Addressing the Evidence Gap in Aneurysmal Subarachnoid Hemorrhage: The Need for a Pragmatic Randomized Trial Platform.

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.

2023 Guideline for the Management of Patients With Aneurysmal Subarachnoid Hemorrhage: A Guideline From the American Heart Association/American Stroke Association.

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.

Maternal and Fetal Outcomes in Women with Brain Arteriovenous Malformation Rupture during Pregnancy.

BACKGROUND: Sporadic brain arteriovenous malformations (BAVM) are a major cause of hemorrhagic stroke in younger persons. Prior studies have reported contradictory results regarding the risk of hemorrhage during pregnancy, and there are no standard guidelines for the management of pregnant women who present with BAVM rupture. The purpose of this study is to describe maternal and fetal outcomes and treatment strategies in patients with BAVM hemorrhage during pregnancy. METHODS: We performed a retrospective review of the University of California, San Francisco Brain AVM Project database for female patients who were pregnant at the time of BAVM hemorrhage between 2000 and 2017. Clinical and angiographic characteristics at presentation, BAVM treatment, and maternal outcomes using modified Rankin scale (mRS) score at presentation and 2-year follow-up were recorded. Fetal outcomes were abstracted from medical records and maternal reports. RESULTS: Sixteen patients presented with BAVM hemorrhage during pregnancy, 81% (n = 13) of whom were in their second or third trimester. Three patients (19%) who were in their first trimester terminated or miscarried pregnancy prior to BAVM intervention. Of the remaining 13 patients, 77% (n = 10) received emergent BAVM treatment at time of hemorrhage prior to delivery, and 85% of patients achieved BAVM obliteration and good maternal outcomes (mRS 0-2) at 2-year follow-up. All patients had uncomplicated deliveries (69% cesarean and 23% vaginal) with no reports of postnatal cognitive or developmental delays in infants at 2-year follow-up. CONCLUSIONS: Our study shows good long-term maternal and fetal outcomes in ruptured BAVM patients presenting during pregnancy, the majority who received BAVM interventional treatment prior to delivery.

Proceedings of the First Curing Coma Campaign NIH Symposium: Challenging the Future of Research for Coma and Disorders of Consciousness.

Coma and disorders of consciousness (DoC) are highly prevalent and constitute a burden for patients, families, and society worldwide. As part of the Curing Coma Campaign, the Neurocritical Care Society partnered with the National Institutes of Health to organize a symposium bringing together experts from all over the world to develop research targets for DoC. The conference was structured along six domains: (1) defining endotype/phenotypes, (2) biomarkers, (3) proof-of-concept clinical trials, (4) neuroprognostication, (5) long-term recovery, and (6) large datasets. This proceedings paper presents actionable research targets based on the presentations and discussions that occurred at the conference. We summarize the background, main research gaps, overall goals, the panel discussion of the approach, limitations and challenges, and deliverables that were identified.

Standards for Studies of Neurological Prognostication in Comatose Survivors of Cardiac Arrest: A Scientific Statement From the American Heart Association.

Significant improvements have been achieved in cardiac arrest resuscitation and postarrest resuscitation care, but mortality remains high. Most of the poor outcomes and deaths of cardiac arrest survivors have been attributed to widespread brain injury. This brain injury, commonly manifested as a comatose state, is a marker of poor outcome and a major basis for unfavorable neurological prognostication. Accurate prognostication is important to avoid pursuing futile treatments when poor outcome is inevitable but also to avoid an inappropriate withdrawal of life-sustaining treatment in patients who may otherwise have a chance of achieving meaningful neurological recovery. Inaccurate neurological prognostication leading to withdrawal of life-sustaining treatment and deaths may significantly bias clinical studies, leading to failure in detecting the true study outcomes. The American Heart Association Emergency Cardiovascular Care Science Subcommittee organized a writing group composed of adult and pediatric experts from neurology, cardiology, emergency medicine, intensive care medicine, and nursing to review existing neurological prognostication studies, the practice of neurological prognostication, and withdrawal of life-sustaining treatment. The writing group determined that the overall quality of existing neurological prognostication studies is low. As a consequence, the degree of confidence in the predictors and the subsequent outcomes is also low. Therefore, the writing group suggests that neurological prognostication parameters need to be approached as index tests based on relevant neurological functions that are directly related to the functional outcome and contribute to the quality of life of cardiac arrest survivors. Suggestions to improve the quality of adult and pediatric neurological prognostication studies are provided.

mRNA Expression Profiles from Whole Blood Associated with Vasospasm in Patients with Subarachnoid Hemorrhage.

