Search

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.

BackgroundGiant cell arteritis (GCA) is a systemic vasculitis that may cause ischemic stroke. Rarely, GCA can present with aggressive intracranial stenoses, which are refractory to medical therapy. Endovascular treatment (EVT) is a possible rescue strategy to prevent ischemic complications in intracranial GCA but the safety and efficacy of EVT in this setting are not well-described.MethodsA systematic literature review was performed to identify case reports and series with individual patient-level data describing EVT for intracranial GCA. The clinical course, therapeutic considerations, and technique of seven endovascular treatments in a single patient from the authors' experience are presented.ResultsThe literature review identified 9 reports of 19 treatments, including percutaneous transluminal angioplasty (PTA) with or without stenting, in 14 patients (mean age 69.6 ± 6.3 years). Out of 12 patients 8 (66.7%) with sufficient data had > 1 pre-existing cardiovascular risk factor. All patients had infarction on MRI while on glucocorticoids and 7/14 (50%) progressed despite adjuvant immunosuppressive agents. Treatment was PTA alone in 15/19 (78.9%) cases and PTA + stent in 4/19 (21.1%). Repeat treatments were performed in 4/14 (28.6%) of patients (PTA-only). Non-flow limiting dissection was reported in 2/19 (10.5%) of treatments. The indications, technical details, and results of PTA are discussed in a single illustrative case. We report the novel use of intra-arterial calcium channel blocker infusion (verapamil) as adjuvant to PTA and as monotherapy, resulting in immediate improvement in cerebral blood flow.ConclusionEndovascular treatment, including PTA with or without stenting or calcium channel blocker infusion, may be effective therapies in medically refractory GCA with intracranial stenosis.

Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits.

BackgroundThough 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.MethodsAdult 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.ResultsAt the gene level, there were 259 differentially expressed genes between SAH patients with vasospasm compared to patients without (false discovery rate

BackgroundInfection 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.MethodsA 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.ResultsOf 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).ConclusionsThere 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.

Brain arteriovenous malformations (AVMs) are abnormal connections of arteries and veins, resulting in arteriovenous shunting of blood. Primary medical therapy is lacking; treatment options include surgery, radiosurgery, and embolization, often in combination. Judicious selection of AVM patients for treatment requires balancing risk of treatment complications against the risk of hemorrhage in the natural history course. This review focuses on the epidemiology, hemorrhage risk, and factors influencing risk of hemorrhage in the untreated natural course associated with sporadic brain AVM.

Purpose: Intracranial aneurysm (IA) growth is associated with increased morbidity. We sought to establish a quantitative computational method based on contrast-enhanced MR angiography (CE-MRA) for estimating aneurysmal volume changes over time.Materials and Methods: Computational volume calculations were tested against a distensible phantom. Untreated patients with IA were followed longitudinally with annual MRI. Maximal linear dimensions along the longitudinal axis and two transverse axes were determined by visual review of maximum intensity projection (MIP) data, and aneurysm volume was approximated as (length x width x height)/2. Averages of the visual approximations were compared to the lumenal volume as determined with a computational algorithm using the MRI data.Results: MRI-based measurements accurately represented volume changes in the phantom (R-2 = 0.97, Y = 1.06x + 271 CM3). In the clinical study there were a total of 11 intervals of one-year follow-up in six patients (mean +/- SD age = 53 +/- 20 years). The raw one-year growth using the computational volume was 9% +/- 17%. The corresponding value for the averaged measurement of the reviewers was 8% +/- 14%. Neither the mean values nor the SDs were different (P = .51).Conclusion: MRI-based measurement of aneurysm volume appears feasible for longitudinal studies of aneurysm natural history.

Intracranial aneurysms (IAs) are usually asymptomatic with a low risk of rupture, but consequences of aneurysmal subarachnoid hemorrhage (aSAH) are severe. Identifying IAs at risk of rupture has important clinical and socio-economic consequences. The goal of this study was to assess the effect of patient and IA characteristics on the likelihood of IA being diagnosed incidentally versus ruptured. Patients were recruited at 21 international centers. Seven phenotypic patient characteristics and three IA characteristics were recorded. The analyzed cohort included 7992 patients. Multivariate analysis demonstrated that: (1) IA location is the strongest factor associated with IA rupture status at diagnosis; (2) Risk factor awareness (hypertension, smoking) increases the likelihood of being diagnosed with unruptured IA; (3) Patients with ruptured IAs in high-risk locations tend to be older, and their IAs are smaller; (4) Smokers with ruptured IAs tend to be younger, and their IAs are larger; (5) Female patients with ruptured IAs tend to be older, and their IAs are smaller; (6) IA size and age at rupture correlate. The assessment of associations regarding patient and IA characteristics with IA rupture allows us to refine IA disease models and provide data to develop risk instruments for clinicians to support personalized decision-making., Competing Interests: The authors declare no conflict of interest.

