Loss of consciousness at onset of aneurysmal subarachnoid hemorrhage in good-grade patients.

Loss of consciousness (LOC) at presentation with aneurysmal subarachnoid hemorrhage (aSAH) has been associated with early brain injury and poor functional outcome. The impact of LOC on the clinical course after aSAH deserves further exploration. A retrospective analysis of 149 aSAH patients who were prospectively enrolled in the Cerebral Aneurysm Renin Angiotensin Study (CARAS) between 2012 and 2015 was performed. The impact of LOC was analyzed with emphasis on patients presenting in excellent or good neurological condition (Hunt and Hess 1 and 2). A total of 50/149 aSAH patients (33.6%) experienced LOC at presentation. Loss of consciousness was associated with severity of neurological condition upon admission (Hunt and Hess, World Federation of Neurosurgical Societies (WFNS), Glasgow Coma Scale (GCS) grade), hemorrhage burden on initial head CT (Fisher CT grade), acute hydrocephalus, cardiac instability, and nosocomial infection. Of Hunt and Hess grade 1 and 2 patients, 21/84 (25.0%) suffered LOC at presentation. Cardiac instability and nosocomial infection were significantly more frequent in these patients. In multivariable analysis, LOC was the predominant predictor of cardiac instability and nosocomial infection. Loss of consciousness at presentation with aSAH is associated with an increased rate of complications, even in good-grade patients. The presence of LOC may identify good-grade patients at risk for complications such as cardiac instability and nosocomial infection.

The role of endothelial nitric oxide synthase -786 T/C polymorphism in cardiac instability following aneurysmal subarachnoid hemorrhage.

INTRODUCTION: Cardiac abnormalities are observed frequently after aneurysmal subarachnoid hemorrhage (aSAH). A subset of aSAH patients develops neurogenic cardiomyopathy, likely induced by catecholamine excess. Genetic polymorphisms of the endothelial nitric oxide synthase (eNOS) gene have been linked to decreased nitric oxide (NO) levels, coronary artery spasm, and myocardial infarction. The role of the eNOS single nucleotide polymorphism (SNP) -786 T/C in cardiac instability following aSAH has not been previously investigated. METHODS: From 2012 to 2015, aSAH patients were prospectively enrolled in the Cerebral Aneurysm Renin Angiotensin System (CARAS) study at two academic institutions. Blood samples were used to assess the eNOS SNP -786 T/C rs2070744 through 5'exonuclease (Taqman) genotyping assays. Associations between this polymorphism and cardiac instability following aSAH were analyzed. RESULTS: Multivariable analysis demonstrated a dominant effect of the C allele of eNOS SNP -786 T/C on cardiac instability in patients with aSAH. A lower Glasgow Coma Scale score and a history of ischemic vascular disease were also associated with cardiac instability. Furthermore, cardiac instability independently predicted poor functional outcome upon discharge from the hospital. CONCLUSIONS: The C allele of the eNOS SNP -786 T/C was independently associated with an increased risk for cardiac instability following aSAH. Cardiac instability itself was a risk factor for an unfavorable functional outcome upon discharge from the hospital.

