Spontaneous cervical artery dissection: is it really a connective tissue disease? A comprehensive review.

Background: Spontaneous cervical artery dissection (sCeAD) is an important cause of stroke in young adults. The underlying pathophysiology remains unclear, without validated biomarkers to identify subjects at risk. Previous studies suggested the role of abnormalities in the connective component of the arterial wall. Purpose: To assess dermal ultrastructural aberrations of connective tissue by skin biopsy and genetic variations in sCeAD patients. Method: We searched the PubMed and Scopus databases until August 2023 with PRISMA guidelines. Original articles assessing skin biopsy in sCeAD patients were included. Two reviewers independently conducted the screening. Findings: We included 16 studies compromising 459 patients. Thirteen studies assessed ultrastructural changes and found aberrations of collagen and elastic fibers, described as irregular contours and calibers of collagen fibrils, composite flower-like fibrils, fragmented moth-eaten elastin, and microcalcifications, cumulatively in 50.5% of patients. Seven studies showed no causative mutations in collagen type I, III, V, or elastin genes. One study showed linkage between connective tissue alterations and mutation on chromosomes 15q2 and 10q26 using genome-wide linkage analysis, while another study found significant copy number variant enrichments in genes involved in extracellular matrix (COL5A2/COL3A1/SNTA1) and collagen fibril organizations (COL5A2/COL3A1). Finally, differential expression of extracellular proteins was linked to connective tissue disorder in patients with recurrent sCeAD using a quantitative proteomics approach. Conclusion: Current literature supports the hypothesis that an underlying, subclinical connective tissue disorder, likely genetically determined, may predispose to arterial wall weakness and sCeAD. Further studies with larger sample sizes and robust methodology are needed to better define the role of connective tissue in sCeAD pathogenesis.

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.

IV Thrombolysis With or Without Endovascular Treatment for Suspected Ischemic Stroke in Patients With Intracranial Tumors.

BACKGROUND AND OBJECTIVES: IV thrombolysis (IVT) for suspected ischemic stroke in patients with intracranial neoplasms is off-label. However, data on risks of intracranial hemorrhage (ICH) are scarce. METHODS: In a multicenter registry-based analysis within the European Thrombolysis in Ischemic Stroke Patients (TRISP) collaboration, we assessed frequencies of symptomatic and fatal ICH after IVT for suspected ischemic stroke in patients with intracranial tumors by descriptive statistics and analyzed associations with clinical and imaging characteristics by binary logistic regression. Definition of symptomatic ICH was based on the clinical criteria of the European Cooperative Acute Stroke-II trial including hemorrhage at any site in cranial imaging and concurrent clinical deterioration. RESULTS: Screening data of 21,289 patients from 14 centers, we identified 105 patients receiving IVT; among them were 29 patients (28%) with additional endovascular treatment, with suspected, that is, imaging-based, or histologically confirmed diagnosis of intracranial tumors. Among 104 patients with CT or MRI after IVT available, symptomatic and fatal ICH were observed in 9 and 4 patients (9% and 4%, respectively). Among 82 patients with suspected or confirmed meningioma, symptomatic and fatal ICH occurred in 6 and 3 patients (7% and 4%), respectively. In 18 patients with intra-axial suspected or confirmed primary or secondary brain tumors, there was 1 symptomatic nonfatal ICH (6%). Of 4 patients with tumors of the pituitary region, 2 patients (50%) had symptomatic ICH including 1 fatal ICH (25%). Tumor size was not associated with the occurrence of symptomatic ICH (odds ratio 2.8, 95% CI 0.3-24.8, p = 0.34). DISCUSSION: In our dataset from routine clinical care, we provide insights on the safety of IVT for suspected ischemic stroke in patients with intracranial tumors, a population that is commonly withheld thrombolysis in clinical practice and prospective trials. Except for a potential high risk of symptomatic ICH after IVT in patients with tumors of the pituitary region, frequencies of symptomatic ICH in patients with intracranial tumors in our cohort seem to be in the upper range of rates observed in previous studies within the TRISP cooperation. These results may guide individual treatment decisions in patients with acute stroke and intracranial tumors with potential benefit of IVT.

Ischaemic cerebral small vessel disease caused by adenosine deaminase 2 deficiency syndrome.