BACKGROUND: Though there are many biomarker studies of plasma and serum in patients with aneurysmal subarachnoid hemorrhage (SAH), few have examined blood cells that might contribute to vasospasm. In this study, we evaluated inflammatory and prothrombotic pathways by examining mRNA expression in whole blood of SAH patients with and without vasospasm. METHODS: Adult SAH patients with vasospasm (n = 29) and without vasospasm (n = 21) were matched for sex, race/ethnicity, and aneurysm treatment method. Diagnosis of vasospasm was made by angiography. mRNA expression was measured by Affymetrix Human Exon 1.0 ST Arrays. SAH patients with vasospasm were compared to those without vasospasm by ANCOVA to identify differential gene, exon, and alternatively spliced transcript expression. Analyses were adjusted for age, batch, and time of blood draw after SAH. RESULTS: At the gene level, there were 259 differentially expressed genes between SAH patients with vasospasm compared to patients without (false discovery rate < 0.05, |fold change| ≥ 1.2). At the exon level, 1210 exons representing 1093 genes were differentially regulated between the two groups (P < 0.005, ≥ 1.2 |fold change|). Principal components analysis segregated SAH patients with and without vasospasm. Signaling pathways for the 1093 vasospasm-related genes included adrenergic, P2Y, ET-1, NO, sildenafil, renin-angiotensin, thrombin, CCR3, CXCR4, MIF, fMLP, PKA, PKC, CRH, PPARα/RXRα, and calcium. Genes predicted to be alternatively spliced included IL23A, RSU1, PAQR6, and TRIP6. CONCLUSIONS: This is the first study to demonstrate that mRNA expression in whole blood distinguishes SAH patients with vasospasm from those without vasospasm and supports a role of coagulation and immune systems in vasospasm.

Common Data Elements for Subarachnoid Hemorrhage and Unruptured Intracranial Aneurysms: Recommendations from the Working Group on Subject Characteristics.

BACKGROUND: The National Institute of Neurological Disorders and Stroke (NINDS) Common Data Elements (CDEs) have been generated to standardize and define terms used by the scientific community. The widespread use of these CDEs promotes harmonized data collection in clinical research. The aim of the NINDS Unruptured Intracranial Aneurysms (UIA) and Subarachnoid Hemorrhage (SAH), and Subject Characteristics working group (WG) was to identify, define, and classify CDEs describing the characteristics of patients diagnosed with an UIA and SAH. Thus, "Participant/Subject characteristics" is a set of factors defining a population of selected individuals and allowing comparisons with a reference population and overtime. METHODS: Based on standard terms defined by the United States' Census Bureau, CDEs previously defined by several (Stroke, Epilepsy and Traumatic Brain Injury) NINDS CDE working groups literature and expert opinion of the WG, the "Participant/Subject characteristics" domain has been defined. RESULTS: A set of 192 CDEs divided in 7 subsections: demographics (8 CDEs), social status (8 CDEs), behavioral status (22 CDEs), family and medical history (144 CDEs), pregnancy and perinatal history (8 CDEs), history data source reliability (3 CDEs), and prior functional status (3 CDEs) was defined. SAH is characterized by 6 core elements, all classified in the "Participant/Subject characteristics" domain. Four exploratory elements out of the 39 for SAH overall are in the "Participant/Subject characteristics" domain, and all remaining 182 CDEs in the "Participant/Subject characteristics" domain are classified as Supplemental-Highly Recommended elements. CONCLUSIONS: These CDEs would allow the development of best practice guidelines to standardize the assessment and reporting of observations concerning UIA and SAH.

Numerical Investigation of Vasospasm Detection by Extracranial Blood Velocity Ratios.

