Genetic Insights on the Relation of Vascular Risk Factors and Cervical Artery Dissection.

BACKGROUND: The association between vascular risk factors and cervical artery dissections (CeADs), a leading cause of ischemic stroke (IS) in the young, remains controversial. OBJECTIVES: This study aimed to explore the causal relation of vascular risk factors with CeAD risk and recurrence and compare it to their relation with non-CeAD IS. METHODS: This study used 2-sample Mendelian randomization analyses to explore the association of blood pressure (BP), lipid levels, type 2 diabetes, waist-to-hip ratio, smoking, and body mass index with CeAD and non-CeAD IS. To simulate effects of the most frequently used BP-lowering drugs, this study constructed genetic proxies and tested their association with CeAD and non-CeAD IS. In analyses among patients with CeAD, the investigators studied the association between weighted genetic risk scores of vascular risk factors and the risk of multiple or early recurrent dissections. RESULTS: Genetically determined higher systolic BP (OR: 1.51; 95% CI: 1.32-1.72) and diastolic BP (OR: 2.40; 95% CI: 1.92-3.00) increased the risk of CeAD (P < 0.0001). Genetically determined higher body mass index was inconsistently associated with a lower risk of CeAD. Genetic proxies for ß-blocker effects were associated with a lower risk of CeAD (OR: 0.65; 95% CI: 0.50-0.85), whereas calcium-channel blockers were associated with a lower risk of non-CeAD IS (OR: 0.75; 95% CI: 0.63-0.90). Weighted genetic risk scores for systolic BP and diastolic BP were associated with an increased risk of multiple or early recurrent CeAD. CONCLUSIONS: These results are supportive of a causal association between higher BP and increased CeAD risk and recurrence and provide genetic evidence for lower CeAD risk under ß-blockers. This may inform secondary prevention strategies and trial design for CeAD.

Delayed Development of Aneurysmal Dilatations in Patients with Extracranial Carotid Artery Dissections.

OBJECTIVE: Dissection of the carotid artery (CaAD) may result in aneurysm formation. The present study was undertaken to evaluate the time of onset of post-dissection extracranial carotid artery aneurysms (ECAA) following CaAD, and to analyse independent risk factors for the development of these aneurysms. METHODS: From four European stroke centres, 360 patients with extracranial CaAD were included. The time between the estimated dissection onset and aneurysm formation was analysed, and the clinical risk factors increasing the probability of aneurysm were assessed. RESULTS: The median duration of follow up was 5.2 months (range 0 - 24 months). A total of 75 post-dissection ECAAs were identified in 70 patients (19.4%, 95% confidence interval [CI] 15.7 - 23.8). In 52 of 70 (74%) patients, the ECAA was diagnosed at the initial clinical work up of CaAD diagnosis, with the median estimated time of dissection onset to ECAA diagnosis being six days (interquartile range [IQR] 0 - 25). In the remaining 18 (26%) patients who had normal carotid arteries at the initial imaging, the aneurysm diagnosis was made a median of 6.2 months (189 days) from the original imaging (IQR 128 - 198). A Cox proportional hazards model showed that both multiple artery dissections (hazard ratio [HR] 2.58, 95% CI 1.54 - 4.33) and arterial tortuosity (HR 1.79, 95% CI 1.08 - 2.95) were associated with presence of ipsilateral ECAA. CONCLUSION: This post hoc cohort analysis showed substantially delayed development of ipsilateral ECAA in patients with CaAD, months after baseline. Multiple dissections and arterial tortuosity are associated with the presence of ECAA and can be used in future prediction models of ECAA development in patients with CaAD.

Determinants and outcome of multiple and early recurrent cervical artery dissections.

OBJECTIVE: To assess putative risk factors and outcome of multiple and early recurrent cervical artery dissection (CeAD). METHODS: We combined data from 2 multicenter cohorts and compared patients with multiple CeAD at initial diagnosis, early recurrent CeAD within 3 to 6 months, and single nonrecurrent CeAD. Putative risk factors, clinical characteristics, functional outcome, and risk of recurrent ischemic events were assessed. RESULTS: Of 1,958 patients with CeAD (mean ± SD age 44.3 ± 10 years, 43.9% women), 1,588 (81.1%) had single nonrecurrent CeAD, 340 (17.4%) had multiple CeAD, and 30 (1.5%) presented with single CeAD at admission and had early recurrent CeAD. Patients with multiple or early recurrent CeAD did not significantly differ with respect to putative risk factors, clinical presentation, and outcome. In multivariable analyses, patients with multiple or early recurrent CeAD more often had recent infection (odds ratio [OR] 1.81, 95% confidence interval [CI] 1.29-2.53), vertebral artery dissection (OR 1.82, 95% CI 1.34-2.46), family history of stroke (OR 1.55, 95% CI 1.06-2.25), cervical pain (OR 1.36, 95% CI 1.01-1.84), and subarachnoid hemorrhage (OR 2.85, 95% CI 1.01-8.04) at initial presentation compared to patients with single nonrecurrent CeAD. Patients with multiple or early recurrent CeAD also had a higher incidence of cerebral ischemia (hazard ratio 2.77, 95% CI 1.49-5.14) at 3 to 6 months but no difference in functional outcome compared to patients with single nonrecurrent CeAD. CONCLUSION: Patients with multiple and early recurrent CeAD share similar risk factors, clinical characteristics, and functional outcome. Compared to patients with single nonrecurrent CeAD, they are more likely to have recurrent cerebral ischemia at 3 to 6 months, possibly reflecting an underlying transient vasculopathy.

