Elisabetta Del Zotto

Inherited Thrombophilic Disorders in Young Adults With Ischemic Stroke and Patent Foramen Ovale

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, 34.7±7.3 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 TT 677 genotype of methylenetetrahydrofolate reductase (MTHFR) were performed in all subjects. Results— A pathogenic role of PFO was presumed in 36 patients (PFO+). Interatrial right-to-left shunt either was not detected or was considered unrelated to stroke occurrence in the remaining 89 patients (PFO−). The PTG20210A variant was more frequent in the PFO+ group compared with control subjects and the PFO− group (PFO+ versus control subjects, 11% versus 2%; 95% CI, 0.04 to 0.94; PFO+ versus PFO−, 11% versus 1.1%; 95% CI, 1.09 to 109;P =0.047). A similar distribution was observed for subjects carrying either the PTG20210A variant or the FVG1691A mutation (PFO+ versus control subjects, 19.4% versus 5.3%; 95% CI, 0.08 to 0.75; PFO+ versus PFO−, 19.4% versus 3.3%; 95% CI, 1.45 to 26.1;P =0.021). Combined thrombophilic defects were observed in 3 subjects of the PFO+ group, in 2 control subjects (8.3% versus 1.3%; 95% CI, 0.01 to 0.66;P =0.015), and in 0 subjects in the PFO− group. A trend toward a difference in the frequency of the FVG1691A mutation between PFO+ and control subjects was found after bivariate analysis (11% versus 3.3%;P =0.068) but not after multinomial logistic regression analysis. No significant association was found in the distribution of the TT MTHFR genotype in the 3 groups. Conclusions— In young adults, the PTG20210A variant and, to a lesser extent, the FVG1691A mutation may represent risk factors for PFO-related cerebral infarcts. A role of systemic thrombophilic disorders in the pathogenesis of this specific subtype of stroke may be hypothesized.

Prevalence and pattern of cognitive impairment in systemic lupus erythematosus patients with and without overt neuropsychiatric manifestations

The prevalence and pattern of cognitive impairment in systemic lupus erythematosus (SLE) patients with (NPSLE) and without (nSLE) overt neuropsychiatric manifestations were investigated. Fifty-two nSLE patients, 23 NPSLE patients and 27 healthy controls were evaluated with a battery of standardized neuropsychological and psychological tests. Disease duration, disease activity index, and current corticosteroid therapy were collected. Cognitive impairment was identified in 14 (26.9%) and in 12 (52.2%) of subjects with nSLE and NPSLE, respectively. Both SLE groups showed a significant impairment compared with controls on tasks assessing verbal and non-verbal long-term memory, and visuoconstructional abilities. In addition, NPSLE patients reported worse performances than both nSLE patients and controls on task evaluating short-term visuospatial memory. NPSLE subjects were significantly more anxious and depressed compared to both nSLE subjects and controls. By multivariate analysis, only depression levels, among clinical variables, significantly predicted cognitive performance. This study shows that cognitive impairment occurs frequently in both nSLE and NPSLE subjects. The higher frequency in NPSLE may be related to coexisting depressive disturbances.

Migraine Mediates the Influence of C677T MTHFR Genotypes on Ischemic Stroke Risk With a Stroke-Subtype Effect

