treatment from January 2014 through July 2019. Race and ethnicity, insurance type, and SES data were collected for each patient. Comparative analysis of the aSAH and UIA groups was conducted. Logistic regression models were also employed to predict the likelihood of aSAH presentation based on demographic and socioeconomic factors. A total of 640 patients were included (aSAH group, 251; UIA group, 389). Significant associations were observed between race and ethnicity, SES, insurance type, and aneurysm rupture. Non-White race or ethnicity, lower SES, and having public or no insurance were associated with increased odds of aSAH presentation. The aSAH group had poorer functional outcomes and higher mortality rates than the UIA group. Patients who are non-White, have low SES, and have public or no insurance were disproportionately affected by aSAH, which is historically associated with poorer functional outcomes.

Dural arteriovenous fistulas are not observed to convert to a higher grade after partial embolization.

OBJECTIVE: Borden-Shucart type I dural arteriovenous fistulas (dAVFs) lack cortical venous drainage and occasionally necessitate intervention depending on patient symptoms. Conversion is the rare transformation of a low-grade dAVF to a higher grade. Factors associated with increased risk of dAVF conversion to a higher grade are poorly understood. The authors hypothesized that partial treatment of type I dAVFs is an independent risk factor for conversion. METHODS: The multicenter Consortium for Dural Arteriovenous Fistula Outcomes Research database was used to perform a retrospective analysis of all patients with type I dAVFs. RESULTS: Three hundred fifty-eight (33.2%) of 1077 patients had type I dAVFs. Of those 358 patients, 206 received endovascular treatment and 131 were not treated. Two (2.2%) of 91 patients receiving partial endovascular treatment for a low-grade dAVF experienced conversion to a higher grade, 2 (1.5%) of 131 who were not treated experienced conversion, and none (0%) of 115 patients who received complete endovascular treatment experienced dAVF conversion. The majority of converted dAVFs localized to the transverse-sigmoid sinus and all received embolization as part of their treatment. CONCLUSIONS: Partial treatment of type I dAVFs does not appear to be significantly associated with conversion to a higher grade.

Microsurgical Resection of Brainstem Cavernous Malformations in Older Adults: A Multicenter, 30-Year Experience.

BACKGROUND AND OBJECTIVES: Microsurgical resection is the only curative intervention for symptomatic brainstem cavernous malformations (BSCMs), but the management of these lesions in older adults (≥65 years) is not well described. This study sought to address this gap by examining the safety and efficacy of BSCM resection in a cohort of older adults. METHODS: Records of patients who underwent BSCM resection over a 30-year period were reviewed retrospectively. Baseline characteristics and outcomes were compared between older (≥65 years) and younger (<65 years) patients. RESULTS: Of 550 patients with BSCM who met inclusion criteria, 41 (7.5%) were older than 65 years. Midbrain (43.9% vs 26.1%) and medullary lesions (19.5% vs 13.6%) were more common in the older cohort than in the younger cohort ( P = .01). Components of the Lawton BSCM grading system (ie, lesion size, crossing axial midpoint, developmental venous anomaly, and timing of hemorrhage) were not significantly different between cohorts ( P ≥ .11). Mean (SD) Elixhauser comorbidity score was significantly higher in older patients (1.86 [1.06]) than in younger patients (0.66 [0.95]; P < .001). Older patients were significantly more likely than younger patients to have poor outcomes at final follow-up (28.9% vs 13.8%, P = .01; mean follow-up duration, 28.7 [39.1] months). However, regarding relative neurological outcome (preoperative modified Rankin Scale to final modified Rankin Scale), rate of worsening was not significantly different between older and younger patients (23.7% vs 14.9%, P = .15). CONCLUSION: BSCMs can be safely resected in older patients, and when each patient's unique health status and life expectancy are taken into account, these patients can have outcomes similar to younger patients.

Endovascular biopsy in neurointerventional surgery: A systematic review.

INTRODUCTION: Endothelial cells (ECs) continuously line the cerebrovasculature. Molecular aberrations in the ECs are hallmarks and contributory factors to the development of cerebrovascular diseases, including intracranial aneurysms and arteriovenous malformations (AVMs). Endovascular biopsy has been introduced as a method to harvest ECs and obtain relevant biologic information. We aimed to summarize the literature on endovascular biopsy in neurointerventional surgery. METHODS: We conducted a comprehensive literature search in multiple databases, identifying eligible studies focusing on neurosurgical applications of endovascular biopsy. The systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The relevant information was collected, including study characteristics, biopsy techniques, and key findings. RESULTS: Nine studies met the inclusion criteria and were included. The studies involved the collection of ECs using various endovascular devices including coils, guide wires, different stents, and forceps. Endothelial-enrichment techniques, such fluorescence-activated cell sorting (FACS), collected ECs and facilitated downstream applications of bulk or single-cell RNA sequencing (scRNAseq). The studies provided insights into gene expression profiles and identified potential biomarkers associated with intracranial aneurysms. However, challenges were observed in obtaining an adequate number of ECs and identifying consistent biomarkers. CONCLUSION: Endovascular biopsy of endothelial cells (ECs) in cerebrovascular pathologies shows promise for gene expression profiling. However, many studies have been limited in sample size and underpowered to identify "signature genes" for aneurysm growth or rupture. Advancements in minimally invasive biopsy methods have potential to facilitate applications of precision medicine in the treatment of cerebrovascular disorders.