Haplotype analysis of SERPINE1 gene: Risk for aneurysmal subarachnoid hemorrhage and clinical outcomes.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) has high fatality and permanent disability rates due to the severe damage to brain cells and inflammation. The SERPINE1 gene that encodes PAI-1 for the regulation of tissue plasminogen activator is considered an important therapeutic target for aSAH. METHODS: Six SNPs in the SERPINE1 gene (in order of rs2227631, rs1799889, rs6092, rs6090, rs2227684, rs7242) were investigated. Blood samples were genotyped with Taqman genotyping assays and pyrosequencing. The experiment-wide statistically significant threshold for single marker analysis was set at p < 0.01 after evaluation of independent markers. Haplotype analysis was performed in Haplo.stats package with permutation tests. Bonferroni correction for multiple comparison in dominant, additive, and recessive model was applied. RESULTS: A total of 146 aSAH patients and 49 control subjects were involved in this study. The rs2227631 G allele is significant (p = 0.01) for aSAH compared to control. In aSAH group, haplotype analysis showed that G5GGGT homozygotes in recessive model were associated with delayed cerebral ischemia (p < 0.01, Odds Ratio = 5.14, 95% CI = 1.45-18.18), clinical vasospasm (p = 0.01, Odds Ratio = 4.58, 95% CI = 1.30-16.13), and longer intensive care unit stay (p = 0.01). By contrast, the G5GGAG carriers were associated with less incidence of cerebral edema (p < 0.01) and higher Glasgow Coma Scale (p < 0.01). The A4GGGT carriers were associated with less incidence of severe hypertension (>140/90) (p < 0.01). CONCLUSION: The results suggested an important regulatory role of the SERPINE1 gene polymorphism in clinical outcomes of aSAH.

PHASES score applied to a prospective cohort of aneurysmal subarachnoid hemorrhage patients.

The treatment of unruptured intracranial aneurysms remains controversial. The PHASES score was developed to predict the 5-year risk of aneurysm rupture. We have assigned PHASES scores to a cohort of aneurysmal subarachnoid hemorrhage (aSAH) patients to assess the distribution of scores and its ability to predict outcome. In this study, the PHASES score was applied to a prospective cohort of aSAH patients that were enrolled in the Cerebral Aneurysm Renin Angiotensin System (CARAS) study. The CARAS study enrolled patients from two academic institutions in the United States from 2012 to 2015. Univariable and multivariable analyses were performed to identify factors predictive of outcome at last follow up. One hundred and forty-nine aSAH patients were included with a mean age of 54.9 ±â€¯12.5 years. Most ruptured aneurysms were <7 mm (62.4%) and located in the anterior circulation (80.5%). Favorable functional outcome (mRS 0-2) at last follow up was achieved in 61.7% of patients. PHASES scores ranged from 0 to 16 with a median of 5; the majority of patients had a score of 4 (20.1%) or 5 (32.2%). Multivariable modeling identified higher PHASES scores (OR 1.235, CI 1.016-1.501, p = 0.034) and higher Hunt and Hess grades (OR 2.224, CI 1.353-3.655, p = 0.002) as independent predictors of poor functional outcome (mRS 3-6) at last follow up. The majority of aSAH patients present with low (≤5) PHASES scores. Elevated PHASES scores are independently associated with poor functional outcome in patients with aSAH.

Association of cystathionine beta-synthase polymorphisms and aneurysmal subarachnoid hemorrhage.

OBJECTIVE Cystathionine ß-synthase (CBS) is involved in homocysteine and hydrogen sulfide (H2S) metabolism. Both products have been implicated in the pathophysiology of cerebrovascular diseases. The impact of CBS polymorphisms on aneurysmal subarachnoid hemorrhage (aSAH) and its clinical sequelae is poorly understood. METHODS Blood samples from all patients enrolled in the CARAS (Cerebral Aneurysm Renin Angiotensin System) study were used for genetic evaluation. The CARAS study prospectively enrolled aSAH patients at 2 academic institutions in the United States from 2012 to 2015. Common CBS polymorphisms were detected using 5'exonuclease genotyping assays. Analysis of associations between CBS polymorphisms and aSAH was performed. RESULTS Samples from 149 aSAH patients and 50 controls were available for analysis. In multivariate logistic regression analysis, the insertion allele of the 844ins68 CBS insertion polymorphism showed a dominant effect on aSAH. The GG genotype of the CBS G/A single nucleotide polymorphism (rs234706) was independently associated with unfavorable functional outcome (modified Rankin Scale Score 3-6) at discharge and last follow-up, but not clinical vasospasm or delayed cerebral ischemia (DCI). CONCLUSIONS The insertion allele of the 844ins68 CBS insertion polymorphism was independently associated with aSAH while the GG genotype of rs234706 was associated with an unfavorable outcome both at discharge and last follow-up. Increased CBS activity may exert its neuroprotective effects through alteration of H2S levels, and independent of clinical vasospasm and DCI.

