Common genetic markers and prediction of recurrent events after ischemic stroke in young adults.

BACKGROUND: Scarce information is available on the usefulness of new prediction markers for identifying young ischemic stroke patients at highest risk of recurrence. METHODS: The predictive effect of traditional risk factors as well as of the 20210A variant of prothrombin gene, the 1691A variant of factor V gene, and the TT677 genotype of the methylenetetrahydrofolate reductase (MTHFR) gene on the risk of recurrence was investigated in a hospital-based cohort study of 511 ischemic stroke patients younger than 45 years followed up for a mean of 43.4 months. Outcome measures were fatal/nonfatal myocardial infarction, ischemic stroke, or TIA. Risk prediction was assessed with the use of the concordance c (c index), and the Net Reclassification Improvement (NRI). RESULTS: The risk of recurrence increased with increasing number of traditional factors (hazard ratio [HR] 2.29, 95% confidence interval [CI] 1.57-3.35 for subjects with 1 factor: HR 5.25, 95% CI 2.45-11.2 for subjects with 2), as well as with that of predisposing genotypes (HR 1.96, 95% CI 1.33-2.89 for subjects carrying 1 at-risk genotype; HR 3.83, 95% CI 1.76-8.34 for those carrying 2). The c statistics increased significantly when the genotypes were included into a model with traditional risk factors (0.696 vs 0.635, test z = 2.41). The NRI was also significant (NRI = 0.172, test z = 2.17). CONCLUSIONS: Addition of common genetic variants to traditional risk factors may be an effective method for discriminating young stroke patients at different risk of future ischemic events.

A case series of young stroke in Rome.

In this hospital case series study we enrolled 394 consecutive ischemic stroke patients aged 14-47 years, all of whom were submitted to a diagnostic protocol. We evaluated the incidence of cerebral ischemia in young adults, as well as the risk factors and the etiopathogenesis of this pathology. Modified diagnostic criteria adopted from the TOAST and Baltimore-Washington Cooperative Young Stroke Study were used for the etiologic classification. The crude annual incidence rate was 8.8/100,000 (95% CI 7.7-9.9), which is in keeping with the rates reported in comparable registries. Risk factors were distributed as follows: smoking in 56% of patients, hypertension in 23%, dyslipidemia in 15%, migraine in 26%, and diabetes mellitus in 2%. Oral contraceptives were being taken by 38% of the women enrolled. The etiology of stroke in the patients was as follows: cardioembolism in 34%, atherothrombosis in 12%, non-atherosclerotic vasculopathies in 14% (including arterial dissection in 12%), other determined causes in 13%, lacunar stroke in 2.5%, migraine in 1%, and undetermined causes in 24%. Despite its biased sampling frame, this large hospital case series, in which risk factor distribution and etiopathogenesis were investigated, stresses the need for an adequate diagnostic approach in young ischemic patients.

A role of TNF-alpha gene variant on juvenile ischemic stroke: a case-control study.

The role of genetic factors in the individual predisposition to develop ischemic stroke has been assessed by previous studies performed both in animal models and in humans. The main goal of the current investigation was to determine the possible contribution of genes encoding procoagulant and inflammatory factors on the occurrence of ischemic stroke in a cohort of young cases and corresponding controls. One hundred and fifteen cases of ischemic stroke were recruited for this study. A detailed clinical assessment, a definite etiologic diagnosis, as well as the presence/absence of known risk factors for ischemic stroke were obtained for each patient. As a control group 180 healthy, unrelated subjects were included. The whole population was screened for polymorphisms belonging to genes encoding FII, FV, alpha-fibrinogen, beta-fibrinogen, GP IIb/IIIa, tumor necrosis factor (TNF)-alpha, interleukin 1-beta. Hypertension was the most important risk factor for ischemic stroke in our cohort [OR = 6.9, confidence interval (CI) 2.9-16.7, P < 0.0001]. Among all genes tested, the TNF-alpha gene variant exerted a significant, independent effect on individual predisposition to ischemic stroke occurrence (OR = 1.8, CI = 1.01-3.3, P < 0.05). Our findings, obtained in a cohort of young Italian patients, may support the existence of a direct contributory role of TNF-alpha, a proinflammatory cytokine protein, in the susceptibility to brain damage.

Young stroke and basal plasma and post-methionine load homocysteine and cysteine levels 1 year after the acute event: do plasma folates make the difference?

We conducted a case-control study to evaluate the relationship between ischemic stroke in young adults (<45 years of age) and plasma homocysteine (Hcy), plasma folate and vitamin B(12), after a methionine load. We studied 42 patients with a history of ischemic stroke and 29 controls with a negative clinical history of cardio- or cerebrovascular diseases, venous thrombosis and renal disease. A fasting blood sample was drawn from each participant; the second and third samples were collected, respectively, 120 and 240 min after the methionine load. Whilst there was no difference between controls and patients in basal total homocysteine (tHcy), we found a statistically significant difference in both the 120- and 240-min samples. We compared the basal and 240-min tHcy in patients and controls. We obtained a median value of 17.8 and 11.6 micromol/l in patients and controls, respectively. The difference between these two values was highly significant. The methionine loading test (MLT) reveals Hcy metabolism abnormalities that were not revealed by the basal sample. MLT may help identify and treat this new risk factor, which seems to be both atherogenic and prothrombotic, and is hypothesized to operate through various mechanisms.

