Introduction: Cerebral cavernous malformations (CCM) can rupture causing life-threatening hemorrhagic stroke or acute neurological symptoms from seizures or deficits, necessitating urgent medical care. Disparities at the individual and neighborhood levels may contribute to delays in primary health care utilization and poorer health outcomes. We hypothesized that neighborhood socioeconomic status (SES) would be associated with CCM-related hospitalizations and emergency department (ED) visits in patients with familial CCM. Methods: Among 130 familial CCM patients enrolled in a longitudinal cohort study at our institution, 100 were California residents with valid addresses and demographic information. We used state-specific Area Deprivation Index (ADI), a validated decile measure utilizing census block group variables (income, education, employment, housing) to quantify neighborhood SES disadvantage. Higher ADI decile indicates greater disadvantage. We used multivariable Poisson regression to test for associations between ADI and lifetime cumulative counts of CCM-related hospitalizations and ED visits and report Incidence Rate Ratios (IRR); we adjusted for sex, non-White race, prior hemorrhage, and prior seizure. Results: Mean age of the cohort was 44.7 ± 18.5 years, 58% were female, 34% were Non-White ethnicity, 37% had a history of hemorrhage, and 47% had a history of seizures. Mean CA State ADI was 4.98 (range 1–10). A total of 58% had at least 1 ED visit (range 0–6), and 48% had at least 1 hospitalization (range 0–4). We found that ADI was significantly associated with hospitalizations and ED visits. After adjustments, for each increase in ADI, there was a 12% increase in rate of hospitalizations (IRR=1.12, 95% CI: 1.04–1.21, p=0.004) and a 7% increase in rate of ED visits (IRR=1.07, 95% CI: 1.01–1.14, p=0.019). Conclusions: Patients with familial CCM residing in higher neighborhood disadvantaged areas had increased rates of hospitalizations and ED visits, even after adjusting for individual-level characteristics. Further studies are needed to better understand reasons underlying this association, which may inform interventions to reduce urgent care visits.

Introduction: Parenchymal hemorrhage (PH) is a feared complication of reperfusion therapies in patients with acute ischemic stroke (AIS), which can significantly worsen the prognosis. This study aimed to evaluate whether the MRI perfusion biomarkers could predict PH development in AIS patients undergoing reperfusion therapy. Methods: In this retrospective cohort study, AIS patients with anterior circulation large vessel occlusions included if the patients underwent pre-treatment diffusion-weighted imaging (DWI) and dynamic susceptibility contrast (DSC) perfusion MRI as well as follow up imaging to assess PH. Using a novel vascular model based on Bayesian framework, parametric maps including cerebral blood flow (CBF) and blood-brain barrier leakage were obtained. Apparent diffusion coefficient (ADC) from diffusion MRI was also included. Mask of baseline infarct (ADC < 620 × 10 -6 ) generated and registered to perfusion maps to extracted voxel values. The associations between PH and clinical and imaging parameters were assessed in univariate and multivariate analyses. A predictive model was developed using logistic regression analysis and a decision tree classifier following 5-fold stratified cross-validation. The performance of this model was tested in a separate external cohort of patients. Results: Among 124 patients included, 35 (28%) developed PH. Multivariate logistic regression analysis showed extreme values of perfusion parameters including 95 th% -leakage (OR=1.31, 95% CI: 1.1-1.63, p=0.006), 95 th% -CBF (OR=0.37, 95% CI: 0.13-0.89, p=0.002), and 5 th% -ADC (OR=0.98, 95% CI: 0.96-0.99, p<0.001) as independent biomarkers predictive of PH. The 5-fold cross validated combined model of these 3 variables (95 th% -leakage≥7.9, 95 th% -CBF≤0.7, and ADC≤360) resulted in an average AUC of 0.84 ± 0.05, 91% sensitivity and 78% specificity. In external validation cohort (n=20), the model correctly identified 80% of PHs with 90% specificity. Conclusions: We developed a multiparametric model by integrating baseline MRI biomarkers including ADC, CBF, and leakage to identify AIS patients at elevated risk of parenchymal hematoma after reperfusion. Extreme values of these markers were independently associated with PH and provided complementary information beyond single-parameter models. Incorporating multiparametric MRI into periprocedural workflows may enable more precise risk stratification and guide individualized treatment decisions.