BACKGROUND AND PURPOSE: Only a small proportion of cerebral small vessel disease (cSVD), a frequent cause of stroke and cognitive or motor disability in adults, is attributable to monogenic conditions. The hereditary nature of a patient's cSVD may be masked by a mild or non-informative phenotype, as single-gene disorders have a variable mode of presentation, penetrance and disease severity. CASE DESCRIPTION: An adult patient is here described with recurrent acute ischaemic strokes due to cSVD with no other phenotypic manifestation, in whom the pathogenic c.139G>A (p.G47R) missense variant in ADA2 (NM_001282225.2), consistent with the diagnosis of adenosine deaminase 2 deficiency syndrome, was detected by targeted next-generation sequencing. CONCLUSIONS: Clinical suspicion of adenosine deaminase 2 deficiency syndrome may be overlooked in stroke patients in whom other specific disease features are lacking. This case enlarges the mode of presentation of the syndrome and highlights the diagnostic potential of next-generation sequencing of known cSVD genes in young adults with recurrent small subcortical infarcts presenting with a lacunar syndrome.

Aortic tortuosity in Turner syndrome is associated with larger ascending aorta.

Turner syndrome (TS) is associated with aortic coarctation, dissection and dilation/aneurysm. Predictors of dissection are not well delineated, making decisions regarding prophylactic root replacement challenging. In other disorders, arterial tortuosity is an imaging biomarker associated with increased risk for aortic dissection and adverse cardiovascular events. We aimed to determine if, in TS, arterial tortuosity was associated with aortic dilation or aortic events. We performed a retrospective cohort analysis of unselected women and children with TS who underwent cardiovascular magnetic resonance angiography (MRA) for a prior prospective study. We calculated tortuosity indices including vertebral artery tortuosity index, aortic arch tortuosity index, thoracic aortic tortuosity index (ATI-D), and aortic tortuosity index to the celiac artery (ATI-C). We compared tortuosity in TS patients against age and gender matched controls. We evaluated univariable and multivariable associations between the tortuosity indices and aortic root and ascending aorta size as defined by z-scores, which give a sense of how far a measurement deviates from the mean. We also studied associations between tortuosity and need for aortic root replacement or aortic dissection. Of 184 subjects, with median age 34 years, mean general aortic root z-score was 0.1 ± 1.2 and mean general ascending aortic z-score was 0.4 ± 1.5. Three patients had aortic dissection, and one had prophylactic root replacement, which all occurred prior to first MRA. Vertebral tortuosity index, ATI-D, and ATI-C all increased with age (p < 0.0001) for all. ATI-C was associated with larger general ascending z-score. In multivariable analysis, ATI-C remained independently associated with larger ascending aortic z-scores. The relationship between aortic indices and surgery/dissection could not be evaluated since all were collected post-surgery/dissection. Thoracic aortic tortuosity as measured by ATI-C is independently associated with larger ascending aortic dimensions. In this population with only three aortic dissections occurring prior to imaging assessment, we could not assess for associations between aortic tortuosity and dissection. Studies including more patients with aortic dissection are needed to draw further conclusions.

Cervical Artery Dissections: Etiopathogenesis and Management.

Cervical Artery Dissection (CeAD) is a frequent stroke etiology for patients younger than 50 years old. The most common immediate complications related to CeAD are headache and neck pain (65-95%), TIA/ischemic stroke (>50%), and partial Horner's syndrome (25%). The prevailing hypothesis regarding the pathogenesis of sCeAD is that the underlying constitutional vessel wall weakness of patients with sCeAD is genetically determined and that environmental factors could act as triggers. The stroke prevention treatment of CeAD remains controversial, involving anticoagulation or antiplatelet therapy and potentially emergent stenting and/or thrombectomy or angioplasty for selected cases of carotid artery dissection with occlusion. The treatment of headache associated with CeAD depends on the headache phenotype and comorbidities. Radiographically, more than 75% of CeAD cases present with occlusion or non-occlusive stenosis. Many patients demonstrate partial and complete healing, more commonly in the carotid arteries. One-fifth of the patients develop dissecting pseudoaneurysm, but this is a benign clinical entity with an extremely low rupture and stroke recurrence risk. Good recovery is achieved in many CeAD cases, and mortality remains low. Family history of CeAD, connective tissue disorders like Ehlers-Danlos syndrome type IV, and fibromuscular dysplasia are risk factors for recurrent CeAD, which can occur in 3-9% of the cases. This review serves as a comprehensive, updated overview of CeAD, emphasizing etiopathogenesis and management.