BACKGROUND: Early diagnosis of vasospasm following subarachnoid hemorrhage can prevent cerebral ischemia and improve neurological outcomes. This study numerically evaluates the relevance of extracranial blood velocity indices to detect vasospasm. METHODS: A numerical model of cerebral blood flow was used to evaluate the hemodynamics associated with anterior and posterior vasospasm under normal and impaired cerebral autoregulation conditions. Extracranial blood velocities at the carotid and vertebral arteries and their ratios between ipsilateral and contralateral, anterior and posterior, and downstream and upstream arteries were monitored during vasospasm progression. RESULTS: For current clinical indices that track blood velocities at vasospastic arterial segments using transcranial Doppler (TCD), we observed that velocities increased initially and then decreased with vasospasm progression. This nonmonotonic behavior can lead to false-negative decisions in moderate to severe vasospasm. Alternatively, volumetric flow decreased monotonically at the affected arteries, leading to blood velocities upstream of the vasospastic artery also decreasing monotonically. Based on this principle, we demonstrate that velocity ratios between the carotid and vertebral arteries may better identify moderate to severe vasospasm and improve sensitivity and specificity of vasospasm detection. CONCLUSION: The velocity indices proposed in this study may enable new or improved noninvasive diagnosis of vasospasm using extracranial Doppler ultrasound. Compared to current clinical indices, the new indices may improve the handling of (1) scenarios of severe vasospasm or impaired cerebral autoregulation, (2) systemic changes in blood pressure and cardiac output, (3) vasospasm occurring in arteries distal to the cerebral circle region, and (4) cases with insufficient acoustic bone window for TCD. The results provide a concrete basis for future clinical evaluation of extracranial indices for vasospasm detection.

Frequency and Risk Factors for Cerebral Arterial Disease in a HIV/AIDS Neuroimaging Cohort.

BACKGROUND: Infection with HIV predisposes patients to a myriad of neurologic disorders, including cerebrovascular disease. The pathophysiology is likely multifactorial, with proposed mechanisms including infectious vasculitis, HIV-induced endothelial dysfunction and adverse effects of combination antiretroviral therapy (cART). Epidemiologic data on clinically evident cerebral vasculopathy in HIV-infected adults is scarce, even though stroke hospitalizations are rising in this patient population. METHODS: A total of 6,298 HIV-infected adults (San Francisco General Hospital, 2000-2013) were screened to generate a cohort of patients with dedicated neuroimaging of the intra- and extracranial cerebral vasculature. We extracted information regarding the extent of HIV disease (including serial viral load and CD4 counts), cardiovascular disease risk factors and exposure to cART (cross-referenced with pharmacy records) and performed multivariate logistic regression analysis to identify predictors of vasculopathy. RESULTS: Of 144 patients, 55 patients (38.2%) had radiographic evidence of cerebral vasculopathy. Twenty (13.9%) had a vasculopathy characterized by vessel dolichoectasia and intracranial aneurysm formation. Thirty-five patients (24.3%) had intra- and or extracranial stenosis/occlusion. cART use (OR 2.27, 95% CI 1.03-5) and tobacco abuse (OR 2.35, 95% CI 1.04-5.25) were independently associated with the development of any vasculopathy, whereas cART use was also an independent risk factor for the stenosis/occlusion subtype specifically (OR 2.87, 95% CI 1.11-7.45). CONCLUSIONS: There was a high frequency of cerebral arterial disease in this neuroimaging cohort of HIV/AIDS patients. A history of cART use and a history of tobacco abuse were independent risk factors for vasculopathy, though these findings should be confirmed with large-scale prospective studies.

High resolution imaging of the intracranial vessel wall at 3 and 7 T using 3D fast spin echo MRI.

OBJECTIVES: High resolution MRI of the intracranial vessel wall provides important insights in the assessment of intracranial vascular disease. This study aims to refine high resolution 3D MRI techniques for intracranial vessel wall imaging at both 3 and 7 T using customized flip angle train design, and to explore their comparative abilities. MATERIALS AND METHODS: 11 patients with intracranial artery disease (four atherosclerotic plaques, six aneurysms and one reversible cerebral vasoconstriction syndrome) were imaged at 3 and 7 T with a 3D T 1-weighted fast-spin-echo sequence (SPACE) both pre and post Gd contrast injection. Wall to lumen contrast ratio (CRwall-lumen), contrast enhancement ratio (ER) and the sharpness of the vessel wall were quantified. Two experienced radiologists evaluated the image quality on a 0-5 scale. RESULTS: Both 3 and 7 T achieved good image quality with high resolution (nominal 0.5 mm isotropic) and whole brain coverage. The CRwall-lumen and the ER measurements were comparable (p > 0.05). The 7 T images were significantly sharper (sharpness: 2.69 ± 0.50 vs. 1.88 ± 0.53 mm(-1), p < 0.001) with higher image quality (reader 1 score: 3.5 ± 1.1 vs. 2.4 ± 1.1, p = 0.002) compared to 3 T. CONCLUSIONS: 3D T 1-weighted SPACE can be used for intracranial vessel wall evaluation at both 3 and 7 T. 7 T provides significantly better image quality and improves the confidence of diagnosis.