Introduction: Venous transit delay (VTD), a marker of poor venous outflow, has been successfully measured on CTP using time-to-maximum (Tmax) maps and is associated with unfavorable outcomes in patients with acute ischemic stroke (AIS) caused by large vessel occlusion (LVO). Mean transit time (MTT) is a perfusion parameter that encompasses both arterial input and venous outflow allowing for a more robust representation of cerebral arteriovenous transit time compared to Tmax which is heavily arterially weighted. In this study, using a Bayesian framework, we aimed to compare the association of VTD calculated from MTT and arterial delay (Tmax equivalent in Bayesian) with poor clinical outcomes after reperfusion in AIS-LVO patients. Methods: This retrospective study included AIS-LVO patients with baseline CTP and follow-up MRI from two comprehensive stroke centers. CTPs were processed with the Bayesian method using an FDA approved software (Olea Medical) to generate MTT and arterial delay (AD) maps. VTD was measured in the transverse sinus on both the ischemic and normal side and the posterior superior sagittal sinus (SSS) in each patient. Two outcome measures were included: Infarct growth (poor: ≥ 10 mL) and functional outcome defined by 90-day modified Rankin Scale score (mRS) (poor: ≥3). Results: A total of 80 patients were included (51% infarct growth ≥10 mL, 34% 90-day mRS≥3). MTT-derived VTD from the transvers sinus ipsilateral to the ischemic hemisphere was significantly longer in patients with substantial infarct growth (p=0.0007) and poor functional outcome (p=0.001). Similarly, MTT-derived VTD from the SSS was significantly longer in patients with substantial infarct growth (p=0.003) and poor functional outcome (p=0.012). However, AD-derived VTDs from the transverse sinus nor SSS were not significantly different (p>0.05) for either outcome measure. The difference between VTDs measured on MTT and AD (ΔVTD MTT -VTD AD ) was significantly higher in patients with substantial infarct growth (p<0.0001 for transverse sinus and p=0.0002 for SSS) and poor functional outcomes (p=0.0002 for transverse sinus and p=0.0307 for SSS). Conclusion: MTT-derived VTD measured in the transverse sinus and SSS was significantly different between patients with poor and favorable outcomes, which was not reflected on arterially weighted AD maps. This signifies the potential for MTT to be superior for VTD measurements and prediction of outcomes in AIS patients.

BACKGROUND AND PURPOSE:Parenchymal hematoma (PH) is a severe complication of reperfusion therapy in acute ischemic stroke and is associated with poor functional outcome. We evaluated whether baseline quantitative imaging biomarkers derived from MR diffusion and perfusion could predict PH after reperfusion therapy. MATERIALS AND METHODS:In this retrospective study, consecutive adults with acute ischemic stroke due to large-vessel occlusion who underwent endovascular thrombectomy between 2015 and 2020 and had baseline MRI and follow-up imaging were included. Quantitative imaging biomarkers were extracted from the baseline ischemic core, including apparent diffusion coefficient (ADC), relative cerebral blood flow (rCBF), relative cerebral blood volume (rCBV), and relative K2 (rK2) derived from Bayesian-based DSC perfusion processing. The primary outcome was PH on follow-up imaging. Baseline imaging and clinical variables were compared between patients with and without PH. An elastic-net logistic regression model was developed using nested stratified group 5-fold cross-validation, and model performance was summarized by receiver operating characteristic analysis and SHAP-based feature importance. RESULTS:The final cohort included 100 patients, of whom 32 developed PH. Baseline demographic, clinical, and conventional imaging characteristics did not differ significantly between groups. Patients with PH had significantly lower values of rCBF, rCBV, and ADC and higher values of rK2 in comparison to those without PH. The final model incorporated 5th% ADC, rCBF, rCBV, and 95th% rK2 showed discrimination with an AUC of 0.88 ± 0.07 (mean ± SD) and overall accuracy of 77%. CONCLUSIONS:We developed a quantitative model using ADC, rCBV, rCBF, and rK2 from bassline MRI that can identify stroke patients with an increased risk of PH with approximately 77% accuracy.