Sex differences in patients with and without high-risk factors associated with aneurysmal subarachnoid hemorrhage.

BACKGROUND: Controversy remains regarding the appropriate screening for intracranial aneurysms or for the treatment of aneurysmal subarachnoid hemorrhage (aSAH) for patients without known high-risk factors for rupture. This study aimed to assess how sex affects both aSAH presentation and outcomes for aSAH treatment. METHOD: A retrospective cohort study was conducted of all patients treated at a single institution for an aSAH during a 12-year period (August 1, 2007-July 31, 2019). An analysis of women with and without high-risk factors was performed, including a propensity adjustment for a poor neurologic outcome (modified Rankin Scale [mRS] score > 2) at follow-up. RESULTS: Data from 1014 patients were analyzed (69% [n = 703] women). Women were significantly older than men (mean ± SD, 56.6 ± 14.1 years vs 53.4 ± 14.2 years, p < 0.001). A significantly lower percentage of women than men had a history of tobacco use (36.6% [n = 257] vs 46% [n = 143], p = 0.005). A significantly higher percentage of women than men had no high-risk factors for aSAH (10% [n = 70] vs 5% [n = 16], p = 0.01). The percentage of women with an mRS score > 2 at the last follow-up was significantly lower among those without high-risk factors (34%, 24/70) versus those with high-risk factors (53%, 334/633) (p = 0.004). Subsequent propensity-adjusted analysis (adjusted for age, Hunt and Hess grade, and Fisher grade) found no statistically significant difference in the odds of a poor outcome for women with or without high-risk factors for aSAH (OR = 0.7, 95% CI = 0.4-1.2, p = 0.18). CONCLUSIONS: A higher percentage of women versus men with aSAH had no known high-risk factors for rupture, supporting more aggressive screening and management of women with unruptured aneurysms.

Hematologic and Inflammatory Predictors of Outcome in Patients with Brain Arteriovenous Malformations.

OBJECTIVE: This study investigated the prognostic value of admission blood counts for arteriovenous malformation (AVM) outcomes and compared admission blood counts for patients with ruptured and unruptured AVMs. METHODS: A retrospective analysis of patients who underwent surgical treatment for a ruptured cerebral AVM between February 1, 2014, and March 31, 2020, was conducted. The primary outcome was poor neurologic outcome, defined as a modified Rankin Scale score ≥2 in patients with unruptured AVMs or >2 in patients with ruptured AVMs. RESULTS: Of 235 included patients, 80 (34%) had ruptured AVMs. At admission, patients with ruptured AVMs had a significantly lower mean (SD) hemoglobin level (12.78 [2.07] g/dL vs. 13.71 [1.60] g/dL, P < 0.001), hematocrit (38.1% [5.9%] vs. 40.7% [4.6%], P < 0.001), lymphocyte count (16% [11%] vs. 26% [10%], P < 0.001), and absolute lymphocyte count (1.41 [0.72] × 103/µL vs. 1.79 [0.68] × 103/µL, P < 0.001), and they had a significantly higher mean (SD) white blood cell count (10.4 [3.8] × 103/µL vs. 7.6 [2.3] × 103/µL, P < 0.001), absolute neutrophil count (7.8 [3.8] × 103/µL vs. 5.0 [2.5] × 103/µL, P < 0.001), and neutrophil count (74% [14%] vs. 64% [13%], P < 0.001). Among patients with unruptured AVMs, white blood cell count ≥6.4 × 103/µL and absolute neutrophil count ≥3.4 × 103/µL were associated with a favorable neurologic outcome, whereas hemoglobin level ≥13.4 g/dL was associated with an unfavorable outcome. Among patients with ruptured AVMs, hypertension was associated with a 3-fold increase in odds of a poor neurologic outcome. CONCLUSIONS: Patients with ruptured and unruptured AVMs present with characteristic profiles of hematologic and inflammatory parameters evident in their admission blood work.