Imaging features and ultraearly hematoma growth in intracerebral hemorrhage associated with COVID-19.

PURPOSE: Intracerebral hemorrhage (ICH) is an uncommon but deadly event in patients with COVID-19 and its imaging features remain poorly characterized. We aimed to describe the clinical and imaging features of COVID-19-associated ICH. METHODS: Multicenter, retrospective, case-control analysis comparing ICH in COVID-19 patients (COV19 +) versus controls without COVID-19 (COV19 -). Clinical presentation, laboratory markers, and severity of COVID-19 disease were recorded. Non-contrast computed tomography (NCCT) markers (intrahematoma hypodensity, heterogeneous density, blend sign, irregular shape fluid level), ICH location, and hematoma volume (ABC/2 method) were analyzed. The outcome of interest was ultraearly hematoma growth (uHG) (defined as NCCT baseline ICH volume/onset-to-imaging time), whose predictors were explored with multivariable linear regression. RESULTS: A total of 33 COV19 + patients and 321 COV19 - controls with ICH were included. Demographic characteristics and vascular risk factors were similar in the two groups. Multifocal ICH and NCCT markers were significantly more common in the COV19 + population. uHG was significantly higher among COV19 + patients (median 6.2 mL/h vs 3.1 mL/h, p = 0.027), and this finding remained significant after adjustment for confounding factors (systolic blood pressure, antiplatelet and anticoagulant therapy), in linear regression (B(SE) = 0.31 (0.11), p = 0.005). This association remained consistent also after the exclusion of patients under anticoagulant treatment (B(SE) = 0.29 (0.13), p = 0.026). CONCLUSIONS: ICH in COV19 + patients has distinct NCCT imaging features and a higher speed of bleeding. This association is not mediated by antithrombotic therapy and deserves further research to characterize the underlying biological mechanisms.

Spontaneous cervical artery dissection and fibromuscular dysplasia: Epidemiologic and biologic evidence of a mutual relationship.

Cervical artery dissection (CeAD) is the most common cause of ischemic stroke in young and middle-aged adults. Over the last decade, a relation between CeAD and fibromuscular dysplasia (FMD), an idiopathic, segmental, non-atherosclerotic and non-inflammatory arterial disease, has been suggested based on a number of epidemiologic observations, while preliminary data support the idea that the two conditions may share common biologic mechanisms. In this article, we review the literature on the relation between CeAD and FMD, focus on the potential pathogenetic mechanisms common to the two conditions, summarize clinical features, management and outcome, and provide support to the hypothesis that the coexistence of the two diseases in one individual might be conceptualized as a distinct non-atherosclerotic non-inflammatory arteriopathy.

Clinical Features of Patients With Cervical Artery Dissection and Fibromuscular Dysplasia.

BACKGROUND AND PURPOSE: Observational studies have suggested a link between fibromuscular dysplasia and spontaneous cervical artery dissection (sCeAD). However, whether patients with coexistence of the two conditions have distinctive clinical characteristics has not been extensively investigated. METHODS: In a cohort of consecutive patients with first-ever sCeAD, enrolled in the setting of the multicenter IPSYS CeAD study (Italian Project on Stroke in Young Adults Cervical Artery Dissection) between January 2000 and June 2019, we compared demographic and clinical characteristics, risk factor profile, vascular pathology, and midterm outcome of patients with coexistent cerebrovascular fibromuscular dysplasia (cFMD; cFMD+) with those of patients without cFMD (cFMD-). RESULTS: A total of 1283 sCeAD patients (mean age, 47.8±11.4 years; women, 545 [42.5%]) qualified for the analysis, of whom 103 (8.0%) were diagnosed with cFMD+. In multivariable analysis, history of migraine (odds ratio, 1.78 [95% CI, 1.13-2.79]), the presence of intracranial aneurysms (odds ratio, 8.71 [95% CI, 4.06-18.68]), and the occurrence of minor traumas before the event (odds ratio, 0.48 [95% CI, 0.26-0.89]) were associated with cFMD. After a median follow-up of 34.0 months (25th to 75th percentile, 60.0), 39 (3.3%) patients had recurrent sCeAD events. cFMD+ and history of migraine predicted independently the risk of recurrent sCeAD (hazard ratio, 3.40 [95% CI, 1.58-7.31] and 2.07 [95% CI, 1.06-4.03], respectively) in multivariable Cox proportional hazards analysis. CONCLUSIONS: Risk factor profile of sCeAD patients with cFMD differs from that of patients without cFMD. cFMD and migraine are independent predictors of midterm risk of sCeAD recurrence.