Associations between endothelin polymorphisms and aneurysmal subarachnoid hemorrhage, clinical vasospasm, delayed cerebral ischemia, and functional outcome.

OBJECTIVE Endothelin-1, a potent vasoconstrictor, and its receptors may be involved in the pathogenesis of aneurysmal subarachnoid hemorrhage (aSAH), clinical vasospasm, delayed cerebral ischemia (DCI), and functional outcome following aSAH. In the present study, common endothelin single nucleotide polymorphisms (SNPs) and their relation to aSAH were evaluated. METHODS Blood samples from all patients enrolled in the Cerebral Aneurysm Renin Angiotensin System (CARAS) study were used for genetic evaluation. The CARAS study prospectively enrolled patients with aSAH at 2 academic institutions in the US from 2012 to 2015. Common endothelin SNPs were detected using 5' exonnuclease (TaqMan) genotyping assays. Analysis of associations between endothelin SNPs and aSAH and its clinical sequelae was performed. RESULTS Samples from 149 patients with aSAH and 50 controls were available for analysis. In multivariate logistic regression analysis, the TG (odds ratio [OR] 2.102, 95% confidence interval [CI] 1.048-4.218, p = 0.036) and TT genotypes (OR 7.884, 95% CI 1.003-61.995, p = 0.05) of the endothelin-1 T/G SNP (rs1800541) were significantly associated with aSAH. There was a dominant effect of the G allele (CG/GG genotypes; OR 4.617, 95% CI 1.311-16.262, p = 0.017) of the endothelin receptor A G/C SNP (rs5335) on clinical vasospasm. Endothelin SNPs were not associated with DCI or functional outcome. CONCLUSIONS Common endothelin SNPs were found to be associated with presentation with aSAH and clinical vasospasm. Further studies are required to elucidate the relevant pathophysiology and its potential implications in the treatment of patients with aSAH.

Association of renin-angiotensin system genetic polymorphisms and aneurysmal subarachnoid hemorrhage.

OBJECTIVE Renin-angiotensin system (RAS) genetic polymorphisms are thought to play a role in cerebral aneurysm formation and rupture. The Cerebral Aneurysm Renin-Angiotensin System (CARAS) study prospectively evaluated common RAS polymorphisms and their relation to aneurysmal subarachnoid hemorrhage (aSAH). METHODS The CARAS study prospectively enrolled aSAH patients and controls at 2 academic centers in the United States. A blood sample was obtained from all patients for genetic evaluation and measurement of plasma angiotensin-converting enzyme (ACE) concentration. Common RAS polymorphisms were detected using 5' exonuclease (TaqMan) genotyping assays and restriction fragment length polymorphism analysis. RESULTS Two hundred forty-eight patients were screened, and 149 aSAH patients and 50 controls were available for analysis. There was a recessive effect of the C allele of the angiotensinogen ( AGT) C/T single-nucleotide polymorphism (SNP) (OR 1.94, 95% CI 0.912-4.12, p = 0.0853) and a dominant effect of the G allele of the angiotensin II receptor Type 2 ( AT2) G/A SNP (OR 2.11, 95% CI 0.972-4.57, p = 0.0590) on aSAH that did not reach statistical significance after adjustment for potential confounders. The ACE level was significantly lower in aSAH patients with the II genotype (17.6 ± 8.0 U/L) as compared with the ID (22.5 ± 12.1 U/L) and DD genotypes (26.6 ± 14.2 U/L) (p = 0.0195). CONCLUSIONS The AGT C/T and AT2 G/A polymorphisms were not significantly associated with aSAH after controlling for potential confounders. However, a strong trend was identified for a dominant effect of the G allele of the AT2 G/A SNP. Downregulation of the local RAS may contribute to the formation of cerebral aneurysms and subsequent presentation with aSAH. Further studies are required to elucidate the relevant pathophysiology and its potential implication in treatment of patients with aSAH.