Introduction: While mean transit time (MTT) was initially used as a surrogate for penumbra, today estimates rely on time-to-maximum (Tmax) due to poor image quality of MTT. Most commercially available software packages for CTP analysis use single value decomposition (SVD), which is highly sensitive to noise. The Bayesian approach is a robust probabilistic method with potential in improving image quality of perfusion maps. We aimed to perform a comparative analysis between MTT maps generated using Bayesian and SVD postprocessing to assess differences in diagnostic image quality and estimated penumbral volumes. Methods: This retrospective study included acute ischemic stroke patients with anterior large vessel occlusion stroke with baseline CTP from two comprehensive stroke centers. CTPs were processed using FDA-approved software: RAPID (iSchemaView)(SVD-1), Olea Medical (SVD-2) and the Bayesian method. Image quality assessment was performed by 2 independent board-certified neuroradiologists blinded to the method of postprocessing for the side of hypoperfusion (right, left) and overall image quality using a 1-4 Likert-like scale. Differences in image quality were tested by Mann-Whitney test and interobserver agreement was assessed by kappa statistics. For quantitative analysis, penumbral volumes were estimated by applying relative MTT> 1.4 to both SVD and Bayesian-generated MTT maps and compared against volumes obtained in routine clinical practice (Tmax>6 sec). Bland-Altman plots were generated for comparative analysis. Results: A total of 78 patients were included. The overall image quality was significantly (p<0.001) higher for Bayesian-MTT in comparison to SVD-MTT regardless of the commercial software used. There was substantial interobserver agreement for rating image quality scores for Bayesian-MTT (k=0.70), SVD-1 (k=0.69) and SVD-2 (k=0.78). Estimated penumbral volume (median, IQR) using Tmax>6 sec was 103, 67-131 mL, while MTT-estimated penumbral was 91, 62-127 mL for Bayesian and 25, 14-37 mL for SVD. The mean (SD) difference of estimated penumbral volume between Bayesian-MTT and Tmax was 3 (8) mL (p=0.60), while this difference was significantly (p<0.001) higher for SVD-MTT and Tmax (74, 10 mL). Discussion/Conclusion: MTT maps generated from a Bayesian framework significantly outperform SVD, which is used in most commercially available software packages, both in terms of image quality and estimation of penumbral volume.

Background: Despite successful macrovascular reperfusion following endovascular treatment patients with large vessel occlusion (LVO) acute ischemic stroke (AIS), persistent microvascular hypoperfusion known as “no-reflow” can occur in 20–30% of patients and is associated with poor outcomes. We aimed to characterize the MRI biomarker profile of no-reflow regions on posttreatment MRI and evaluate the predictive value of individual and combined parameters. Methods: In this retrospective study, patients were included if they had anterior circulation LVO-AIS, who achieved excellent reperfusion (TICI ≥2c) and had posttreatment MRI including dynamic susceptibility contrast (DSC) perfusion within 48 hrs of reperfusion. DSC was processed with a novel vascular model using Bayesian voxel-wise transit time distribution to generate perfusion maps including capillary transit-time heterogeneity (CTH) and cerebral metabolic rate of oxygen (CMRO 2 ). Final infarct was segmented on diffusion-weighted MRI. Segmentation masks and perfusion maps were coregistered via linear registration, and voxel values extracted. All voxel values were normalized to median value of contralateral region-of-interest to calculate relative measures. No-reflow was defined as voxel values with relative CBV (rCBV) and CBF (rCBF) ≥15% below contralateral median. Group comparisons, multivariate logistic regression, and ROC analyses were performed. Results: A total of 53 patients met the inclusion criteria. Among 42,761 voxels defined as infarction on final MRI, a total of 14,765 (34%) designated as no reflow voxels. Ischemic tissue with no-reflow had significantly higher rCTH and Tmax, and significantly lower rCMRO 2 (all p < 0.001) compared to the completely reperfused tissue. In multivariable logistic regression, lower rCMRO 2 (OR = 0.14; 95% CI, 0.14–0.15; p < 0.001), longer Tmax (OR = 0.99; 95% CI, 0.98–1; p=0.04), and higher rCTH (OR = 2.4; 95% CI, 2.3–2.5; p < 0.001) were independently associated with no-reflow. The combined model of these 3 predictors demonstrated good discriminative performance (AUC = 0.87; 95% CI, 0.86–0.87). The optimal Youden threshold corresponded to rCMRO 2 ≤ 0.98, Tmax ≥ 0.2, and rCTH ≥ 1.2, yielding a sensitivity of 80% and specificity of 78%. Conclusion: No-reflow regions exhibit a distinctive MRI biomarker profile of elevated Tmax and CTH, as well as reduced CMRO 2 . A combined multi-parametric model provides superior discrimination compared to individual predictors.