Background and Purpose: Symptomatic cerebral hyperperfusion has an incidence of 5% after endovascular stent placement. We hypothesized that increases in cerebral blood flow (CBF) after endovascular stent placement are positively correlated with the severity of stenosis., Methods: We studied patients with carotid (n=20) or vertebrobasilar (n=3) stenosis who were undergoing endovascular stent placement. Hemispheric CBF was measured by using intra-arterial xenon-133 technique (initial slope)., Results: CBF increased from 29 +/- 10 to 35 +/- 12 mL/100 g/min (P=.0003) at 39 +/- 12 minutes (range 13-60 minutes) after endovascular stent placement. Baseline characteristics or type of anesthesia did not affect the findings. Physiologic parameters remained constant between measurements: PaCO2 was 43 +/- 6 mmHg and arterial pressure was 89 +/- 16 mmHg. The degree of vascular stenosis (70% +/- 13%, range, 40-99%) was not correlated with change in CBF (r2=0.007, P=.70) or baseline CBF (r2=0.005, P=.31)., Conclusion: CBF increased by 21% +/- 10% after treatment in the absence of clinical symptoms and without intracranial hemorrhage. Modest increases in CBF were common after endovascular revascularization. However, the increased CBF appeared to be unrelated to the degree of vascular stenosis, suggesting a relationship to availability of collateral flow pathways or a neurogenic influence.

Background and Purpose: Dynamic perfusion CT (PCT) with deconvolution produces maps of time-to-peak (TTP), mean transit time (MTT), regional cerebral blood flow (rCBF), and regional cerebral blood volume (rCBV), with a computerized automated map of the infarct and penumbra. We determined the accuracy of these maps in patients with suspected acute hemispheric stroke., Methods: Forty-six patients underwent nonenhanced CT and dynamic PCT, with follow-up CT or MR imaging. Two observers reviewed the nonenhanced studies for signs of stroke and read the PCT maps for TTP, MTT, rCBF, and rCBV abnormalities. Sensitivity, specificity, accuracy, and interobserver agreement were compared (Wilcoxon tests). Nonenhanced CT and PCT data were reviewed for stroke extent according to previously reported methods. Sensitivity, specificity, and accuracy of the computerized maps in detecting ischemia and its extent were determined., Results: Compared with nonenhanced CT, PCT maps were significantly more accurate in detecting stroke (75.7-86.0% vs. 66.2%; P <.01), MTT maps were significantly more sensitive (77.6% vs. 69.2%; P <.01), and rCBF and rCBV maps were significantly more specific (90.9% and 92.7%, respectively, vs. 65.0%; P <.01). Regarding stroke extent, PCT maps were significantly more sensitive than nonenhanced CT (up to 94.4% vs. 42.9%; P <.01) and had higher interobserver agreement (up to 0.763). For the computerized map, sensitivity, specificity, and accuracy, respectively, were 68.2%, 92.3%, and 88.1% in detecting ischemia and 72.2%, 91.8%, and 87.9% in showing the extent., Conclusion: Dynamic PCT maps are more accurate than nonenhanced CT in detecting hemispheric strokes. Despite limited spatial coverage, PCT is highly reliable to assess the stroke extent.

Background and Purpose: Numerous parameters are involved in dynamic perfusion CT (PCT). We assessed the influence of the temporal sampling rate and the volume of contrast material., Methods: Sixty patients with ischemic hemispheric stroke lasting > or = 12 hours underwent PCT. Groups of 15 patients each received 30, 40, 50, or 60 mL of contrast agent. Regional cerebral blood volume (rCBV), regional cerebral blood flow (rCBF), mean transit time (MTT), and time-to-peak (TTP) maps were calculated for temporal sampling intervals of 0.5, 1, 2, 3, 4, 5, and 6 seconds. Results were statistically compared. Signal-to-noise ratios (SNRs), duration of arterial entrance to venous exit, and radiation dose were also assessed., Results: Increasing temporal sampling intervals lead to significant overestimation of rCBV, rCBF, and TTP and significant underestimation of MTT compared with values for an interval of 1 second. Maximal allowable intervals to avoid these effects were 2, 3, 3, and 4 seconds for 30, 40, 50, and 60-mL boluses, respectively. Venous exit of contrast material occurred in 97.5% of patients after 36, 42, 42, and 48 seconds, respectively, for the four volumes. SNRs did not differ with volume. The effective radiation dose varied between 0.852 and 1.867 mSv, depending on the protocol. The cine mode with two 40-mL boluses and the toggling-table technique with one 60-mL bolus had the lowest doses., Conclusion: Temporal sampling intervals greater than 1 second can be used without altering the quantitative accuracy of PCT. Increased sampling intervals reduce the radiation dose and may allow for increased spatial coverage.