Giant intracranial teratoma with epignathus in a neonate. Case report and review of the literature.

Epignathus, a congenital oropharyngeal teratoma, is a rare clinical entity with variable clinical outcomes described in the literature. Even fewer cases of epignathus with intracranial extension have been reported, all with poor outcomes. In this manuscript, the authors present a case of epignathus with intracranial extension, emphasizing clinical presentation, imaging findings, a staged surgical approach, multidisciplinary management, and outcome.

Extended survival after evacuation of subdural hematoma in a 102-year-old patient: case report and review of the literature.

BACKGROUND: Outcomes for elderly patients undergoing craniotomy for evacuation of subdural hematoma (SDH) have been reported to be poor with high mortality rates. CASE DESCRIPTION: We present the case of a patient who underwent craniotomies at the age of 102 years, and again at the age of 103 years, for acute SDHs with good recovery to her premorbid neurologic condition. A 102-year-old woman presented after falling to the floor, and underwent a left-sided craniotomy for evacuation of a large, left hemispheric acute SDH. She recovered from that event and returned home. Six months later, she presented after falling again and was found to have a large, right hemispheric acute SDH. A right-sided craniotomy was performed and again she made good recovery with return to her neurologic baseline. CONCLUSION: We report this unique case of good recovery after 2 separate craniotomies for acute SDH in a patient older than 100 years. Implications of acute SDH in the elderly are discussed, as relevant to this case, with a review of the literature. Although the morbidity and mortality of acute SDH are high, particularly in elderly patients, there is potential for good recovery and excellent outcome in appropriately selected patients.

Endothelial Nitric Oxide Synthase Polymorphism Is Associated with Delayed Cerebral Ischemia Following Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND AND PURPOSE: Nitric oxide is critical in the regulation of cerebral blood flow and smooth muscle proliferation. It is synthesized by 3 nitric oxide synthase (NOS) isoforms: neuronal, inducible, and endothelial NOS (eNOS). Aneurysmal subarachnoid hemorrhage (aSAH) causes endothelial dysfunction that, in turn, contributes to pathophysiologic processes surrounding aSAH. Previous studies reported an association of an eNOS single nucleotide polymorphism (SNP) with the clinical sequelae of aSAH. Here, we further elucidate the impact of this eNOS SNP on the clinical course after aSAH. METHODS: The Cerebral Aneurysm Renin Angiotensin System study prospectively enrolled aSAH patients at 2 academic institutions in the United States from 2012-2015. Blood samples from all patients enrolled in the study were used for genetic evaluation using 5'exonuclease (Taqman) genotyping assays. Associations between the eNOS SNP rs2070744 (786 T->C) and clinical course after aSAH were analyzed. RESULTS: Samples from 149 aSAH patients were available for analysis. The C allele of the eNOS SNP independently predicted an increased risk for delayed cerebral ischemia (OR = 2.936, 95% CI 1.048-8.226, P = 0.040). The eNOS SNP rs2070744 was not associated with functional outcome or size of aneurysm at the time of rupture. CONCLUSIONS: The present study is the first to demonstrate that the C allele of the eNOS SNP 786 T->C rs2070744 is independently associated with an increased risk for delayed cerebral ischemia following aSAH.

