In the largest published series of patients with CEAD, we observed significant differences between VAD and ICAD in terms of risk factors, baseline features, and functional outcome.

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Background Several preclinical and clinical investigations have argued for nervous system involvement in SARS-CoV-2 infection. Some sparse case reports have described various forms of encephalitis in COVID-19 disease, but very few data have focused on clinical presentations, clinical course, response to treatment and outcomes. Methods The ENCOVID multicentre study included patients with encephalitis with full infectious screening, CSF, EEG, MRI data and confirmed SARS-CoV-2 infection recruited from 13 centres in northern Italy. Clinical presentation and laboratory markers, severity of COVID-19 disease, response to treatment and outcomes were recorded. Results twenty-five cases of encephalitis positive for SARS-CoV-2 infection were included. CSF showed hyperproteinorrachia and/or pleocytosis in 68% of cases whereas SARS-CoV-2 RNA by RT-PCR resulted negative. Based on MRI, cases were classified as ADEM (n=3), limbic encephalitis (LE, n=2), encephalitis with normal imaging (n=13) and encephalitis with MRI alterations (n=7). ADEM and LE cases showed a delayed onset compared to the other encephalitis (p=0.001) and were associated with previous more severe COVID-19 respiratory involvement. Patients with MRI alterations exhibited worse response to treatment and final outcomes compared to other encephalitis. Conclusions SARS-CoV-2 infection is associated with a wide spectrum of encephalitis characterized by different clinical presentation, response to treatment and outcomes.

on behalf of IGIGI InvestigatorsObjectives-To investigate the role of interleukin-1␤ (IL-1␤) gene polymorphisms as a link between inflammation, coagulation, and risk of ischemic vascular disease at young age. Methods and Results-A total of 406 patients with myocardial infarction (MI) at young age, frequency-matched for age, sex, and recruitment center, with 419 healthy population-based controls and 134 patients with ischemic stroke at young age, matched by age and sex, with 134 healthy population-based controls, were studied. Subjects carrying the TT genotype of the Ϫ511C/T IL-1␤ polymorphism showed a decreased risk of MI (odds ratio [OR], 0.36; 95% CI, 0.20 to 0.64) and stroke (OR, 0.32; 95% CI, 0.13 to 0.81) after adjustment for conventional risk factors. In both studies, the T allele showed a codominant effect (Pϭ0.0020 in MI; Pϭ0.021 in stroke). Mononuclear cells from volunteers carrying the T allele showed a decreased release of IL-1␤ and a decreased expression of tissue factor after stimulation with lipopolysaccharide compared with CC homozygotes. The presence of a monoclonal antibody against IL-1␤ during cell stimulation resulted in a marked reduction of tissue factor activity expression. Key Words: risk factors Ⅲ genetics Ⅲ stroke Ⅲ myocardial infarction Ⅲ inflammation Ⅲ coagulation I ncreased levels of inflammatory markers are associated with ischemic vascular disease. [1][2][3][4] Inflammation has a relevant role in the initiation and progression of atherosclerosis; 5 however, it can also play a primary role in thrombosis development by activating the coagulation process. 6 Interleukin-1␤ (IL-1␤), a proinflammatory cytokine, stimulates the synthesis of tissue factor (TF) from monocytes and endothelial cells. 7,8 TF triggers activation of the coagulation cascade toward thrombus formation. 9 Inflammatory responses show a high interindividual variability and have been associated with polymorphisms in IL-1␤ gene; 10,11 the latter have also been related to the risk of several chronic inflammatory diseases. 11,12 We hypothesized that IL-1␤ gene polymorphisms might modulate the inflammation-triggered pathway of thrombus formation and the risk of ischemic arterial disease such as myocardial infarction (MI) and ischemic stroke. Patients with early-onset disease represent a subset of individuals in whom the impact of genes is more expressed and can be more easily identified. [13][14][15] Therefore, we investigated whether the risk of MI and ischemic stroke at young age is associated with polymorphisms in IL-1␤ gene and whether these polymorphisms can influence thrombosis by modulating the IL-1␤-mediated TF activation in response to inflammation. Conclusions--511C/T IL- Methods Study Population Patients With MIBetween May 1995 and July 2002, 430 patients Ͻ45 (males) or Ͻ50 (females) years of age admitted to cardiology centers (see the list in the Appendix) with a first episode of MI were consecutively included into the study. Acute MI was defined as resting chest pain lasting Ͼ30 minutes accompanied by ST-segment...

Background and Purpose-The role of mild hyperhomocysteinemia as a risk factor for cerebral ischemia may depend on stroke subtype. To test this hypothesis, we undertook a prospective case-control study of a group of patients with spontaneous cervical artery dissection (sCAD), a group of patients with atherothrombotic stroke (non-CAD), and a group of control subjects. Methods-Fasting total plasma homocysteine (tHcy) concentration, C677T MTHFR genotype, and 844ins68bp CBS genotype were determined in 25 patients with sCAD, 31 patients Ͻ45 years of age with non-CAD ischemic stroke, and 36 control subjects. Biochemical data in the patient groups were obtained within the first 72 hours of stroke onset. Results-Median tHcy levels were significantly higher in patients with sCAD (13.2 mol/L; range, 7 to 32.8 mol/L) compared with control subjects (8.9 mol/L; range, 5 to 17.3 mol/L; 95% CI, 1.05 to 1.52; Pϭ0.006). Cases with tHcy concentration above the cutoff level of 12 mol/L were significantly more represented in the group of patients with sCAD compared with control subjects (64% versus 13.9%; 95% CI, 2.25 to 44.23; Pϭ0.003); a significant association between the MTHFR TT genotype and sCAD was also observed (36% versus 11.1%; 95% CI, 1.10 to 19.23; Pϭ0.045). No significant difference in tHcy levels and in the prevalence of thermolabile MTHFR was found between patients with non-CAD ischemic stroke and control subjects and between patients with sCAD and non-CAD ischemic stroke. The distribution of the 844ins68bp CBS genotype and the prevalence of subjects carrying both the TT MTHFR and 844ins68bp CBS genotypes were not significantly different among the 3 groups. Conclusions-Our