Background and Purpose— The objective was to investigate the role of C677T MTHFR polymorphism in migraine pathogenesis and in the migraine–ischemic stroke pathway. Methods— A first genotype–migraine association study was conducted on 100 patients with migraine with aura (MA), 106 with migraine without aura (MO), and 105 subjects without migraine, which provided evidence in favor of association of the TT677 MTHFR genotype with increased risk of MA compared with both control subjects (OR, 2.48; 95% CI, 1.11 to 5.58) and patients with MO (OR, 2.21; 95% CI, 1.01 to 4.82). Based on these findings, mediational models of the genotype–migraine–stroke pathway were fitted on a group of 106 patients with spontaneous cervical artery dissection, 227 young patients whose ischemic stroke was unrelated to a spontaneous cervical artery dissection (noncervical artery dissection), and 187 control subjects, and a genotype–migraine partial mediation model was selected. Results— Both migraine and the TT genotype were more strongly associated to the subgroup of patients with spontaneous cervical artery dissection (OR, 4.06; 95% CI, 1.63 to 10.02 for MA; OR, 5.45; 95% CI, 3.03 to 9.79 for MO; OR, 2.87; 95% CI, 1.45 to 5.68 for TT genotype) than to the subgroup of patients with noncervical artery dissection ischemic stroke (OR, 2.22; 95% CI, 1.00 to 4.96 for MA; OR, 1.81; 95% CI, 1.02 to 3.22 for TT genotype) as compared with controls. Conclusions— Migraine may act as mediator in the methylenetetrahydrofolate reductase–ischemic stroke pathway with a more prominent effect in the subgroup of patients with spontaneous artery dissection.

Cumulative Effect of Predisposing Genotypes and Their Interaction With Modifiable Factors on the Risk of Ischemic Stroke in Young Adults

Background and Purpose— Combinations of multiple predisposing polymorphisms and their interactions with modifiable factors may result in synergistic effects on the risk of ischemic stroke. These mechanisms are more likely to play a relevant role in younger individuals. Methods— The cumulative effect of the 20210A variant of prothrombin gene, the 1691A variant of factor V gene, the TT677 genotype of the methylenetetrahydrofolate reductase (MTHFR) gene, and the &egr;4-carriership of the apolipoprotein (APOE) gene, as well as their interactions with modifiable predisposing factors, were determined in a series of 163 stroke patients aged younger than 45 years and 158 controls. Results— Odds ratios (ORs) for stroke were 1.73 (95% confidence interval [CI], 1.20 to 2.51) in subjects with 1 polymorphism and 3.00 (95% CI, 1.43 to 6.30) in those with ≥2. Compared with nonsmokers with none of the studied polymorphisms, ORs for stroke were 1.88 (95% CI, 1.18 to 3.00) and 3.55 (95% CI, 1.40 to 8.98) for nonsmokers with 1 and 2 polymorphisms, respectively, and 3.99 (95% CI, 2.00 to 7.96) and 15.99 (95% CI, 4.01 to 63.3) for smokers. Compared with nonhypertensive subjects bearing no polymorphisms, ORs were 1.91 (95% CI, 1.28 to 2.87) and 3.68 (95% CI, 1.64 to 8.26) for nonhypertensive subjects with 1 and 2 polymorphisms, 3.28 (95% CI, 1.01 to 10.7) and 10.79 (95% CI, 1.01 to 115.4) for hypertensive. Conclusions— These data suggest a gene–dose effect of the examined prothrombotic and proatherogenic gene variants and a synergistic effect of these polymorphisms and modifiable risk factors in the pathogenesis of cerebral ischemia in young adults.

Synergistic effect of apolipoprotein E polymorphisms and cigarette smoking on risk of ischemic stroke in young adults.

Background and Purpose— The effect of apolipoprotein E (APOE) polymorphisms on stroke risk may be influenced by the coexistence of modifiable predisposing conditions. We explored the interactions of APOE genotypes and conventional risk factors in a case-control study of young adults with cerebral infarct. Methods— We analyzed 124 consecutive patients (age, 34.7±7.3 years) and 147 age- and sex-matched controls. APOE genotypes were determined by restriction fragment-length polymorphism analysis. Results— The prevalence of the &egr;4 allele and &egr;34 genotype was slightly higher in cases than in controls (0.125 versus 0.071 and 0.242 versus 0.136, respectively). Carriers of the &egr;34 genotype and &egr;4 allele were associated with an increased risk of stroke on multivariate analysis compared with the &egr;33 genotype and non-&egr;4 carriers, respectively (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.10 to 4.76; and OR, 2.27; 95% CI, 1.13 to 4.56). ORs for stroke were 2.99 (95% CI, 1.64 to 5.45), 2.69 (95% CI, 1.25 to 5.77), and 5.39 (95% CI, 1.59 to 18.30) for smokers with the &egr;33 genotype, nonsmokers with the &egr;34 genotype, and smokers with the &egr;34 genotype, respectively, compared with nonsmokers with the &egr;33 genotype. Similar results were obtained when &egr;4 carriers and non-&egr;4 carriers were compared in the same interaction model. No significant interaction between APOE and hypertension was found. Conclusions— In young adults, the APOE &egr;4 allele and cigarette smoking act synergistically, increasing an individual’s propensity to have a cerebral ischemic event. This finding may help in determining an individual’s predisposition to stroke and more targeted preventive interventions.

