Nerissa U. Ko

Predictors of Neurocardiogenic Injury After Subarachnoid Hemorrhage

Background and Purpose— Subarachnoid hemorrhage (SAH) frequently results in myocardial necrosis with release of cardiac enzymes. Historically, this necrosis has been attributed to coronary artery disease, coronary vasospasm, or oxygen supply-demand mismatch. Experimental evidence, however, indicates that excessive release of norepinephrine from the myocardial sympathetic nerves is the most likely cause. We hypothesized that myocardial necrosis after SAH is a neurally mediated process that is dependent on the severity of neurological injury. Methods— Consecutive patients admitted with SAH were enrolled prospectively. Predictor variables reflecting demographic (age, sex, body surface area), hemodynamic (heart rate, systolic blood pressure), treatment (phenylephrine dose), and neurological (Hunt-Hess score) factors were recorded. Serial cardiac troponin I measurements and echocardiography were performed on days 1, 3, and 6 after enrollment. Troponin level was treated as a dichotomous outcome variable. We performed univariate and multivariate analyses on the relationships between the predictor variables and troponin level. Results— The study included 223 patients with an average age of 54 years. Twenty percent of the subjects had troponin I levels >1.0 &mgr;g/L (range, 0.3 to 50 &mgr;g/L). By multivariate logistic regression, a Hunt-Hess score >2, female sex, larger body surface area and left ventricular mass, lower systolic blood pressure, and higher heart rate and phenylephrine dose were independent predictors of troponin elevation. Conclusions— The degree of neurological injury as measured by the Hunt-Hess grade is a strong, independent predictor of myocardial necrosis after SAH. This finding supports the hypothesis that cardiac injury after SAH is a neurally mediated process.

Hypertonic saline versus mannitol for the treatment of elevated intracranial pressure: a meta-analysis of randomized clinical trials.

Objectives:Randomized trials have suggested that hypertonic saline solutions may be superior to mannitol for the treatment of elevated intracranial pressure, but their impact on clinical practice has been limited, partly by their small size. We therefore combined their findings in a meta-analysis. Data Sources:We searched for relevant studies in MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, and ISI Web of Knowledge. Study Selection:Randomized trials were included if they directly compared equiosmolar doses of hypertonic sodium solutions to mannitol for the treatment of elevated intracranial pressure in human subjects undergoing quantitative intracranial pressure measurement. Data Extraction:Two investigators independently reviewed potentially eligible trials and extracted data using a preformed data collection sheet. Disagreements were resolved by consensus or by a third investigator if needed. We collected data on patient demographics, type of intracranial pathology, baseline intracranial pressure, osms per treatment dose, quantitative change in intracranial pressure, and prespecified adverse events. Our primary outcome was the proportion of successfully treated episodes of elevated intracranial pressure. Data Synthesis:Five trials comprising 112 patients with 184 episodes of elevated intracranial pressure met our inclusion criteria. In random-effects models, the relative risk of intracranial pressure control was 1.16 (95% confidence interval, 1.00–1.33), and the difference in mean intracranial pressure reduction was 2.0 mm Hg (95% confidence interval, −1.6 to 5.7), with both favoring hypertonic saline over mannitol. A mild degree of heterogeneity was present among the included trials. There were no significant adverse events reported. Conclusions:We found that hypertonic saline is more effective than mannitol for the treatment of elevated intracranial pressure. Our meta-analysis is limited by the small number and size of eligible trials, but our findings suggest that hypertonic saline may be superior to the current standard of care and argue for a large, multicenter, randomized trial to definitively establish the first-line medical therapy for intracranial hypertension.

Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm

Genetic risk factors for intracranial aneurysm (IA) are not yet fully understood. Genomewide association studies have been successful at identifying common variants; however, the role of rare variation in IA susceptibility has not been fully explored. In this study, we report the use of whole exome sequencing (WES) in seven densely-affected families (45 individuals) recruited as part of the Familial Intracranial Aneurysm study. WES variants were prioritized by functional prediction, frequency, predicted pathogenicity, and segregation within families. Using these criteria, 68 variants in 68 genes were prioritized across the seven families. Of the genes that were expressed in IA tissue, one gene (TMEM132B) was differentially expressed in aneurysmal samples (n=44) as compared to control samples (n=16) (false discovery rate adjusted p-value=0.023). We demonstrate that sequencing of densely affected families permits exploration of the role of rare variants in a relatively common disease such as IA, although there are important study design considerations for applying sequencing to complex disorders. In this study, we explore methods of WES variant prioritization, including the incorporation of unaffected individuals, multipoint linkage analysis, biological pathway information, and transcriptome profiling. Further studies are needed to validate and characterize the set of variants and genes identified in this study.