Background In patients with acute ischemic stroke (AIS), ischemic core volume overestimation at diffusion-weighted MRI due to diffusion reversal has been described following successful reperfusion. Purpose To assess the potential role of the oxygen extraction fraction (OEF), derived from baseline dynamic susceptibility contrast (DSC) MRI, in diffusion reversal prediction in patients with AIS after successful reperfusion. Materials and Methods This retrospective study (January 2015 to December 2020) included patients with anterior-circulation large-vessel occlusion stroke who underwent pretreatment MRI, including diffusion-weighted imaging and DSC perfusion, achieved successful reperfusion (modified Thrombolysis in Cerebral Infarction score ≥2c), and underwent follow-up MRI within 48 hours. Ischemic core masks were generated from baseline MRI using an apparent diffusion coefficient (ADC) threshold of 620 × 10-6 mm2/sec or less, and infarct masks were generated from the final DWI scans. DSC perfusion was used to calculate the relative OEF (rOEF). Image co-registration and subtraction were performed to determine the final voxel fate as persistent infarct versus surviving tissue. Logistic regression and receiver operating characteristic (ROC) curve analyses were performed to assess imaging biomarker predictive value. Results Seventy patients were included (mean age, 72.2 years ± 13.1 [SD]; 40 female). Approximately 35% of the volume initially designated as the ischemic core showed diffusion reversal. Following logistic regression, the independent imaging variables associated with reducing the odds that ischemic core voxels would evolve to infarct voxels were ADC (odds ratio [OR], 0.99; 95% CI: 0.94, 1.0; P < .001) and rOEF (OR, 0.33; 95% CI: 0.32, 0.35; P < .001). A combined ADC plus rOEF model showed an area under the ROC curve (AUC) of 0.80 (95% CI: 0.80, 0.81), sensitivity of 74%, and specificity of 76% for infarct prediction, outperforming ADC alone (AUC, 0.65 [95% CI: 0.64, 0.66], sensitivity, 60%; specificity, 63%; P < .001). The added value of rOEF in delineating ischemic core was time-dependent, with the strongest negative impact within 120 minutes from stroke onset. Conclusion In patients with AIS for whom reperfusion was successful, the addition of rOEF to ADC improved ischemic core definition by predicting diffusion reversal and reducing core volume overestimation, especially in the hyperacute window. © RSNA, 2026 Supplemental material is available for this article. See also the editorial by Rapalino in this issue.

Background: Familial cerebral cavernous malformation (fCCM) is an autosomal dominant neurovascular disorder characterized by multiple lesions that increase risk of intracranial hemorrhage (ICH), seizures, and headaches. The impact of these symptoms on physical, mental, and social quality of life (QoL) in children with fCCM is unknown. We aimed to assess QoL domains and their associations with clinical symptoms and functional status at baseline and longitudinally in pediatric fCCM. Methods: Patient-Reported Outcomes Measurement Information System (PROMIS) surveys were completed by children or parent proxy for 66 pediatric fCCM participants (ages 5–17) enrolled in the Brain Vascular Malformation Consortium CCM study (2019–2025). Domain scores were converted to T-scores standardized to a U.S. pediatric reference population (mean=50, SD=10); higher scores reflect worse QoL. One-sample t-tests compared domain scores to population norms. Multivariable regression assessed associations between baseline PROMIS scores and prior ICH, seizures, headaches, or modified Rankin Scale (mRS) scores, adjusting for age, sex, and respondent type. Longitudinal analyses evaluated whether new symptom onset was associated with changes in PROMIS scores over time. Results: Among 66 participants (mean age 11.6±4.5), <50% reported prior ICH, seizures, or headaches; 93.3% had mRS scores of 0–1. PROMIS scores in anxiety (45.59 [95% CI: 42.51–48.67], p=0.006), depression (43.89 [41.63–46.14], p<0.001), fatigue (41.7 [39.03–44.37], p<0.001), and pain (43.29 [40.84–45.74], p<0.001) were significantly better than population norms. No significant baseline symptom-domain associations were observed, though moderate effect sizes were noted for prior ICH and worse fatigue (+3.83), mobility (+3.01), and sleep disturbance (+4.34); and for prior headache and fatigue (+3.64). Longitudinally, new headache onset was associated with increasing fatigue (+5.59 [0.046–11.13], p=0.048), with trends for worsening anxiety, pain, and sleep. Higher mRS scores correlated with worse pain (p=0.001), mobility (p=0.004), and sleep (p=0.011). Conclusions: PROMIS surveys captured QoL variation in pediatric fCCM, with moderate symptom-domain associations and significant correlations with mRS scores. Longitudinal changes in PROMIS scores tracked evolving symptom burden, particularly with new onset headaches and fatigue. Larger studies are needed to confirm PROMIS validity and refine its clinical utility in pediatric fCCM.

