Search

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 P P =0.858), and decreased for BAVMs ( P =0.001). Detection rates increased 15% per year for unruptured IAs ( P 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.

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 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.

Background and Purpose— Identification of single-nucleotide polymorphisms (SNPs) associated with increased risk of new intracranial hemorrhage (ICH) after brain arteriovenous malformation (BAVM) diagnosis would facilitate risk stratification and identify potential targets for therapeutic intervention. Methods— Patients with BAVM were longitudinally followed. Primary outcome was new ICH after diagnosis; censoring events were last follow-up or any BAVM treatment. We genotyped 4 promoter SNPs in 2 inflammatory cytokine genes: interleukin-6 (IL-6–174G>C; IL-6–572G>C) and tumor necrosis factor-α (TNF-α–238G>A; TNF-α–308G>A). Association of genotype with risk of new ICH was screened using χ 2 ; SNPs associated with new ICH were further characterized using Cox proportional hazards. Results— We genotyped 280 patients (50% female; 59% white, mean±SD age at diagnosis 37±17 years; 40% presenting with ICH). TNF-α–238G>A was associated with increased risk of new ICH after diagnosis (χ 2 ; P =0.003). After adjusting for age, race/ethnicity, and clinical presentation, the risk of new ICH was increased for patients with TNF-α–238 AG genotype (hazard ratio, 4.01; P =0.015). No other SNP was found to be associated with new ICH. Conclusion— A TNF-α SNP was associated with increased risk of new ICH in the natural course of BAVMs. The role of inflammatory cytokines in the pathogenesis of BAVM hemorrhage merits further study.

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 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.

Background and Purpose— Mutations in endoglin ( ENG ) and activin-like kinase ( ALK1 ) cause hereditary hemorrhagic telangiectasias, disorders characterized by pulmonary and brain arteriovenous malformations (BAVMs). We investigated whether polymorphisms in these genes are also associated with sporadic BAVM. Methods— A total of 177 sporadic BAVM patients and 129 controls (all subjects white) were genotyped for 2 variants in ALK1 and 7 variants in ENG . Results— The ALK1 IVS3-35A>G polymorphism was associated with BAVM: (AnyA [AA+AG] genotype: odds ratio, 2.47; 95% CI, 1.38 to 4.44; P =0.002). Two ENG polymorphisms, ENG −1742A>G and ENG 207G>A, showed a trend toward association with BAVM that did not reach statistical significance. Conclusions— A common polymorphism in ALK1 is associated with sporadic BAVM, suggesting that genetic variation in genes mutated in familial BAVM syndromes may play a role in sporadic BAVMs.

Background and Purpose— Children with brain arteriovenous malformations (BAVMs) are said to be at higher risk for intracranial hemorrhage (ICH) than adults. Although this notion affects treatment decisions, the evidence to support this claim is limited. Methods— To compare the risk of ICH in children versus adults with BAVM, we studied all cases of BAVM evaluated at the University of California, San Francisco (January 2000 to December 2004; n=400) and Kaiser Permanente Northern California (January 1993 to December 2004; n=819). In Kaplan–Meier survival analyses, the index date was the date of initial BAVM detection; cases were censored at time of subsequent ICH (the primary outcome, defined as ICH after initial presentation), first BAVM treatment, or loss to follow-up. Cox proportional hazards models included childhood presentation ( Results— Our study included 996 person-years of follow-up in the childhood presentation group and 3260 in the adult presentation group. In the unadjusted survival analysis, the subsequent ICH rates were similar for the 2 age groups (average annual rate 2.0% for children; 2.2% for adults; P =0.82 by log-rank test). BAVMs in childhood were more likely to present initially with ICH ( P P =0.036). Conclusions— Children with BAVMs do not appear to be at increased risk for a subsequent ICH compared with adults, and may even be relatively protected. Confounding by hemorrhagic presentation should be considered in any study comparing BAVM hemorrhage rates in children versus adults.