Characterization of Shape Differences Among ICP Pulses Predicts Outcome of External Ventricular Drainage Weaning Trial.

BACKGROUND: External ventricular drains (EVD) are widely used to manage intracranial pressure (ICP) and hydrocephalus for aneurysmal subarachnoid hemorrhage (aSAH) patients. After days of use, a decision is made to remove the EVD or replace it with a shunt, involving EVD weaning and CT imaging to observe ventricular size and clinical status. This practice may lead to prolonged hospital stay, extra radiation exposure, and neurological insult due to ICP elevation. This study aims to apply a validated morphological clustering analysis of ICP pulse (MOCAIP) algorithm to detect signatures from the pulse waveform to differentiate an intact CSF circulatory system from an abnormal one during EVD weaning. METHODS: We performed a retrospective study with 50 aSAH patients with reported weaning trial admitted to our institution between 03/2013 and 08/2014. By reviewing clinical notes and pre/post-brain imaging results, 32 patients were determined as having passed the weaning trial and 18 patients as having failed the trial. MOCAIP algorithm was applied to ICP signals to form a series of artifact-free dominant pulses. Finally, pulses with similar mean ICP were identified, and amplitude, Euclidean, and geodesic inter-pulse distances were calculated in a 4-h moving window. RESULTS: While the traditional measure of mean ICP failed to differentiate the two groups of patients, the proposed amplitude and morphological inter-pulse measures presented significant differences (p ≤ 0.004). Moreover, receiver operating characteristic (ROC) analyses showed their usability to predict the outcome of the EVD weaning trial (AUC 0.85, p < 0.001). CONCLUSIONS: Patients with an impaired CSF system showed a larger mean and variability of inter-pulse distances, indicating frequent changes on the morphology of pulses. This technique may provide a method to rapidly determine if patients will need placement of a shunt or can simply have the EVD removed.

Cranial Accelerometry Can Detect Cerebral Vasospasm Caused by Subarachnoid Hemorrhage.

BACKGROUND: We previously reported the presence of a cranial "bruit" in patients with cerebral vasospasm by signal processing cranial accelerometry signals time locked to the cardiac cycle. This shift to higher frequencies is likely related to the turbulence of blood flow produced by vascular narrowing. We sought to build a more quantitative model to predict cerebral vasospasm then test the accuracy of this technique to detect cerebral vasospasm in a prospective blinded study. METHODS: Skull accelerometry was performed using an array of 6 highly sensitive accelerometers placed in contact with the scalp. Paired transcranial Doppler (TCD) recordings and accelerometry epochs were obtained in consecutive patients with subarachnoid hemorrhage undergoing TCD recordings for surveillance of cerebral vasospasm. The energy of rectified acceleration measurements within systolic and diastolic bands of the cardiac cycle were measured and correlated with TCD-defined spasm. This model was then tested prospectively in a blinded consecutive sample of subarachnoid hemorrhage patients to determine accuracy of the technique. RESULTS: We developed a model predicting cerebral vasospasm from analysis of 14 unblinded subjects with varying degrees of cerebral vasospasm as detected by TCD. We then recorded from 58 subjects obtaining 125-paired recordings of accelerometry and TCD to test this model in a blinded analysis. Accelerometry detection of any spasm versus non-spasm correlated with TCD-defined vasospasm (P < 0.001). The model was 81 % sensitive for detecting any cerebral vasospasm in patients, while the negative predictive value was 61 %. CONCLUSION: Highly sensitive skull accelerometry can detect cerebral vasospasm with clinically meaningful accuracy. This tool holds promise in the ICU environment to detect as well as reject cerebral vasospasm as the cause of neurological deficits in subarachnoid hemorrhage.

Spontaneous echo-contrast in the internal jugular veins of patients with ischemic stroke.