Association between Migraine and Cryptogenic Ischemic Stroke in Young Adults.

OBJECTIVE: To assess the association between migraine and cryptogenic ischemic stroke (CIS) in young adults, with subgroup analyses stratified by sex and presence of patent foramen ovale (PFO). METHODS: We prospectively enrolled 347 consecutive patients aged 18 to 49 years with a recent CIS and 347 age- and sex-matched (±5 years) stroke-free controls. Any migraine and migraine with (MA) and migraine without aura (MO) were identified by a screener, which we validated against a headache neurologist. We used conditional logistic regression adjusting for age, education, hypertension, diabetes, waist-to-hip ratio, physical inactivity, current smoking, heavy drinking, and oral estrogen use to assess independent association between migraine and CIS. The effect of PFO on the association between migraine and CIS was analyzed with logistic regression in a subgroup investigated with transcranial Doppler bubble screen. RESULTS: The screener performance was excellent (Cohen kappa > 0.75) in patients and controls. Compared with nonmigraineurs, any migraine (odds ratio [OR] = 2.48, 95% confidence interval [CI] = 1.63-3.76) and MA (OR = 3.50, 95% CI = 2.19-5.61) were associated with CIS, whereas MO was not. The association emerged in both women (OR = 2.97 for any migraine, 95% CI = 1.61-5.47; OR = 4.32 for MA, 95% CI = 2.16-8.65) and men (OR = 2.47 for any migraine, 95% CI = 1.32-4.61; OR = 3.61 for MA, 95% CI = 1.75-7.45). Specifically for MA, the association with CIS remained significant irrespective of PFO. MA prevalence increased with increasing magnitude of the right-to-left shunt in patients with PFO. INTERPRETATION: MA has a strong association with CIS in young patients, independent of vascular risk factors and presence of PFO. ANN NEUROL 2021;89:242-253.

Steroid-Responsive Encephalitis in Coronavirus Disease 2019.

Coronavirus disease 2019 (COVID-19) infection has the potential for targeting the central nervous system, and several neurological symptoms have been described in patients with severe respiratory distress. Here, we described the case of a 60-year-old patient with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection but only mild respiratory abnormalities who developed an akinetic mutism attributable to encephalitis. Magnetic resonance imaging was negative, whereas electroencephalography showed generalized theta slowing. Cerebrospinal fluid analyses during the acute stage were negative for SARS-CoV-2, positive for pleocytosis and hyperproteinorrachia, and showed increased interleukin-8 and tumor necrosis factor-α concentrations. Other infectious or autoimmune disorders were excluded. A progressive clinical improvement along with a reduction of cerebrospinal fluid parameters was observed after high-dose steroid treatment, thus arguing for an inflammatory-mediated brain involvement related to COVID-19. ANN NEUROL 2020;88:423-427.

Validation and Comparison of Noncontrast CT Scores to Predict Intracerebral Hemorrhage Expansion.