BACKGROUND:In patients with acute ischemic stroke, infarct growth occurs despite successful reperfusion. Oxygen extraction fraction (OEF) has shown promising results in evaluating ischemic tissue viability and can now be quantified from routinely performed dynamic susceptibility contrast perfusion. We aimed to determine the association of OEF alterations within the ischemic tissue on pretreatment magnetic resonance imaging and infarct growth in patients who underwent successful reperfusion. METHODS:In this retrospective cohort study from the University of California, Los Angeles, between 2015 and 2020, patients were included if they had anterior circulation large vessel occlusion, achieved successful reperfusion (Thrombolysis in Cerebral Infarction ≥2b), had pretreatment dynamic susceptibility contrast perfusion and posttreatment magnetic resonance imaging within 48 hours from reperfusion. Dynamic susceptibility contrast-derived OEF values were quantified from the segmented ischemic core (apparent diffusion coefficient ≤620×10-6 mm2/s) and penumbra tissue (time-to-maximum [Tmax] >6 s) on pretreatment magnetic resonance imaging and normalized to contralateral hemisphere (relative oxygen extraction fraction [OEFr]). Primary outcome was substantial infarct growth ≥10 mL, and secondary outcomes were continuous measures of infarct growth volume and penumbra-to-infarct conversion ratio. The associations between baseline clinical and imaging variables, including OEFr and outcome measures, were tested by multivariate and regression analysis. RESULTS:Among 89 patients who met inclusion criteria, 33 (37%) patients had infarct growth ≥10 mL. Patients with infarct growth had significantly (P<0.0001) lower penumbra-OEFr values compared with those without infarct growth. There was significant association between penumbra OEFr and infarct growth (β=-2.9 [95% CI, -5.0 to -0.8]; P=0.007) and similarly for penumbra-to-infarct conversion ratio (β=-10.4 [95% CI, -19.6 to -1.2]; P=0.028). CONCLUSIONS:Our results showed penumbra-OEFr is a promising imaging biomarker for predicting infarct growth in acute ischemic stroke following successful reperfusion. Although elevation of penumbra-OEFr is protective, patients with lower penumbra-OEFr values sustained further ischemic injury and infarct growth.

Background: Subarachnoid Hemorrhage (SAH) accounts for 2-7% of strokes and has high mortality and morbidity. We sought to identify peripheral blood transcriptome changes in the acute SAH phase that associated with 90-day outcome, as measured by the modified Rankin Scale (mRS), to gain insights about potential mechanisms contributing to long term outcome. Methods: We sequenced the peripheral blood transcriptome of SAH patients within 3 days post ictus and stratified the patients into patients with Good (mRS≤2, n=37) and Poor (mRS≥3, n=23) outcomes at 90-day follow up. We generated the co-expression networks using the Weighted Gene Co-Expression Network Analysis (WGCNA) package to determine modules (groups of co-expressed genes) associated with 90-day SAH outcome. The outcome-significant modules (p<0.05) were further analyzed for their biological relevance using pathway analysis. Results: We identified two outcome-significant modules, the Pink module and the Purple module. The Pink module was enriched (corrected p<0.05) in Monocyte- and Granulocyte-specific genes, while the Purple module and its hubs were enriched in Monocyte-specific genes. The hub genes are the most interconnected genes in each module, which are therefore potential master regulators. The Pink module was enriched (corrected p<0.05) in Neutrophil Degranulation, an inflammatory pathway which was predicted to be activated in patients with worse outcome, in Histone Modification Signaling, which is involved in epigenetic control of gene expression, and in SUMOylation of transcriptional cofactors, which confers post-transcriptional modifications of these cofactors. The Purple module was enriched in 45 canonical biological pathways, including numerous inflammatory pathways predicted to be activated in SAH patients with worse outcomes, such as Neutrophil Degranulation, Phagosome Formation, IL-8 Signaling, and Macrophage Classical Activation Signaling. Conclusions: Early peripheral blood changes in the transcriptome architecture following SAH are associated with long-term outcome. The identified genes and networks may guide the search for potential biomarkers of outcome and novel treatment targets.