PURPOSE: Spontaneous echo-contrast (SEC) appears on B-mode images as moving curls of smoke in the lumen of veins. The aims of this study were to investigate the prevalence and characteristics of internal jugular vein SEC among patients with stroke, in comparison with control subjects. METHODS: We enrolled 97 Korean patients with acute ischemic stroke and 50 controls. Both internal jugular veins were examined for the presence and severity of SEC and measurement of flow velocity. Venous samples were obtained for laboratory evaluation of hematologic factors. RESULTS: In 294 internal jugular veins, the prevalence of SEC was 81% in stroke patients and 68% in controls (odds ratio, 2.0; 95% confidence interval, 1.1-3.6; p = 0.013). Stroke patients were more likely to have SEC on the left (p = 0.025) than on the right (p = 0.184) internal jugular vein. Overall, the association between stroke and SEC remained significant after adjustment for other variables (odds ratio, 4.3; 95% confidence interval, 1.7-10.8; p = 0.002). CONCLUSIONS: Internal jugular vein SEC was found more frequently in stroke patients than in controls. However, local as well as systemic factors must be considered in the interpretation of this finding.

Genome-wide association study of intracranial aneurysm identifies a new association on chromosome 7.

BACKGROUND AND PURPOSE: Common variants have been identified using genome-wide association studies which contribute to intracranial aneurysms (IA) susceptibility. However, it is clear that the variants identified to date do not account for the estimated genetic contribution to disease risk. METHODS: Initial analysis was performed in a discovery sample of 2617 IA cases and 2548 controls of white ancestry. Novel chromosomal regions meeting genome-wide significance were further tested for association in 2 independent replication samples: Dutch (717 cases; 3004 controls) and Finnish (799 cases; 2317 controls). A meta-analysis was performed to combine the results from the 3 studies for key chromosomal regions of interest. RESULTS: Genome-wide evidence of association was detected in the discovery sample on chromosome 9 (CDKN2BAS; rs10733376: P<1.0×10(-11)), in a gene previously associated with IA. A novel region on chromosome 7, near HDAC9, was associated with IA (rs10230207; P=4.14×10(-8)). This association replicated in the Dutch sample (P=0.01) but failed to show association in the Finnish sample (P=0.25). Meta-analysis results of the 3 cohorts reached statistical significant (P=9.91×10(-10)). CONCLUSIONS: We detected a novel region associated with IA susceptibility that was replicated in an independent Dutch sample. This region on chromosome 7 has been previously associated with ischemic stroke and the large vessel stroke occlusive subtype (including HDAC9), suggesting a possible genetic link between this stroke subtype and IA.

The Clinical Impact of Recent Methamphetamine Exposure in Aneurysmal Subarachnoid Patients.

Background: Methamphetamines (MA) are a frequently used drug class with potent sympathomimetic properties that can affect cerebral vasculature. Conflicting reports in literature exist about the effect of exposure to MA on vasospasm risk and clinical outcomes in aneurysmal subarachnoid hemorrhage (aSAH). This study aimed to characterize the impact of recent MA use on the timing, severity and features of vasospasm in aneurysmal subarachnoid as well as neurological outcomes. Methods: We retrospectively screened 441 consecutive patients admitted to a tertiary care hospital with a diagnosis of SAH who underwent at least one cerebral digital subtraction angiogram (DSA). Patients were excluded if no urinary toxicology screen was performed within 24 hours of admission, if there was a diagnosis of non-aneurysmal SAH, or if ictus was greater than 72 hours from hospital admission. Vasospasm characteristics were collected from DSA and transcranial doppler (TCD) studies and demographic as well as clinical outcome data was abstracted from the chart. Results: 129 patients were included and 24 tested positive for MA. Among the 312 excluded patients, 281 did not have a urinary toxicology screen and 31 had a non-aneurysmal pattern of SAH or ictus occurring greater than 72 hours from hospital admission. No significant differences were found in respect to patient age, sex, or admission Hunt and Hess Score or Modified Fisher Scale based on MA use. There was no difference in the severity of vasospasm or time to peak severity using either TCD or DSA criteria on multivariate analysis. Aneurysms were more likely to be in the anterior circulation for both groups, however the MA cohort experienced less vasospasm involving the anterior circulation and more isolated posterior circulation vasospasm. There was no difference in delayed cerebral ischemia (DCI) incidence, length of ICU stay, need for ventriculoperitoneal shunt placement, functional outcome at discharge or hospital mortality. Interpretation: Recent MA use was not associated with worse vasospasm severity, time to vasospasm, or DCI in aSAH patients. Further investigations about localized MA effects in the posterior circulation and impact on long-term functional outcomes are warranted.

Intracranial Hemorrhage Rate and Lesion Burden in Patients With Familial Cerebral Cavernous Malformation.