Impact of High-Mobility Group Box 1 Polymorphism on Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND AND OBJECTIVE: The high-mobility group box 1 (HMGB1) protein is a eukaryotic, ubiquitously expressed protein that serves as a biomarker for various diseases and is involved in the promotion of a proinflammatory response to cell injury. In aneurysmal subarachnoid hemorrhage (aSAH), increased HMGB1 levels have been linked to poor outcome and an increased risk for cerebral vasospasm. The role of HMGB1 polymorphisms in aSAH has not been previously investigated. METHODS: Patients with aSAH and controls enrolled in the prospective, 2-center CARAS (Cerebral Aneurysm Renin Angiotensin System) study were evaluated. The 3814 C/G HMGB1 single nucleotide polymorphism (SNP) rs2249825 was detected using 5'exonuclease (Taqman) genotyping assays from blood samples from patients with aSAH and controls. Associations between aSAH and its clinical sequelae with the HMGB1 SNP were assessed. RESULTS: Samples from 149 patients with aSAH and 50 controls were available for analysis. No increased risk for aSAH associated with the SNP was found compared with the control group. Delayed cerebral ischemia (DCI) was defined as a cerebral infarction at the time of discharge from the intensive care unit and identified in 21.2% of patients with aSAH. In multivariable logistic regression analysis, the G allele of rs2249825 was independently associated with DCI (odds ratio, 5.695; 95% confidence interval, 1.804-17.975; P = 0.003). CONCLUSIONS: The minor allele G of rs2249825 was associated with an increased risk for DCI, or cerebral infarction, after aSAH. This finding may be attributable to an increased HMGB1 protein expression in these patients.

Association of Plasminogen Activator Inhibitor 1 (SERPINE1) Polymorphisms and Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Genetic variations of the serine proteinase inhibitor family E member 1 (SERPINE1) gene, which encodes plasminogen activator inhibitor 1, correlate with serum levels of its product and are associated with thrombophilia and coronary atherosclerosis. Various SERPINE1 ;gene polymorphisms have been identified. However, only the functional 5G/4G polymorphism has been assessed in the context of aneurysmal subarachnoid hemorrhage (aSAH). We assessed associations of 6 SERPINE1 polymorphisms with the clinical sequelae of aSAH. METHODS: From 2012 to 2015, patients with aSAH were prospectively enrolled into the CARAS (Cerebral Aneurysm Renin Angiotensin System) study at 2 major academic institutions. Blood samples were used to evaluate 6 common SERPINE1 single nucleotide polymorphisms via 5' exonuclease (Taqman) genotyping assays. RESULTS: There was an association of the AA genotype of rs2227631 with the 4G/4G genotype and of the GG genotype of rs7242 with the AA genotype of rs2227684. In multivariable analysis, patients with the AA genotype of rs2227631 and 4G/4G genotype had an increased risk for developing delayed cerebral ischemia. Patients with the GG genotype of rs7242 and AA genotype of rs2227684 had a decreased risk for a poor functional outcome. CONCLUSIONS: SERPINE1 gene polymorphisms were associated with delayed cerebral ischemia and functional outcome after aSAH. These associations may arise from alterations of plasminogen activator inhibitor 1 levels.

Ryanodine Receptor 1 Polymorphism Is Not Associated with Aneurysmal Subarachnoid Hemorrhage or its Clinical Sequelae.

OBJECTIVE: The pathophysiologic mechanisms underlying cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH) remain poorly understand. Ryanodine receptors (RYR) are intracellular calcium channels involved in the regulation of vascular smooth muscle cells and cerebrovascular tone and diameter. Previous work reported an association between an RYR polymorphism and cerebral vasospasm. Here, we sought to assess the impact of that RYR polymorphism on aSAH and its clinical sequelae. METHODS: Blood samples from all patients enrolled in the CARAS (Cerebral Aneurysm Renin Angiotensin System) study were used for genetic evaluation. The RYR1 single nucleotide polymorphism (SNP) rs35364374 was detected using 5'exonuclease (Taqman) genotyping assays. Associations between the RYR1 polymorphism and aSAH and its clinical sequelae were analyzed. RESULTS: Samples from 149 patients with aSAH and 50 controls were available for analysis. Multivariable regression analysis did not show an association of RYR1 SNP rs35364374 with aSAH. Moreover, there was no association of RYR1 SNP rs35364374 with clinical vasospasm, delayed cerebral ischemia, functional outcome at discharge, or functional outcome at last follow-up. CONCLUSIONS: Contrary to a previous report, the RYR1 SNP rs35364374 was not associated with aSAH or its clinical sequelae.