University education and cervical artery dissection.

BACKGROUND AND PURPOSE: We investigated whether university education is more likely in cervical artery dissection (CeAD)-patients than in age- and sex-matched patients with ischemic stroke (IS) due to other causes (non-CeAD-IS-patients). METHODS: Patients from the Cervical Artery Dissection and Ischemic Stroke Patients study with documented self-reported profession before onset of IS due to CeAD (n = 715) or non-CeAD causes (n = 631) were analyzed. In the reported profession, the absence or presence of university education was assessed. Professions could be rated as academic or non-academic in 518 CeAD and 456 non-CeAD patients. Clinical outcome at 3 months was defined as excellent if modified Rankin Scale was 0-1. RESULTS: University education was more frequent in CeAD-patients (100 of 518, 19.3%) than in non-CeAD-IS-patients (61 of 456, 13.4%, p = 0.008). CeAD-patients with and without university education differed significantly with regard to smoking (39 vs. 57%, p = 0.001) and excellent outcome (80 vs. 66%, p = 0.004). In logistic regression analysis, university education was associated with excellent outcome in CeAD-patients (OR 2.44, 95% CI 1.37-5.38) independent of other outcome predictors such as age (OR 0.97, 95% CI 0.84-0.99), NIHSS (OR 0.80, 95% CI 0.76-0.84) and local signs (OR 2.77, 95% CI 1.37-5.57). CONCLUSION: We observed a higher rate of university education in patients with CeAD compared with non-CeAD patients in our study population. University education was associated with favorable outcome in CeAD-patients. The mechanism behind this association remains unclear.

Predictors of delayed stroke in patients with cervical artery dissection.

BACKGROUND: Stroke in patients with acute cervical artery dissection may be anticipated by initial transient ischemic or nonischemic symptoms. AIM: Identifying risk factors for delayed stroke upon cervical artery dissection. METHODS: Cervical artery dissection patients from the multicenter Cervical Artery Dissection and Ischemic Stroke Patients study were classified as patients without stroke (n = 339), with stroke preceded by nonstroke symptoms (delayed stroke, n = 244), and with stroke at onset (n = 382). Demographics, clinical, and vascular findings were compared between the three groups. RESULTS: Patients with delayed stroke were more likely to present with occlusive cervical artery dissection (P < 0.001), multiple cervical artery dissection (P = 0.031), and vertebral artery dissection (P < 0.001) than patients without stroke. No differences were observed in age, smoking, arterial hypertension, hypercholesterolemia, migraine, body mass index, infections during the last week, and trauma during the last month, but patients with delayed stroke had less often transient ischemic attack (P < 0.001) and local signs (Horner syndrome and cranial nerve palsy; P < 0.001). CONCLUSIONS: Occlusive cervical artery dissection, multiple cervical artery dissection, and vertebral artery dissection were associated with an increased risk for delayed stroke. No other risk factors for delayed stroke were identified. Immediate cervical imaging of cervical artery dissection patients without ischemic stroke is needed to identify patients at increased risk for delayed ischemia.

Characteristics and outcomes of patients with multiple cervical artery dissection.