Introduction: Pediatric and young adult cerebrovascular disease is more commonly associated with genetic conditions compared to in adults. This pilot study aims to characterize utility of genetic testing in a pediatric and young adult neurovascular clinic. Methods: This was a single center cohort study of pediatric and young adult patients (age <25 years) with cerebrovascular conditions who underwent clinical genetic testing between 7/2023-7/2024. Cerebrovascular conditions included brain or spine AVM, cavernous malformation, cerebral aneurysm, Moya-Moya vasculopathy, and/or unexplained hemorrhagic stroke. Individuals with perinatal or isolated arterial ischemic stroke were not included. Genetic testing ranged from a custom gene panel (including 4-175 genes) to whole exome/genome sequencing. Chart review was performed by a pediatric vascular neurologist to determine clinical details and genetic results. Identified genetic variants were further classified as 1) pathogenic or highly suspicious, 2) actionable but unrelated to phenotype, and 3) possibly relevant. Results: Twenty patients underwent genetic testing, including 7 with brain or spine AVM, 3 with ruptured cerebral aneurysm, 5 with spontaneous intracranial hemorrhage without underlying vascular malformation, and 5 with other cerebrovascular malformations. Median age at testing was 14 years (range 2mo – 24 years), and 11 (55%) were male. Panel testing was performed on 16/20; exome/genome trio sequencing was performed in 4/20. Definite pathogenic or highly suspicious variants relevant to underlying phenotype were noted in 4/20 (20%), an unrelated but actionable pathogenic variant was noted in 1/20 (5%), and possibly relevant variants were noted in an additional 3/20 (15%) patients. Genes with identified variants included RNF213 (n=2), ENG, EPHB4, F2, F5, COL4A1, and DIAPH1. Positive or negative results informed or changed clinical management in 17/20 (85%) patients, prompting additional testing, altered imaging surveillance, and/or expectant guidance for the patient and family members. Conclusions: Genetic testing has become increasingly available and has relatively high yield in pediatric and young adult hemorrhagic stroke and cerebrovascular malformations. Panel or exome/genome-based testing can inform care in these individuals and their families. Larger cohort studies are needed to determine more precise yield of genetic testing across a variety of cerebrovascular conditions.

Introduction: Brain arteriovenous malformations (bAVMs) are vascular anomalies resulting from defective morphogenesis of blood vessels in the brain. Kirsten rat sarcoma virus ( KRAS) somatic activating gene mutations have been identified in the majority of bAVMs using digital droplet PCR-based assays (ddPCR). Currently, bAVM somatic mutation genetic characterization requires sequencing surgically excised lesion DNA, but recent advancements have overcome some conventional biopsy limitations through sequencing cell-free DNA (cfDNA) which is directly released into the blood circulation from cell breakdown and turnover at the site of the lesion. Therefore, cfDNA released from the mutated bAVM tissue cells may be detectable in a peripheral blood sample, providing a non-invasive approach for somatic mutation screening. Hypothesis: We hypothesize that somatic KRAS G12D mutations in bAVM patients can be detected using non-invasive cfDNA screening. Methods: We selected six bAVM patients whose surgically-resected bAVM lesions screened positive for somatic KRAS G12D mutation using ddPCR and had contributed a peripheral blood sample for research within 2 months prior to surgery. For each patient, cfDNA was isolated from 1.0 mL of banked plasma using the Circulating cfDNA/RNA Isolation Kit (Qiagen). We used the ddPCR KRAS G12D assay (Bio-Rad) to screen cfDNA samples for presence of the mutation. Samples were screened in duplicate using 8 uL and 4 uL of cfDNA eluate and assays included both positive controls (synthetic KRAS G12D oligo sequence (Integrated DNA Technologies)) and negative controls (no template and water). The variant allele frequency was estimated for each sample as the (target concentration)/(target + reference concentration). Results: Of the six bAVM cases, five screened positive for KRAS G12D mutation in the cfDNA sample. The KRAS G12D cfDNA variant allele frequency ranged from 0.20 - 0.54% for the five positive samples. Conclusions: We detected somatic KRAS G12D mutations in bAVM patients using non-invasive cfDNA screening. While further studies are needed to validate these findings, these exciting results suggest that we may be able to perform non-invasive KRAS somatic mutation screening using cfDNA in a greater number of bAVM cases (e.g., not just those undergoing surgery), which may be useful to clinically stratify bAVM patients and provide targeted therapies based on specific genetic defect.