Endothelin polymorphisms as a risk factor for cerebral aneurysm rebleeding following aneurysmal subarachnoid hemorrhage.

BACKGROUND: Aneurysm rebleeding following presentation with aneurysmal subarachnoid hemorrhage (aSAH) is associated with high mortality and poor functional outcome. While a substantial genetic contribution to aneurysm formation and rupture is known, the genetic influence on the risk of rebleeding is poorly understood. OBJECTIVE: To evaluate the role of common endothelin polymorphisms in aneurysm rebleeding. PATIENTS AND METHODS: Blood sample from all patients enrolled in the CARAS (Cerebral Aneurysm Renin Angiotensin System) study were used for genetic evaluation. The CARAS study prospectively enrolled aSAH patients at two academic institutions in the United States from 2012 to 2015. Common endothelin SNPs were detected using 5'exonnuclease (Taqman) genotyping assays. Analysis of associations between endothelin single nucleotide polymorphisms (SNP) and aneurysm rebleeding was performed. RESULTS: One hundred and forty-nine aSAH patients were included. Acute spontaneous aneurysm rebleeding occurred in 5 (3.4%) patients. Multivariable analysis identified the TT genotype for EDN1 G/T SNP (rs2070699; OR 97.4, 95% CI 3.825-2479.984, p=0.006) as an independent risk factor for aneurysm rebleeding. Aneurysm rebleeding was associated with an unfavorable functional outcome (mRS 3-6) at last follow up in all 5 patients. CONCLUSION: Aneurysm rebleeding following presentation with aSAH was independently associated with the TT genotype of the EDN1 G/T SNP. All patients with acute spontaneous aneurysm rebleeding suffered a poor functional outcome at last follow up.

Associations of renin-angiotensin system genetic polymorphisms and clinical course after aneurysmal subarachnoid hemorrhage.

OBJECTIVE Renin-angiotensin system (RAS) genetic polymorphisms are thought to play a role in cerebral aneurysm formation and rupture. The Cerebral Aneurysm Renin Angiotensin System (CARAS) study prospectively evaluated associations of common RAS polymorphisms and clinical course after aneurysmal subarachnoid hemorrhage (aSAH). METHODS The CARAS study prospectively enrolled aSAH patients at 2 academic centers in the United States. A blood sample was obtained from all patients for genetic evaluation and measurement of plasma angiotensin converting enzyme (ACE) concentration. Common RAS polymorphisms were detected using 5'exonuclease genotyping assays and pyrosequencing. Analysis of associations of RAS polymorphisms and clinical course after aSAH were performed. RESULTS A total of 166 patients were screened, and 149 aSAH patients were included for analysis. A recessive effect of allele I (insertion) of the ACE I/D (insertion/deletion) polymorphism was identified for Hunt and Hess grade in all patients (OR 2.76, 95% CI 1.17-6.50; p = 0.0206) with subsequent poor functional outcome. There was a similar effect on delayed cerebral ischemia (DCI) in patients 55 years or younger (OR 3.63, 95% CI 1.04-12.7; p = 0.0439). In patients older than 55 years, there was a recessive effect of allele A of the angiotensin II receptor Type 2 (AT2) A/C single nucleotide polymorphism (SNP) on DCI (OR 4.70, 95% CI 1.43-15.4; p = 0.0111). CONCLUSIONS Both the ACE I/D polymorphism and the AT2 A/C single nucleotide polymorphism were associated with an age-dependent risk of delayed cerebral ischemia, whereas only the ACE I/D polymorphism was associated with poor clinical grade at presentation. Further studies are required to elucidate the relevant pathophysiology and its potential implication in the treatment of patients with aSAH.