BACKGROUND AND PURPOSE: The BAT, BRAIN, and HEP scores have been proposed to predict hematoma expansion (HE) with noncontrast computed tomography (NCCT). We sought to validate these tools and compare their diagnostic performance. METHODS: We retrospectively analyzed two cohorts of patients with primary intracerebral hemorrhage. HE expansion was defined as volume growth > 33% or > 6 mL. Two raters analyzed NCCT scans and calculated the scores, blinded to clinical and imaging data. The inter-rater reliability was assessed with the interclass correlation statistic. Discrimination and calibration were calculated with area under the curve (AUC) and Hosmer-Lemeshow χ2 statistic, respectively. AUC comparison between different scores was explored with DeLong test. We also calculated the sensitivity, specificity, positive, and negative predictive values of the dichotomized scores with cutoffs identified with the Youden's index. RESULTS: A total of 230 subjects were included, of whom 86 (37.4%) experienced HE. The observed AUC for HE were 0.696 for BAT, 0.700 for BRAIN, and 0.648 for HEP. None of the scores had a significantly superior AUC compared with the others (all p > 0.4). All the scores had good calibration (all p > 0.3) and good-to-excellent inter-rater reliability (interclass correlation > 0.8). BAT ≥ 3 showed the highest specificity (0.81), whereas BRAIN ≥ 6 had the highest sensitivity (0.76). CONCLUSIONS: The BAT, BRAIN, and HEP scores can predict HE with acceptable discrimination and require just a baseline NCCT scan. These tools may be used to stratify the risk of HE in clinical practice or randomized controlled trials.

Triple and quadruple cervical artery dissections: a systematic review of individual patient data.

BACKGROUND AND PURPOSE: Simultaneous dissection of three or four cervical arteries rarely occurs. As a result, limited information is available on clinical characteristics, underlying causes, treatment, and outcome of these patients. METHODS: We performed a systematic review of individual patient data on triple and quadruple cervical artery dissection (CeAD). We included all cases for whom, at minimum, data on age, sex and affected cervical arteries were available. RESULTS: Out of 1396 publications identified in the initial search, 52 were included, with data available on 96 patients. Mean age was 42 years and 66% were women. 63% had triple CeAD. The most common manifestations were headache (69%), neck pain (44%), motor deficit (36%), and Horner syndrome (34%). 57% had an ischemic stroke, in the majority of these patients the stroke was confined to the vascular territory of a single artery. 83% were managed medically (antiplatelets or anticoagulants) and 11% underwent endovascular treatment. An underlying disease or triggering event was identified in 71%, most commonly trauma (35%, cervical manipulative therapy in 13%), infection (18%), fibromuscular dysplasia (16%), and hereditary connective tissue disorder (8%). In-hospital mortality was 1%. 80% of patients had a good functional outcome (mRS 0-1) at follow-up. Two recurrences (3%) were reported. CONCLUSIONS: Triple or quadruple CeAD mostly affected young women, and underlying disease or triggering event could be identified in more than two-thirds of patients. Less than two-thirds of triple or quadruple CeAD patients suffered ischemic stroke. Most patients were managed medically and the majority had a favorable outcome.

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.

PPM1A Methylation Is Associated With Vascular Recurrence in Aspirin-Treated Patients.

BACKGROUND AND PURPOSE: Despite great efforts by pharmacogenetic studies, the causes of aspirin failure to prevent the recurrence of ischemic events remain unclear. Our aim was to study whether epigenetics could be associated with the risk of vascular recurrence in aspirin-treated stroke patients. METHODS: We performed an epigenetic joint analysis study in 327 patients treated with aspirin. In the discovery stage, we performed a nested case-control study in 38 matched ischemic stroke patients in whom 450 000 methylation sites were analyzed. Nineteen patients presented vascular recurrence after stroke, and 19 matched patients did not present vascular recurrence during the first year of follow-up. In a second stage, 289 new patients were analyzed by EpiTYPER. RESULTS: The following 3 differentially methylated candidate CpG sites, were identified in the discovery stage and analyzed in the second stage: cg26039762 (P=9.69×10(-06), RAF1), cg04985020 (P=3.47×10(-03), PPM1A), and cg08419850 (P=3.47×10(-03), KCNQ1). Joint analysis identified an epigenome-wide association for cg04985020 (PPM1A; P=1.78×10(-07)), with vascular recurrence in patients treated with aspirin. CONCLUSIONS: The pattern of differential methylation in PPM1A is associated with vascular recurrence in aspirin-treated stroke patients.