BACKGROUND AND PURPOSE: Little is known about factors contributing to multiple rather than single cervical artery dissections (CeAD) and their associated prognosis. METHODS: We compared the baseline characteristics and short-term outcome of patients with multiple to single CeAD included in the multicenter Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) study. RESULTS: Among the 983 patients with CeAD, 149 (15.2%) presented with multiple CeAD. Multiple CeADs were more often associated with cervical pain at admission (odds ratio [OR], 1.59; 95% confidence interval [CI], 1.10-2.30), a remote history of head or neck surgery (OR, 1.87; 95% CI, 1.16-3.00), a recent infection (OR, 1.71; 95% CI, 1.12-2.61), and cervical manipulation (OR, 2.23; 95% CI, 1.26-3.95). On imaging, cervical fibromuscular dysplasia (OR, 3.97; 95% CI, 2.04-7.74) and the presence of a pseudoaneurysm (OR, 2.91; 95% CI, 1.86-4.57) were more often seen in patients with multiple CeAD. The presence of multiple rather than single CeAD had no effect on functional 3-month outcome (modified Rankin Scale score, ≥3; 12% in multiple CeAD versus 11.9% in single CeAD; OR, 1.20; 95% CI, 0.60-2.41). CONCLUSIONS: In the largest published series of patients with CeAD, we highlighted significant differences between multiple and single artery involvement. Features suggestive of an underlying vasculopathy (fibromuscular dysplasia) and environmental triggers (recent infection, cervical manipulation, and a remote history of head or neck surgery) were preferentially associated with multiple CeAD.

Association of vascular risk factors with cervical artery dissection and ischemic stroke in young adults.

BACKGROUND: Little is known about the risk factors for cervical artery dissection (CEAD), a major cause of ischemic stroke (IS) in young adults. Hypertension, diabetes mellitus, smoking, hypercholesterolemia, and obesity are important risk factors for IS. However, their specific role in CEAD is poorly investigated. Our aim was to compare the prevalence of vascular risk factors in CEAD patients versus referents and patients who suffered an IS of a cause other than CEAD (non-CEAD IS) in the multicenter Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) study. METHODS AND RESULTS: The study sample comprised 690 CEAD patients (mean age, 44.2 ± 9.9 years; 43.9% women), 556 patients with a non-CEAD IS (44.7 ± 10.5 years; 39.9% women), and 1170 referents (45.9 ± 8.1 years; 44.1% women). We compared the prevalence of hypertension, diabetes mellitus, hypercholesterolemia, smoking, and obesity (body mass index ≥ 30 kg/m²) or overweightness (body mass index ≥ 25 kg/m² and <30 kg/m²) between the 3 groups using a multinomial logistic regression adjusted for country of inclusion, age, and gender. Compared with referents, CEAD patients had a lower prevalence of hypercholesterolemia (odds ratio 0.55; 95% confidence interval, 0.42 to 0.71; P<0.0001), obesity (odds ratio 0.37; 95% confidence interval, 0.26 to 0.52; P<0.0001), and overweightness (odds ratio 0.70; 95% confidence interval, 0.57 to 0.88; P=0.002) but were more frequently hypertensive (odds ratio 1.67; 95% confidence interval, 1.32 to 2.1; P<0.0001). All vascular risk factors were less frequent in CEAD patients compared with young patients with a non-CEAD IS. The latter were more frequently hypertensive, diabetic, and current smokers compared with referents. CONCLUSION: These results, from the largest series to date, suggest that hypertension, although less prevalent than in patients with a non-CEAD IS, could be a risk factor of CEAD, whereas hypercholesterolemia, obesity, and overweightness are inversely associated with CEAD.

Analysis of 1008 consecutive patients aged 15 to 49 with first-ever ischemic stroke: the Helsinki young stroke registry.

BACKGROUND AND PURPOSE: To analyze trends in occurrence, risk factors, etiology, and neuroimaging features of ischemic stroke in young adults in a large cohort. METHODS: We evaluated all 1008 consecutive ischemic stroke patients aged 15 to 49 admitted to Helsinki University Central Hospital, 1994 to 2007. Etiology was classified by Trial of Org 10172 in Acute Stroke Treatment criteria. Comparisons were done between groups stratified by gender and age. RESULTS: Estimated annual occurrence was 10.8/100,000 (range 8.4 to 13.0), increasing exponentially with aging. Of our 628 male and 380 female (ratio 1.7:1) patients, females were preponderant among those <30, whereas male dominance rapidly increased around age of 44. The most frequent risk factors were dyslipidemia (60%), smoking (44%), and hypertension (39%). Males and patients >44 clearly had more risk factors. Cardioembolism (20%) and cervicocerebral artery dissection (15%) were the most frequent etiologic subgroups. Proportions of large-artery atherosclerosis (8%) and small-vessel disease (14%) began to enlarge at age 35, whereas frequency of undetermined etiology (33%) decreased along aging. Posterior circulation infarcts were more common among patients <45 years of age. Left hemisphere infarcts were more frequent in general. There were 235 (23%) patients with multiple and 126 (13%) with silent infarcts, and 55 (5%) patients had leukoaraiosis. CONCLUSIONS: The frequency of ischemic stroke increases sharply at age 40. Etiology and risk factors start resembling those seen in the elderly in early midlife but causes defined in younger patients still are frequent in those aged 45 to 49. Subclinical infarcts were surprisingly common in the young.