Ten-Year Detection Rate of Brain Arteriovenous Malformations in a Large, Multiethnic, Defined Population

Background and Purpose— To evaluate whether increased neuroimaging use is associated with increased brain arteriovenous malformation (BAVM) detection, we examined detection rates in the Kaiser Permanente Medical Care Program of northern California between 1995 and 2004. Methods— We reviewed medical records, radiology reports, and administrative databases to identify BAVMs, intracranial aneurysms (IAs: subarachnoid hemorrhage [SAH] and unruptured aneurysms), and other vascular malformations (OVMs: dural fistulas, cavernous malformations, Vein of Galen malformations, and venous malformations). Poisson regression (with robust standard errors) was used to test for trend. Random-effects meta-analysis generated a pooled measure of BAVM detection rate from 6 studies. Results— We identified 401 BAVMs (197 ruptured, 204 unruptured), 570 OVMs, and 2892 IAs (2079 SAHs and 813 unruptured IAs). Detection rates per 100 000 person-years were 1.4 (95% CI, 1.3 to 1.6) for BAVMs, 2.0 (95% CI, 1.8 to 2.3) for OVMs, and 10.3 (95% CI, 9.9 to 10.7) for IAs. Neuroimaging utilization increased 12% per year during the time period (P<0.001). Overall, rates increased for IAs (P<0.001), remained stable for OVMs (P=0.858), and decreased for BAVMs (P=0.001). Detection rates increased 15% per year for unruptured IAs (P<0.001), with no change in SAHs (P=0.903). However, rates decreased 7% per year for unruptured BAVMs (P=0.016) and 3% per year for ruptured BAVMs (P=0.005). Meta-analysis yielded a pooled BAVM detection rate of 1.3 (95% CI, 1.2 to 1.4) per 100 000 person-years, without heterogeneity between studies (P=0.25). Conclusions— Rates for BAVMs, OVMs, and IAs in this large, multiethnic population were similar to those in other series. During 1995 to 2004, a period of increasing neuroimaging utilization, we did not observe an increased rate of detection of unruptured BAVMs, despite increased detection of unruptured IAs.

Adrenoceptor Polymorphisms and the Risk of Cardiac Injury and Dysfunction After Subarachnoid Hemorrhage

Background and Purpose— Cardiac abnormalities occur commonly after subarachnoid hemorrhage (SAH) and may be caused by excessive release of catecholamines from the myocardial sympathetic nerves. We hypothesized that adrenoceptor polymorphisms resulting in greater catecholamine sensitivity would be associated with an increased risk of cardiac injury. Methods— This was a prospective cohort study. The primary outcome variables were the serum level of cardiac troponin I (cTi, abnormal if >1.0 μg/L) and the left ventricular ejection fraction (LVEF, abnormal if <50%). Six adrenoceptor polymorphisms were genotyped: β1AR Arg389Gly, β1AR Ser49Gly, β2AR Gly16Arg, β2AR Gln27Glu, β2AR Thr164Ile, and α2AR del322-325. The effect of each polymorphism on the risk of developing cardiac abnormalities was quantified using multivariable logistic regression. Results— The study included 182 patients. The CC genotype (Arg/Arg) of β1AR Arg389Gly (odds ratio [OR] 3.4, P=0.030) and the CC genotype (Gln/Gln) of β2AR Gln27Glu (OR 3.1, P=0.032) were predictive of cTi release. The presence of the α2AR deletion was predictive of reduced LVEF (OR 4.2, P=0.023). The combination of the β1AR 389 CC and the β2AR 27 CC genotypes resulted in a marked increase in the odds of cTi release (OR 15.5, P=0.012). The combination of the β1AR 389 CC and the α2AR deletion genotypes resulted in a marked increase in the odds of developing a reduced LVEF (OR 10.3, P=0.033). Conclusions— Genetic polymorphisms of the adrenoceptors are associated with an increased risk of cardiac abnormalities after SAH. These data support the hypothesis that cardiac dysfunction after SAH is a form of neurocardiogenic injury.

Racial/Ethnic Differences in Longitudinal Risk of Intracranial Hemorrhage in Brain Arteriovenous Malformation Patients