Background and Purpose— To compare magnetic resonance (MR) perfusion to gold-standard cerebral blood flow (CBF) determined by intra-arterial 133 Xe washout method. Methods— Eight patients with high-grade carotid stenoses underwent bolus-tracking MR perfusion and intra-arterial 133 Xe washout before and after carotid stenting. MR perfusion was compared with 133 Xe-CBF values using Pearson linear correlation analysis. Results— We observed a mean 37±38% increase in 133 Xe-CBF and a mean 19±27% increase in relative CBF (rCBF) by MR perfusion immediately after stent placement. Relative (percent) changes in MR-rCBF showed a close and linear correlation to those seen in 133 Xe-CBF ( r =0.91; R 2 =0.84; P =0.002). There was a trend for MR perfusion to underestimate change in CBF at higher relative changes in flow. Conclusion— Bolus-tracking MR perfusion correlates with 133 Xe-CBF in estimating postprocedural increases in blood flow but may underestimate the magnitude of the change with higher relative changes.

Background and Purpose— Accurate estimates of intracranial hemorrhage (ICH) risk in patients harboring brain arteriovenous malformation (BAVM) are needed to evaluate interventional strategies and to help guide clinical management. Identification of genetic polymorphisms associated with ICH would facilitate risk stratification in BAVM patients. Methods— We identified patients with BAVM and documented clinical presentation, demographic data, venous drainage pattern, and BAVM size. Patients were genotyped for 5 polymorphisms in 3 inflammatory cytokine genes, and 9 polymorphisms in 5 angiogenesis-related genes. Association of genotype with risk of hemorrhagic BAVM presentation was evaluated using logistic regression analysis. Results— We genotyped 180 patients with BAVM (53% female, 57% white, mean age at diagnosis 35±17 years, 41% presenting with ICH). BAVM patients homozygous for the interleukin 6 ( IL6 )–174G allele had a greater risk of ICH presentation (OR, 2.62, P =0.003) than IL6 –174C carriers. In a multivariate logistic regression model, IL6 –174G>C genotype, small BAVM size, and exclusively deep venous drainage were independent predictors of ICH presentation. A similar univariate trend was noted for the TNF α-308 GG genotype ( P =0.055). The other polymorphisms genotyped were not associated with ICH. Conclusions— A polymorphism in the inflammatory cytokine IL6, but not polymorphisms in angiogenesis-related genes, was associated with ICH presentation of BAVM. Further studies are needed to define the role of inflammatory cytokines in the pathogenesis of BAVM hemorrhage.

Background and Purpose— Accurate estimates for risk and rates of intracranial hemorrhage (ICH) in the natural course of patients harboring brain arteriovenous malformation (BAVM) are needed to provide a quantitative basis for planning clinical trials to evaluate interventional strategies and to help guide practice management. Methods— We identified patients with BAVM at the Kaiser Permanente Northern California health maintenance organization and documented their clinical course. The influences of age at diagnosis, gender, race-ethnicity, ICH at presentation, venous draining pattern, and BAVM size on ICH subsequent to presentation were studied using the multivariate Cox proportional hazards model and Kaplan-Meier curves. Results— We identified 790 patients with BAVM (51% female; 63% white; mean age±SD at diagnosis: 38±19 years) between 1961 and 2001. Patients who presented with ICH experienced a higher rate of subsequent ICH than those who presented without ICH under multivariate analysis (hazard ratio, 3.6; 95% CI, 1.1 to 11.9; P Conclusions— Presentation with ICH was the most important predictor of future ICH, confirming previous studies. Future ICH had similar impact on functional outcome as incident ICH. Intervention to prevent ICH would be of potentially greater benefit to patients presenting with ICH, although the advantage decreases over time.

Response: We were interested to read Dr Atanassova’s comments regarding our article. In the design of our study, we excluded patients with a history of myocardial infarction and congestive heart failure (CHF) in order to focus on the pathogenesis of acute cardiac injury and dysfunction. Though subarachnoid hemorrhage (SAH) patients have …