Risk Profile of Symptomatic Lacunar Stroke Versus Nonlobar Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Although lacunar stroke (LS) and deep intracerebral hemorrhage (dICH) represent acute manifestations of the same pathological process involving cerebral small vessels (small vessel disease), it remains unclear what factors predispose to one phenotype rather than the other at individual level. METHODS: Consecutive patients with either acute symptomatic LS or dICH were prospectively enrolled as part of a multicenter Italian study. We compared the risk factor profile of the 2 subgroups using multivariable logistic regression. RESULTS: During a time course of 9.5 years, 1931 subjects (1434 LS and 497 dICH; mean age, 71.3±13.3 years; males, 55.5%) qualified for the analysis. Current smoking was associated with LS (odds ratio [OR], 2.17; P<0.001). Conversely, dICH cases were more likely to be hypertensive (OR, 1.87; P<0.001), excessive alcohol consumers (OR, 1.70; P=0.001), and more frequently under treatment with warfarin (OR, 2.05; P=0.010) and statins (OR, 3.10; P<0.001). Hypercholesterolemia, diabetes mellitus, and antiplatelet treatment were not associated with a specific small vessel disease manifestation. CONCLUSIONS: The risk factor profile of dICH differs from that associated with LS. This might be used for disease risk stratification at individual level.

Infective Endocarditis Presenting with Intracranial Bleeding.

BACKGROUND: Infective endocarditis (IE) can be complicated by intracranial bleeding (ICB) caused by different pathologic mechanisms. The occurrence of ICB in patients with IE significantly influences therapeutic decisions and has a negative impact on outcome. CASE REPORT: We describe the clinical courses of 3 patients with aortic prosthetic valve IE presenting with ICB. Patients 1 and 2 experienced subarachnoid hemorrhage (SAH) and intracerebral hemorrhage (ICH), respectively, caused by rupture of an intracranial infectious aneurysm (IIA). Both underwent endovascular treatment of IIA with good outcome. In patient 3, ICB was the hemorrhagic conversion of an acute ischemic lesion from septic brain embolization. In the subacute phase of the disease, aortic valve replacement was performed, with excellent outcome. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: ICB is a relevant complication and sometimes the first clinical feature of IE. Imaging of brain vessels should be performed to investigate the pathologic mechanism underlying ICB. The prevalence of IIA is probably underestimated and may influence the therapeutic strategy. Cerebrovascular imaging may therefore also be considered in asymptomatic subjects with left-sided IE. Withdrawal of anticoagulant treatment and delay of cardiac surgery are recommended in all cases of IE complicated by ICB. Because of the impact of ICB on IE management and outcome, a high level of clinical suspicion and prompt recognition and treatment of this complication are necessary.

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.

Determinants of premature familial arterial thrombosis in patients with juvenile ischaemic stroke. The Italian Project on Stroke in Young Adults (IPSYS).

Factors predicting family history (FH) of premature arterial thrombosis in young patients with ischaemic stroke (IS) have not been extensively investigated, and whether they might influence the risk of post-stroke recurrence is still unknown. In the present study we analysed 1,881 consecutive first-ever IS patients aged 18-45 years recruited from January 2000 to January 2012 as part of the Italian Project on Stroke in Young Adults (IPSYS). FH of premature arterial thrombosis was any thrombotic event [IS, myocardial infarction or other arterial events event] < 45 years in proband's first-degree relatives. Compared with patients without FH of premature arterial thrombosis, those with FH (n = 85) were more often smokers (odds ratio [OR], 1.94; 95 % confidence interval [CI], 1.21-3.09) and carriers of procoagulant abnormalities (OR, 3.66; 95 % CI, 2.21-6.06). Smoking (OR, 2.48; 95 % CI, 1.20-5.15), the A1691 mutation in factor V gene (OR, 3.64; 95 % CI, 1.31-10.10), and the A20210 mutation in the prothrombin gene (OR, 8.40; 95 % CI 3.35-21.05) were associated with FH of premature stroke (n = 33), while circulating anti-phospholipids to FH of premature myocardial infarction (n = 45; OR, 3.48; 95 % CI, 1.61-7.51). Mean follow-up time was 46.6 ± 38.6 months. Recurrent events occurred more frequently in the subgroup of patients with FH of premature stroke [19.4 %); p = 0.051] compared to patients without such a FH. In conclusion, young IS patients with FH of premature arterial thrombosis exhibit a distinct risk-factor profile, an underlying procoagulant state and have worse vascular prognosis than those with no FH of juvenile thrombotic events.