Predictors of Shunt Insertion in Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVE: Hydrocephalus is a common complication of aneurysmal subarachnoid hemorrhage (aSAH), requiring permanent cerebrospinal fluid (CSF) diversion in up to two thirds of patients. Factors that predict permanent CSF diversion are not well established. METHODS: An exploratory analysis of 149 patients enrolled in the CARAS (Cerebral Aneurysm Renin Angiotensin System) study was performed in an effort to identify factors predictive of permanent CSF diversion after aSAH; only the 135 patients surviving the initial hospitalization were included in the present study. CARAS was a prospective, multicenter study investigating the impact of genetic polymorphisms in patients with aSAH and enrolled patients from September 2012 to January 2015. RESULTS: One hundred and forty-nine patients with aSAH were enrolled in CARAS, with 135 (90.6%) patients surviving the initial hospitalization. Sixty-four of these patients (47.4%) required permanent CSF diversion. Multivariable analysis identified the following as independent risk factors: sympathomimetic illicit drug use, external ventricular drain (EVD) insertion, and hyponatremia. A scoring system based on EVD insertion (2 points), Hunt and Hess grade (1 point if grade ≥4) and modified Fisher computed tomography grade (1 point if grade 4) produced an area under the curve of 0.8 (P < 0.001). CONCLUSIONS: Sympathomimetic illicit drug use, EVD insertion, and hyponatremia are the strongest predictors of shunt insertion in patients with aSAH. Moreover, a scoring system based on EVD insertion, Hunt and Hess grade, and modified Fisher computed tomography grade can reliably predict the need for shunt placement in patients with aSAH.

Associations of Endothelin Polymorphisms and Aneurysm Size at Time of Rupture.

BACKGROUND AND PURPOSE: Aneurysm size is an important risk factor for aneurysm rupture. The pathophysiologic mechanisms underlying aneurysm growth remain poorly understood. Endothelin signaling is critical for cerebrovascular blood flow regulation. The influence of endothelin single nucleotide polymorphisms (SNPs) on aneurysm size at the time of rupture has not been previously investigated. METHODS: Eight common endothelin SNPs were assessed using blood samples from aneurysmal subarachnoid hemorrhage (aSAH) patients enrolled in the Cerebral Aneurysm Renin Angiotensin System study, a prospective, 2-center study that enrolled aSAH patients and controls in the United States from 2012-2015. Genetic evaluation was performed using 5'exonnuclease (Taqman) genotyping assays. Associations of endothelin SNPs and aneurysm size were analyzed. RESULTS: One-hundred and forty-nine blood samples from aSAH patients were available for analysis. There was a dominant effect of the G allele of the endothelin receptor type A (EDNRA) SNP rs5335 on aneurysm size ≥7 mm (odds ratio = 2.740, 95% confidence interval 1.039-7.228, P = 0.042) along with associations with race and presence of additional aneurysms. The other endothelin SNPs were not associated with aneurysm size. CONCLUSIONS: The EDNRA SNP rs5335 was independently associated with aneurysms ≥7 mm in size at the time of rupture. Patients with cerebral aneurysms also carrying the G allele of EDNRA SNP rs5335 may develop larger aneurysms before rupture.

Embolic Stroke: A Rare but Probably Real Cause of Aneurysmal-Like Subarachnoid Hemorrhage.