Background Familial cerebral cavernous alformation (CCM) is an autosomal dominant disease caused by mutations in KRIT1, CCM2, or PDCD10. Cases typically present with multiple lesions, strong family history, and neurological symptoms, including seizures, headaches, or other deficits. Intracranial hemorrhage (ICH) is a severe manifestation of CCM, which can lead to death or long-term neurological deficits. Few studies have reported ICH rates and risk factors in familial CCM. We report ICH rates and assess whether CCM lesion burden, a disease severity marker, is associated with risk of symptomatic ICH during follow-up in a well-characterized cohort of familial CCM cases. Methods and Results We studied 386 patients with familial CCM with follow-up data enrolled in the Brain Vascular Malformation Consortium CCM Project. We estimated symptomatic ICH rates overall and stratified by history of ICH before enrollment. CCM lesion burden (total lesion count and large lesion size) assessed at baseline enrollment was tested for association with increased risk of subsequent ICH during follow-up using Cox regression models adjusted for history of ICH before enrollment, age, sex, and family structure and stratified on recruitment site. The symptomatic ICH rate for familial CCM cases was 2.8 per 100 patient-years (95% CI, 1.9-4.1). Those with ICH before enrollment had a follow-up ICH rate of 4.5 per 100 patient-years (95% CI, 2.6-8.1) compared with 2.0 per 100 patient-years (95% CI, 1.3-3.5) in those without (P=0.042). Total lesion count was associated with increased risk of ICH during follow-up (hazard ratio [HR], 1.37 per doubling of total lesion count [95% CI, 1.10-1.71], P=0.006). The symptomatic ICH rate for familial CCM cases was 2.8 per 100 patient-years (95% CI, 1.9-4.1). Those with ICH before enrollment had a follow-up ICH rate of 4.5 per 100 patient-years (95% CI, 2.6-8.1) compared with 2.0 per 100 patient-years (95% CI, 1.3-3.5) in those without (P=0.042). Total lesion count was associated with increased risk of ICH during follow-up (hazard ratio [HR], 1.37 per doubling of total lesion count [95% CI, 1.10-1.71], P=0.006). Conclusions Patients with familial CCM with prior history of an ICH event are at higher risk for rehemorrhage during follow-up. In addition, total CCM lesion burden is significantly associated with increased risk of subsequent symptomatic ICH; hence lesion burden may be an important predictor of patient outcome and aid patient risk stratification.

Genome-wide association study of intracranial aneurysms confirms role of Anril and SOX17 in disease risk.

BACKGROUND: Genomewide association studies have identified novel genetic factors that contribute to intracranial aneurysm (IA) susceptibility. We sought to confirm previously reported loci, to identify novel risk factors, and to evaluate the contribution of these factors to familial and sporadic IA. METHOD: We utilized 2 complementary samples, one recruited on the basis of a dense family history of IA (discovery sample 1: 388 IA cases and 397 controls) and the other without regard to family history (discovery sample 2: 1095 IA cases and 1286 controls). Imputation was used to generate a common set of single nucleotide polymorphisms (SNP) across samples, and a logistic regression model was used to test for association in each sample. Results from each sample were then combined in a metaanalysis. RESULTS: There was only modest overlap in the association results obtained in the 2 samples. In neither sample did results reach genomewide significance. However, the metaanalysis yielded genomewide significance for SNP on chromosome 9p (CDKN2BAS; rs6475606; P=3.6×10(-8)) and provided further evidence to support the previously reported association of IA with SNP in SOX17 on chromosome 8q (rs1072737; P=8.7×10(-5)). Analyses suggest that the effect of smoking acts multiplicatively with the SNP genotype, and smoking has a greater effect on risk than SNP genotype. CONCLUSIONS: In addition to replicating several previously reported loci, we provide further evidence that the association on chromosome 9p is attributable to variants in CDKN2BAS (also known as ANRIL, an antisense noncoding RNA).

Vascular myelopathies.

Vascular abnormalities of the spinal cord are an important cause of myelopathy. Clinicians need to be aware of these disorders as they can present with a variety of neurologic symptoms ranging from acute spinal neurologic emergencies, relapsing/remitting spells to gradually progressive dysfunction. The unique topography and vascular anatomy of the spinal cord lends to the variety of clinical presentations. Both ischemic and hemorrhagic insults can occur. Increased clinical suspicion, better detection with newer imaging modalities and early treatment can often impact outcomes. The authors review clinical diagnoses, novel imaging, and advanced treatment modalities for the most common causes of vascular myelopathy.