RESUMO
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.
Assuntos
Malformações Vasculares do Sistema Nervoso Central , Hemangioma Cavernoso do Sistema Nervoso Central , Humanos , Hemorragias Intracranianas/etiologia , Hemorragias Intracranianas/genética , Hemangioma Cavernoso do Sistema Nervoso Central/complicações , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Malformações Vasculares do Sistema Nervoso Central/complicações , Fatores de Risco , Hemorragia Cerebral/etiologiaRESUMO
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.
RESUMO
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.
Assuntos
Predisposição Genética para Doença/genética , Hipertensão/genética , Aneurisma Intracraniano/genética , Fumar/genética , Hemorragia Subaracnóidea/genética , Hemorragia Subaracnóidea/patologia , Povo Asiático/genética , Pressão Sanguínea/genética , Estudos de Casos e Controles , Células Endoteliais/patologia , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/fisiopatologia , Aneurisma Intracraniano/patologia , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Fumar/efeitos adversos , População Branca/genéticaRESUMO
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.
Assuntos
Elementos de Dados Comuns , Aneurisma Intracraniano , Sujeitos da Pesquisa , Hemorragia Subaracnóidea , Consumo de Bebidas Alcoólicas , Pesquisa Biomédica , Comorbidade , Status Econômico , Escolaridade , Emprego , Exposição Ambiental , Etnicidade , Exercício Físico , Humanos , National Institute of Neurological Disorders and Stroke (USA) , National Library of Medicine (U.S.) , História Reprodutiva , Fumar , Classe Social , Estados UnidosRESUMO
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.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Doenças Arteriais Cerebrais/epidemiologia , Infecções por HIV/complicações , Neuroimagem/efeitos adversos , Síndrome da Imunodeficiência Adquirida/fisiopatologia , Síndrome da Imunodeficiência Adquirida/virologia , Idoso , Idoso de 80 Anos ou mais , Terapia Antirretroviral de Alta Atividade/métodos , Doenças Arteriais Cerebrais/induzido quimicamente , Estudos de Coortes , Feminino , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de RiscoRESUMO
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.
Assuntos
Fístula Arteriovenosa/epidemiologia , Malformações Arteriovenosas Intracranianas/epidemiologia , Hemorragias Intracranianas/epidemiologia , Humanos , Incidência , Fatores de RiscoRESUMO
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.
Assuntos
Malformações Vasculares do Sistema Nervoso Central/diagnóstico , Malformações Vasculares do Sistema Nervoso Central/fisiopatologia , Isquemia do Cordão Espinal/diagnóstico , Isquemia do Cordão Espinal/fisiopatologia , Doenças Vasculares/diagnóstico , Doenças Vasculares/fisiopatologia , Fístula Arteriovenosa/diagnóstico , Fístula Arteriovenosa/fisiopatologia , Fístula Arteriovenosa/terapia , Malformações Arteriovenosas/diagnóstico , Malformações Arteriovenosas/fisiopatologia , Malformações Arteriovenosas/terapia , Malformações Vasculares do Sistema Nervoso Central/terapia , Diagnóstico Diferencial , Feminino , Hemangioma Cavernoso/diagnóstico , Hemangioma Cavernoso/fisiopatologia , Hemangioma Cavernoso/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia do Cordão Espinal/terapia , Doenças Vasculares/terapiaRESUMO
OBJECTIVE: We previously reported specific genotypes of polymorphisms in two genes, tumor necrosis factor-alpha (TNF-alpha-238G > A) and Apolipoprotein E (ApoE e2), as independent predictors of new intracranial hemorrhage (ICH) in the natural course of untreated brain arteriovenous malformations. We hypothesized that the risk of posttreatment ICH would also be greater in patients with brain arteriovenous malformations with these genotypes. METHODS: Two hundred fifteen patients undergoing brain arteriovenous malformation treatment (embolization, arteriovenous malformation resection, radiosurgery, or any combination of these) were genotyped and followed longitudinally. Association of genotype with new symptomatic ICH after initiation of treatment was assessed using Cox proportional hazards adjusted for treatment type, demographics, and established ICH risk factors censored at the time of the last follow-up evaluation or death. RESULTS: The cohort was 48% male and 55% Caucasian, and 52% had an ICH before the initiation of treatment; the mean age +/- standard deviation was 36.6 +/- 17.2 years. Posttreatment ICH occurred in 34 (16%) patients with a median follow-up period of 1.9 years (interquartile range, 1.6 yr). After adjustment, the risk of posttreatment ICH was greater for TNF-alpha-238 AG genotype (hazard ratio [HR], 3.5; 95% confidence interval [CI], 1.3-9.8; P = 0.016) and ApoE e2 (HR, 3.2; 95% CI, 1.0-9.7; P = 0.042). Similar trends for the TNF-alpha-238 AG genotype were seen in surgery (HR, 4.2; 95% CI, 0.6-28.8; P = 0.14) and radiosurgery subsets (HR, 3.8; 95% CI, 0.7-19.4; P = 0.11). An effect of ApoE e2 was seen in radiosurgery subsets (HR, 10.9; 95% CI, 1.3-93.7; P = 0.030), but not in surgery subsets (HR, 1.4; 95% CI, 0.3-7.4; P = 0.67). CONCLUSION: Despite a variety of different mechanisms for posttreatment hemorrhage, these data suggest that the TNF-alpha and ApoE genotypes may contribute common phenotypes of enhanced vascular instability that increase the risk of hemorrhagic outcome.