Background and Purpose-The pathogenic link between patent foramen ovale (PFO) and stroke remains unknown in most cases. We investigated the association between inherited thrombophilic disorders and PFO-related strokes in a series of young adults in the setting of a case-control study. Methods-We investigated 125 consecutive subjects (age, 34.7Ϯ7.3 years) with ischemic stroke and 149 age-and sex-matched control subjects. PFO was assessed in all patients with transcranial Doppler sonography with intravenous injection of agitated saline according to a standardized protocol. Genetic analyses for the factor V (FV) G1691A mutation, the prothrombin (PT) G20210A variant, and the TT677 genotype of methylenetetrahydrofolate reductase (MTHFR) were performed in all subjects. Results-A pathogenic role of PFO was presumed in 36 patients (PFOϩ). Interatrial right-to-left shunt either was not detected or was considered unrelated to stroke occurrence in the remaining 89 patients (PFOϪ

Background-Data on long-term risk and predictors of recurrent thrombotic events after ischemic stroke at a young age are limited. Methods and Results-We followed 1867 patients with first-ever ischemic stroke who were 18 to 45 years of age (mean age, 36.8±7.1 years; women, 49.0%), as part of the Italian Project on Stroke in Young Adults (IPSYS). Median follow-up was 40 months (25th to 75th percentile, 53). The primary end point was a composite of ischemic stroke, transient ischemic attack, myocardial infarction, or other arterial events. One hundred sixty-three patients had recurrent thrombotic events (average rate, 2.26 per 100 person-years at risk). At 10 years, cumulative risk was 14.7% (95% confidence interval, 12.2%-17.9%) for primary end point, 14.0% (95% confidence interval, 11.4%-17.1%) for brain ischemia, and 0.7% (95% confidence interval, 0.4%-1.3%) for myocardial infarction or other arterial events. Familial history of stroke, migraine with aura, circulating antiphospholipid antibodies, discontinuation of antiplatelet and antihypertensive medications, and any increase of 1 traditional vascular risk factor were independent predictors of the composite end point in multivariable Cox proportional hazards analysis. A point-scoring system for each variable was generated by their β-coefficients, and a predictive score (IPSYS score) was calculated as the sum of the weighted scores. The area under the receiver operating characteristic curve of the 0-to 5-year score was 0.66 (95% confidence interval, 0.61-0.71; mean, 10-fold internally cross-validated area under the receiver operating characteristic curve, 0.65).© 2014 American Heart Association, Inc. 1 Although it is well documented that such a risk is much lower in young patients with stroke than in elderly patients, information on what specific factors may predict recurrent events in younger age groups are limited. Most data derive from single-center studies enrolling several hundred patients or less, 2 using different thresholds of age to define young, and sometimes being biased by the inadequate capture of cases, the inclusion of different ethnic groups, and the high number of patients lost to follow-up.3 This makes such studies somewhat heterogeneous and their findings poorly comparable. In addition, the influential effect of some specific factors is missing in most previous studies. This is the case, for example, of patients' adherence to secondary prevention therapies, which is likely to impact the recurrence of potentially avoidable vascular events. The Italian Project on Stroke in Young Adults (IPSYS) provides the opportunity to investigate these issues owing to its large sample size, the homogeneous demographic characteristics and clinical phenotype of the subjects included, and the standard diagnostic workup. Therefore, in the present study we aimed at (1) elucidating the predictors of long-term recurrent vascular events after first-ever IS, and the extent to which these factors can be modified, which implicates the potential of reducing this risk,...

The pathophysiology of spontaneous cervical artery dissection (sCAD) is largely unknown. An association with migraine has been suggested, but not definitively proven. In the setting of a hospital-based prospective case-control study we assessed personal and family history of migraine in 72 patients with sCAD, 72 patients with cerebral infarct unrelated to a CAD (non-CAD) and 72 control subjects. Personal history of migraine was significantly associated to sCAD compared to non-CAD (59.7% vs. 30.6%; OR 3.14; 95% CI 1.41-7.01) and controls (18.1%; OR 7.41; 95% CI 3.11-17.64). As opposed to migraine with aura, migraine without aura was significantly more frequent among sCAD than among non-CAD (56.9% vs. 25.0%; OR 3.91; 95% CI 1.71-8.90) and controls (12.5%; OR 9.84; 95% CI 3.85-25.16). Similar results were observed when the frequencies of family history of migraine were compared. These findings are consistent with the hypothesis that migraine may represent a predisposing condition for sCAD.