Background and Purpose— Race/ethnicity is associated with overall incidence of intracranial hemorrhage (ICH), but its impact in patients with brain arteriovenous malformation is unknown. We evaluated whether race/ethnicity was a risk factor for ICH in the natural course in a large, multiethnic cohort of patients with brain arteriovenous malformation followed longitudinally. Methods— Data were collected prospectively for patients with brain arteriovenous malformation evaluated at the University of California, San Francisco (n=436) and retrospectively through databases and chart review in the 20 hospitals of the Kaiser Permanente Medical Care Program (n=1028). Multivariate Cox regression was performed to assess the influence of race/ethnicity on subsequent ICH, adjusting for risk factors. Cases were censored at first treatment, loss to follow-up, or death. Results— Average follow up was 4.7±8.0 years for Kaiser Permanente Medical Care Program patients and 2.8±7.3 years for University of California, San Francisco patients with no difference in time to ICH between cohorts (log rank P=0.57). The annualized 5-year ICH rate was 2.1% (3.7% for ruptured at presentation; 1.4% for unruptured). Initial ICH presentation (hazard ratio: 3.0, 95% CI: 1.9 to 4.9, P<0.001) and Hispanic race/ethnicity (hazard ratio: 1.9, 95% CI: 1.1 to 3.3, P=0.02) were independent predictors of ICH, adjusting for age, gender, cohort, and a cohort–age interaction. The ICH risk for Hispanics versus whites increased to 3.1 (95% CI: 1.3 to 7.4, P=0.013) after further adjusting for arteriovenous malformation size and deep venous drainage in a subset of cases with complete data. Similar trends were observed for blacks (hazard ratio: 2.1, 95% CI: 0.9 to 4.8, P=0.09) and Asians (hazard ratio: 2.4, 95% CI: 0.8 to 7.1, P=0.11), although nonsignificant. Conclusions— This study reports the first description of race/ethnic differences in brain arteriovenous malformation, with Hispanics at an increased risk of subsequent ICH compared with whites.

Neurotoxicity of Intra-arterial Papaverine Preserved with Chlorobutanol Used for the Treatment of Cerebral Vasospasm After Aneurysmal Subarachnoid Hemorrhage

Background and Purpose— Papaverine is used to vasodilate cerebral arteries undergoing vasospasm from subarachnoid hemorrhage. However, papaverine inhibits cellular respiration in vitro and could cause neurotoxicity in humans. Methods— We studied 5 consecutive patients with cerebral vasospasm who were treated with intra-arterial papaverine preserved with chlorobutanol and imaged with MRI fluid-attenuated inversion recovery and diffusion-weighted imaging after treatment. One patient had histological analysis of the brain at autopsy. Results— All 5 patients exhibited marked neurological decline immediately after treatment, and this was sustained through hospital discharge. In all cases, MRI images showed selective gray matter–only signal changes within the vascular territory treated with papaverine. Histological analysis of 1 case brought to autopsy showed selective injury to islands of neurons with relative sparing of white matter. Conclusions— Intra-arterial delivery of papaverine preserved with chlorobutanol into vasospastic anterior cerebral arteries may result in marked neurological deterioration with selective gray matter changes on MRI imaging. This effect is consistent with a permanent toxic effect to human brain. It is unclear whether this toxicity is caused by papaverine or chlorobutanol, and its use in the treatment of cerebral vasospasm should be reserved for cases without alternatives.

Predictors of left ventricular regional wall motion abnormalities after subarachnoid hemorrhage.

IntroductionCardiac abnormalities that have been reported after subarachnoid hemorrhage (SAH) include the release of cardiac biomarkers, electrocardiographic changes, and left ventricular (LV) systolic dysfunction. The mechanisms of cardiac dysfunction after SAH remain controversial. The aim of this study was to determine the prevalence of LV regional wall motion abnormalities (RWMA) after SAH and to quantify the independent effects of specific demographic and clinical variables in predicting the development of RWMA.MethodsThree hundred patients hospitalized with SAH were prospectively studied with serial echocardiography. The primary outcome measure was the presence of RWMA. The predictor variables included the admission Hunt & Hess grade, age, gender, cardiac risk factors, aneurysm location, plasma catecholamine levels, cardiac troponin I (cTi) level, heart rate (HR), blood pressure, and phenylephrine dose. Univariate and multivariate logistic regression was performed with adjustment for serial measurements, reporting olds ratios (OR) and 95% confidence intervals (CI).ResultsIn this study, 817 echocardiograms were analysed. RWMA were detected in 18% of those studied. The prevalence of RWMA in patients with Hunt & Hess grades 3–5 was 35%. Among patients with a peak cTi level grater than 1.0 μg/L, 65% had RWMA. Multivariate analysis demonstrated that high Hunt & Hess grade (OR 4.22 for grade 3–5 versus grade 1–2, p=0.046), a cTi level greater than 1.0 μg/L (OR 10.47, p=0.001), a history of prior cocaine or amphetamine use (OR 5.50, p=0.037), and higher HR (OR 1.34 per 10 bpm increase, p=0.024) were predictive of RWMA.ConclusionsRWMA were frequent after SAH. High-grade SAH, an elevation in cTi levels, a history of prior stimulant drug use, and tachycardia are independent predictors of RWMA.

Long-term outcome of endovascular stenting for symptomatic basilar artery stenosis

Eighteen patients underwent stenting for symptomatic basilar artery stenosis. There were three major periprocedural complications (16.7%) without fatality. At a mean 26.7 ± 12.1-month follow-up, 15 patients (83.3%) had an excellent long-term outcome. Only one patient (5.6%) had moderate disability from recurrent stroke, and two patients died of medical illness at 30 and 36 months after stenting. In this uncontrolled study, stenting appeared to be effective in reducing stroke risk and death and worthy of further scrupulous trial.

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. Conclusion— 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).