BackgroundAmphetamines possess sympathomimetic properties that can affect cerebral vasculature though conflicting reports exist about their effect on vasospasm risk and clinical outcomes in aneurysmal subarachnoid hemorrhage. This study aimed to characterize the impact of recent amphetamine use on vasospasm development in aneurysmal subarachnoid hemorrhage as well as neurological outcomes.MethodsWe retrospectively screened 441 consecutive patients admitted with a diagnosis of subarachnoid hemorrhage who underwent at least one cerebral digital subtraction angiogram. Patients were excluded if no urinary toxicology screen was performed within 24 h of admission, if there was a diagnosis of non-aneurysmal subarachnoid hemorrhage, or if ictus was greater than 72 h from hospital admission. Vasospasm characteristics were collected from digital subtraction angiography and transcranial Doppler studies.Results129 patients were included and 24 tested positive for amphetamines on urine drug screen. No significant differences were found in respect to patient age, sex, or admission clinical severity scales (Hunt-Hess and modified Fisher) based on amphetamine use. There was no difference in the severity of vasospasm or time to peak severity based on recent amphetamine use. A trend toward more isolated posterior circulation vasospasm was observed in the amphetamine present group (16.7% vs. 4.8%, p = 0.06), while there was higher incidence of anterior circulation vasospasm in the amphetamine absent group (79.2% vs. 94.3%, p = 0.03). There was no difference in delayed cerebral ischemia incidence, length of hospital stay, need for ventriculoperitoneal shunt placement, functional outcome at discharge or hospital mortality based on amphetamine use.InterpretationRecent amphetamine use was not associated with worse vasospasm severity or delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage patients. Further investigations about localized effects in the posterior circulation and impact on long-term functional outcomes are warranted.

Background: Brain arteriovenous malformations (bAVMs) are an important cause of intracranial hemorrhage, seizure, or other neurological deficits. Clinical heterogeneity of bAVM suggests a role for genetic modifiers that may associate with seizure risk. DNA methylation is a reversible epigenetic mechanism that regulates gene expression in development and disease. We hypothesized that DNA methylation in epilepsy-related genes is associated with seizure at presentation in bAVM patients. Methods: We performed a literature review in PubMed to identify epilepsy-related genes with potential epigenetic regulation using the search terms: epigenetics, DNA methylation, seizure, epilepsy. We selected 19 unruptured bAVM cases (mean age 44.9 y) enrolled in the bAVM study at UCSF, including 10 presenting with seizure. We performed methylome sequencing of genomic DNA extracted from whole blood using bisulfite sequencing services at Psomagen with ~20X coverage. Differentially Methylated Regions (DMR) mapping to or nearby the candidate seizure genes were identified by comparing the average methylation ratio in bAVM cases presenting with and without seizure by t-test. DMRs with a delta average methylation ratio between the two groups ≥

