Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection.

Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year). Minor cervical traumas, infection, migraine and hypertension are putative risk factors, and inverse associations with obesity and hypercholesterolemia are described. No confirmed genetic susceptibility factors have been identified using candidate gene approaches. We performed genome-wide association studies (GWAS) in 1,393 CeAD cases and 14,416 controls. The rs9349379[G] allele (PHACTR1) was associated with lower CeAD risk (odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.69-0.82; P = 4.46 × 10(-10)), with confirmation in independent follow-up samples (659 CeAD cases and 2,648 controls; P = 3.91 × 10(-3); combined P = 1.00 × 10(-11)). The rs9349379[G] allele was previously shown to be associated with lower risk of migraine and increased risk of myocardial infarction. Deciphering the mechanisms underlying this pleiotropy might provide important information on the biological underpinnings of these disabling conditions.

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.

Desmoteplase.

The high fibrin specificity of Desmodus rotundus salivary plasminogen activator alpha1 (desmoteplase) renders it a promising candidate for the treatment of acute ischemic stroke. In the DIAS (Desmoteplase in Acute Ischemic Stroke) and DEDAS (Dose Escalation study of Desmoteplase in Acute ischemic Stroke) Phase II studies, doses of 90 microg/kg and 125 microg/kg desmoteplase were reported to have acceptable safety profiles, leading to potentially superior reperfusion compared with placebo, with possible clinical efficacy for up to 9 h after the onset of symptoms in patients with a significant ischemic penumbra selected from magnetic resonance perfusion-diffusion weighted mismatches imaging. However, a Phase III clinical trial (DIAS-2) was unable to detect any benefit from desmoteplase when given 3 - 9 h after stroke onset. In this study with a modest sample size, certain methodological factors may have reduced its potential to detect a desmoteplase effect, as only 30% of these patients had a visible occlusion at presentation, with only small core and mismatched lesion volumes. Indeed, it is surprising that a study testing an occluded vessel 'reopener' was conducted in a cohort of stroke patients, the majority of whom was known not to have a detected vessel occlusion. It has also been claimed that the DIAS-2 patients selection using core/penumbra mismatch calculation may not have followed an appropriate mismatch threshold. However, the corrective value of changing the mismatch threshold remains unclear, because the relative mismatch volumes were in fact higher in the 'negative' DIAS-2 than in the 'positive' DIAS and DEDAS. Two Phase II randomized trials with tPA, Diffusion-weighted imaging Evaluation For Understanding Stroke Evolution (DEFUSE) and Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) provided strong biological support for the relation between infarct growth, reperfusion and clinical outcome in the 3 - 6 h time window after onset of stroke using penumbral imaging. In this frame, why exactly desmoteplase should have specific advantages over tPA, is not clear. Taken together, these findings may also lead to the disappointing conclusion that vessel recanalization after 4.5 - 5 h from stroke onset may generally be inefficacious for tissue salvage. Nevertheless, other randomized Phase III clinical trials (DIAS-3 and DIAS-4) are currently under way with a planned sample size of 320 patients having vessel occlusion or high-grade stenosis on MRI or CT-angiography in the proximal cerebral arteries.

Assessment of the course and division patterns of the middle cerebral artery M1 segment. Transcranial power doppler compared with 3D time-of-flight magnetic resonance angiography at 3 T.

BACKGROUND AND PURPOSE: The present study was undertaken to assess the ability of bedside transcranial color-coded sonography (TCCS) to define the course and the patterns of the division of the middle cerebral artery (MCA) M1 segment compared with 3D time-of-flight magnetic resonance angiography (MRA) at 3 T. METHODS: Because MRA is considered as a reliable noninvasive technique to depict the normal anatomy of the intracranial artery, we prospectively defined the course and the patterns of division of 100 MCA M1 segments using bedside TCCS and compared the results with MRA findings. RESULTS: In 68/85 cases (80%), the sonographer was able to define the division of the M1 segment, and classified these as bipode for 50/68 (73.5%), monopode for 16/68 (23.5%) and tripode for 2/68 (3%). A comparison of the TCCS and MRA findings showed a perfect correlation (100%) for the course of the M1 segment. As for the type of division, the correlation was good in 45/68 of cases (67%). TCCS had a sensitivity of 78%, a specificity of 67%, a positive predictive value of 87% and a negative predictive value of 52%, when used to determine whether the division was bipode or not. CONCLUSIONS: Our results show that bedside TCCS can now provide anatomical information on the M1 segment of the MCA.

Main anatomical features of the M1 segment of the middle cerebral artery: a 3D time-of-flight magnetic resonance angiography at 3 T study.

The purpose of our study was to determine the main anatomical features of the M1 segment of middle cerebral artery (MRA) using a 3D TOF-MRA at 3 T. Reconstructed and post-processed MRA images were independently analysed by two anatomists in order to determine the course patterns, the division patterns and the early cortical branches patterns of the M1 segments. The division patterns were defined as bipode, tripode or other. The ECB were studied according to their number and their distance from the origin of the M1 segment. The interobserver agreement, to determine the division patterns of the M1 segment, was calculated. The division of the M1 segment was bipode in 73% of the MCAs, monopode in 17%, tripode in 9%, and fan-shaped in 1. In 46% of the cases no ECB was found. In the other cases, only 1 ECB was found and it arose from the medium part of the M1 segment. Our results confirm post-mortem microdissection studies and show that strict anatomical criteria may be applied to 3D TOF MRA at 3 T.