Migraine and arterial dissection in a young woman.

Ischemic stroke in young adults is rare (5%-10% of all ischemic strokes) and, in absence of other risk factors, may be associated with migraine. We describe the case of a 34-year-old woman, with a history of migraine without aura, who presented a sudden onset of headache with Horner's syndrome, and in whom neuroimaging showed evidence compatible with fibromuscular dysplasia (FMD) and arterial dissection of the extracranial internal carotid artery (ICA) and the carotid siphon. In our opinion, in young women with a long history of migraine, a careful study of the extracranial and intracranial arteries would be useful, although the cost/benefit ratio does not at present justify such a procedure. Our aim in the future is, therefore, to study a larger sample of migraine patients in order to find those patients who are most at risk of arterial dissection and who should, consequently, be carefully studied.

Effects of intra-VTA injection of neurotensin on local cerebral glucose utilization in freely moving rats.

The [14C]2-deoxyglucose method was applied to measure the effects of the injection of neurotensin (7 microg) in the ventral tegmental area on local cerebral glucose utilization in the rat. Injection of neurotensin produced significant increases of glucose utilization in the shell of the nucleus accumbens and in the olfactory tubercle. These results indicate that stimulation of neurotensin receptors in the ventral tegmental area produces functional changes that are confined to the regions receiving mesolimbic projections within the rostral extended amygdaloid complex. These findings extend our understanding on the effects of neurotensin in the limbic system, with particular regard to reward pathways.

Central nervous system vasculitis.

Vasculitis is inflammation of blood vessel walls, which produces dysfunction in both the peripheral and central nervous system (CNS). Cerebral ischemia is the major cause for neurological manifestations of CNS vasculitis. Unfortunately, a universally accepted classification of vasculitis has not emerged. Vasculitis affecting the CNS alone is referred to as primary angiitis of the CNS; secondary vasculitis occurs in association with a variety of conditions, including infections, drug abuse, lymphoproliferative disease and connective tissue diseases. The pathogenesis of vasculitis includes different immunological mechanisms. Recently, anti-neutrophil cytoplasmatic antibody (ANCA) has been demonstrated to play an active role in the immunopathogenesis of the vasculitis. Diagnosis of vasculitis depends on a combination of clinical, radiographic and pathologic features. A wide spectrum of clinical features may occur. The most typical clinical picture of CNS vasculitis is troke, encephalopathy or seizures. Assays for ANCA, serum cytokines, antibodies to endothelial cell antigens have been reported to be useful in diagnosing or monitoring the disease activity. The gold standard in diagnosis is confirmation of vasculitis in a biopsy specimen. Angiography may suggest the diagnosis but no abnormalities are pathognomonic. Ideally, the therapy of each vasculitis would focus on the specific immunologic mechanism causing the disease. Such specific interventions are not yet available. In general the most important approaches induce global immunosuppression. The goal of therapy, however, is to prevent recurrence of disease.

Lupus anticoagulant and the fibrinolytic system in young patients with stroke.

BACKGROUND AND PURPOSE: Our purpose was to assess the presence of lupus anticoagulant and fibrinolytic system abnormalities in young patients with stroke. METHODS: We studied 33 consecutive ischemic patients aged < 50 years. Lupus anticoagulant was screened by four different coagulation tests, and the fibrinolytic system was studied by analyzing tissue plasminogen activator antigen and plasminogen activator inhibitor activity. RESULTS: Six patients (18%), two of whom were affected by systemic lupus erythematosus, had lupus anticoagulant. Plasminogen activator inhibitor activity was significantly higher in those positive for lupus anticoagulant than in those negative for lupus anticoagulant and control subjects (p < 0.001). CONCLUSIONS: In young patients with stroke, lupus anticoagulant is associated with an imbalance of the fibrinolytic system as a result of higher levels of plasminogen activator inhibitor.

One year follow-up of patients clinically preselected for excessive risk of stroke.

From a consecutive series of 812 patients at risk of stroke we selected 100 who seemed to be at high risk (excessive stroke risk--ESR) on the following clinical criteria: either multiple reversible ischemic attacks in one carotid territory or multiple (or bilateral) severe stenotic carotid lesions. The patients of the first subgroup received medical therapy and those of the second were referred for surgery. The 100 patients were followed up for 12 months, during which 29 patients had cerebral ischemic events: 17 having stroke and 12 TIA. This study suggests that it is possible to identify beforehand subgroups of ESR patients, thereby facilitating the selection of patients for brain protection and avoiding huge trials of unselected cerebrovascular patients.

Italian multicenter study on reversible cerebral ischemic attacks: III--Influence of age and risk factors on cerebrovascular atherosclerosis.

The influence of age and other risk factors (history of hypertension and diabetes, cigarette smoking, dyslipidemia) on cerebral atherosclerosis was studied in 462 patients with RIA who had cerebral angiography. The degree of atherosclerosis was quantified using extracranial and intracranial cerebrovascular scores (ECS, ICS) based on the number and severity of the lesion in 11 extracranial and 21 intracranial arterial segments. Thirty-six percent of the patients under age 45 had a normal angiogram compared with 17% of the patients over 45. In the subgroup of patients with abnormal angiogram the mean ECS and ICS vascular scores were not significantly different in the two age groups. Cigarette smoking was the only risk factor to show a strong association with the extracranial score, and it was independent of the effect of age and other risk factors.