Aneurysmal subarachnoid hemorrhage (aSAH) occurs less often than other stroke types but affects younger patients, imposing a disproportionately high burden of long-term disability. Although management advances have improved outcomes over time, relatively few aSAH treatments have been tested in randomized clinical trials (RCTs). One lesson learned from COVID-19 is that trial platforms can facilitate the efficient execution of multicenter RCTs even in complex diseases during challenging conditions. An aSAH trial platform with standardized eligibility criteria, randomization procedures, and end point definitions would enable the study of multiple targeted interventions in a perpetual manner, with treatments entering and leaving the platform based on predefined decision algorithms. An umbrella institutional review board protocol and clinical trial agreement would allow individual arms to be efficiently added as amendments rather than stand-alone protocols. Standardized case report forms using the National Institutes of Health/National Institute of Neurological Disorders and Stroke common data elements and general protocol standardization across arms would create synergies for data management and monitoring. A Bayesian analysis framework would emphasize frequent interim looks to enable early termination of trial arms for futility, common controls, borrowing of information across arms, and adaptive designs. A protocol development committee would assist investigators and encourage pragmatic designs to maximize generalizability, reduce site burden, and execute trials efficiently and cost-effectively. Despite decades of steady clinical progress in the management of aSAH, poor patient outcomes remain common, and despite the increasing availability of RCT data in other fields, it remains difficult to perform RCTs to guide more effective care for aSAH. The development of a platform for pragmatic RCTs in aSAH would help close the evidence gap between aSAH and other stroke types and improve outcomes for this important disease with its disproportionate public health burden.

Introduction: Sporadic brain arteriovenous malformations (bAVMs) are a potentially treatable cause of stroke disproportionately affecting young people. Non-inherited somatic activating mutations in KRAS have been reported in ~50% of bAVM specimens primarily from adults. We hypothesized that KRAS mutations would be associated with an earlier age at diagnosis, larger bAVM size, or earlier time to hemorrhage. Methods: Sporadic bAVM tissue and clinical data were collected from patients seen at our institution. Genotyping was performed by digital droplet polymerase chain reaction to detect KRAS mutations (p.G12D, p.G12V or p.Q61H) in three batches and coded as presence/absence of any KRAS mutation (primary predictor). Age at diagnosis was dichotomized into adults (18 years) or children (<18 years). Regression analyses adjusting for genotyping batch were performed to test association of KRAS mutations between children and adults (logistic), with bAVM size (linear), or with time from diagnosis to hemorrhage (survival), censoring at treatment or last follow-up. Results: We analyzed data from 221 patients: median age at bAVM diagnosis was 20 years; 44% were diagnosed as children; 53% were female; and 56% were ruptured on presentation. Median bAVM diameter was 2.1 cm (IQR: 1.4 - 3.0). KRAS mutations were detected in 53% of samples. Childhood bAVMs were significantly more likely to harbor KRAS mutations than those diagnosed in adulthood (OR=2.20, 95% CI: 1.24 - 3.91, p=0.007). KRAS -mutant bAVMs tended to be larger than KRAS -wildtype bAVMs, but this did not reach significance (+0.29 cm, 95% CI: -0.03 - 0.62, p=0.08). No association was observed for time to hemorrhage (HR=1.31, 95% CI: 0.91 - 1.88, p=0.15). Conclusions: Somatic activating KRAS mutations are more prevalent in bAVMs diagnosed in childhood than adulthood. Further work is required to elucidate mechanisms of mutagenesis and bAVM progression, which may differ in children and adults.

Aim: The “2023 Guideline for the Management of Patients With Aneurysmal Subarachnoid Hemorrhage” replaces the 2012 “Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage.” The 2023 guideline is intended to provide patient-centric recommendations for clinicians to prevent, diagnose, and manage patients with aneurysmal subarachnoid hemorrhage. METHODS: A comprehensive search for literature published since the 2012 guideline, derived from research principally involving human subjects, published in English, and indexed in MEDLINE, PubMed, Cochrane Library, and other selected databases relevant to this guideline, was conducted between March 2022 and June 2022. In addition, the guideline writing group reviewed documents on related subject matter previously published by the American Heart Association. Newer studies published between July 2022 and November 2022 that affected recommendation content, Class of Recommendation, or Level of Evidence were included if appropriate. Structure: Aneurysmal subarachnoid hemorrhage is a significant global public health threat and a severely morbid and often deadly condition. The 2023 aneurysmal subarachnoid hemorrhage guideline provides recommendations based on current evidence for the treatment of these patients. The recommendations present an evidence-based approach to preventing, diagnosing, and managing patients with aneurysmal subarachnoid hemorrhage, with the intent to improve quality of care and align with patients’ and their families’ and caregivers’ interests. Many recommendations from the previous aneurysmal subarachnoid hemorrhage guidelines have been updated with new evidence, and new recommendations have been created when supported by published data.