BACKGROUND: Ischemic stroke is being increasingly recognized as a possible cause of spontaneous isolated convexity subarachnoid hemorrhage (SAH). However, it is a much less established cause of cisternal, aneurysmal-like SAH. Only 3 case reports of concomitant cisternal SAH and perforator infarcts exist in the literature, raising the possibility of perforating artery rupture as a potential mechanism. In contrast, embolic stroke is not recognized as a cause of aneurysmal-like SAH. CASE DESCRIPTION: In 2 patients with embolic cerebral infarctions mimicking intracranial aneurysm rupture, diagnosis was confirmed by magnetic resonance imaging with diffusion-weighted imaging after cerebral angiography failed to reveal an underlying vascular lesion. Extracranial atherosclerosis was identified as the source of emboli in each case. One patient was started on antiplatelet therapy, and the other underwent surgical revascularization. Both patients had a favorable hospital course, with no recurrent hemorrhage or ischemia. CONCLUSIONS: Based on these observations, embolic stroke should be included in the differential diagnosis of angiogram-negative SAH. Therefore, brain magnetic resonance imaging and vascular imaging of the neck should be part of the routine work-up of this relatively common entity.

Association of nosocomial infections with delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage.

OBJECTIVE Delayed cerebral ischemia (DCI) is a recognized complication of aneurysmal subarachnoid hemorrhage (aSAH) that contributes to poor outcome. This study seeks to determine the effect of nosocomial infection on the incidence of DCI and patient outcome. METHODS An exploratory analysis was performed on 156 patients with aSAH enrolled in the Cerebral Aneurysm Renin Angiotensin System study. Clinical and radiographic data were analyzed with univariate analysis to detect risk factors for the development of DCI and poor outcome. Multivariate logistic regression was performed to identify independent predictors of DCI. RESULTS One hundred fifty-three patients with aSAH were included. DCI was identified in 32 patients (20.9%). Nosocomial infection (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.09-11.2, p = 0.04), ventriculitis (OR 25.3, 95% CI 1.39-458.7, p = 0.03), aneurysm re-rupture (OR 7.55, 95% CI 1.02-55.7, p = 0.05), and clinical vasospasm (OR 43.4, 95% CI 13.1-143.4, p < 0.01) were independently associated with the development of DCI. Diagnosis of nosocomial infection preceded the diagnosis of DCI in 15 (71.4%) of 21 patients. Patients diagnosed with nosocomial infection experienced significantly worse outcomes as measured by the modified Rankin Scale score at discharge and 1 year (p < 0.01 and p = 0.03, respectively). CONCLUSIONS Nosocomial infection is independently associated with DCI. This association is hypothesized to be partly causative through the exacerbation of systemic inflammation leading to thrombosis and subsequent ischemia.

Recurrent Perimesencephalic Subarachnoid Hemorrhage After 12 Years: Missed Diagnosis, Vulnerable Anatomy, or Random Events?

BACKGROUND: Perimesencephalic subarachnoid hemorrhage (PMSAH) is a well-defined subtype of angiogram-negative SAH, characterized by a benign natural history and a virtually nonexistent risk of recurrence. Few case reports of recurrent PMSAH exist in the literature, all occurring after relatively short time intervals ranging from 5 days to 31 months, mostly in patients on antithrombotic therapy. We present a unique case of ultra-late PMSAH recurrence after 12 years, in a patient not receiving antithrombotic medications. CASE DESCRIPTION: A woman presented with 2 similar episodes of sudden-onset severe headache and neck pain, without associated neurologic deficits: a first episode at the age of 48 years and a second at 60 years. In each instance, the pattern of hemorrhage was consistent with PMSAH, platelet count and coagulation tests were normal, and a full etiologic work-up, including CTA, catheter angiography, and magnetic resonance imaging, failed to reveal an underlying vascular or tumoral etiology. The patient had a favorable clinical course each time. CONCLUSIONS: Although exceptional, recurrence of PMSAH is not impossible. If the 2 events are assumed to be random and independent of each other, binomial statistics yield approximately a 79 per billion chance of 2 or more episodes occurring over an 80-year lifetime. However, other possibilities should be kept in mind, including tiny and radiographically occult vascular lesions or particular venous anatomy predisposing patients to recurrent bouts of PMSAH. Patients should not be told that the risk of recurrence is zero, but that it is close to zero.