Ischemic Stroke during Pregnancy and Puerperium

Ischemic stroke during pregnancy and puerperium represents a rare occurrence but it could be a serious and stressful event for mothers, infants, and also families. Whenever it does occur, many concerns arise about the safety of the mother and the fetus in relation to common diagnostic tests and therapies leading to a more conservative approach. The physiological adaptations in the cardiovascular system and in the coagulability that accompany the pregnant state, which are more significant around delivery and in the postpartum period, likely contribute to increasing the risk of an ischemic stroke. Most of the causes of an ischemic stroke in the young may also occur in pregnant patients. Despite this, there are specific conditions related to pregnancy which may be considered when assessing this particular group of patients such as pre-eclampsia-eclampsia, choriocarcinoma, peripartum cardiomiopathy, amniotic fluid embolization, and postpartum cerebral angiopathy. This article will consider several questions related to pregnancy-associated ischemic stroke, dwelling on epidemiological and specific etiological aspects, diagnostic issue concerning the use of neuroimaging, and the related potential risks to the embryo and fetus. Therapeutic issues surrounding the use of anticoagulant and antiplatelets agents will be discussed along with the few available reports regarding the use of thrombolytic therapy during pregnancy.

Predictors of Migraine Subtypes in Young Adults With Ischemic Stroke: The Italian Project on Stroke in Young Adults

Background and Purpose— The mechanisms underlying the relationship between migraine and ischemic stroke remain uncertain. The aim of the present study was to investigate the predictive value of major cardiovascular risk factors, cardiac interatrial abnormalities, and additional biological markers on migraine subtypes in young adults with ischemic stroke. Methods— Ischemic stroke patients aged 45 years or younger were consecutively enrolled as part of the Italian Project on Stroke in Young Adults. A comprehensive evaluation was performed including assessment of self-reported migraine and cardiovascular risk factors, interatrial right-to-left shunt, and genotyping to detect factor V Leiden and the G20210A mutation in the prothrombin gene. Results— Nine hundred eighty-one patients (mean age, 36.0±7.6 years; 50.7% women) were included. The risk of migraine with aura increased with decreasing number of cardiovascular risk factors (OR, 0.50; 95% CI, 0.24–0.99 for 2 factors or more), increasing number of thrombophilic variants (OR, 2.21; 95% CI, 1.05–4.68 for carriers of at least 1 of the 2), and the presence of right-to-left shunt (OR, 2.41; 95% CI, 1.37–3.45), as compared to patients without migraine. None of these factors had influence on the risk of migraine without aura. Conclusions— In young adults with ischemic stroke, low cardiovascular risk profile, right-to-left shunt, and an underlying procoagulant state are predictors of migraine with aura. The biological effects of these factors should be considered in future studies aimed at investigating the mechanisms linking migraine to brain ischemia.

Predictors of Long-Term Recurrent Vascular Events After Ischemic Stroke at Young Age The Italian Project on Stroke in Young Adults

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 &bgr;-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). Conclusions— Among patients with ischemic stroke aged 18 to 45 years, the long-term risk of recurrent thrombotic events is associated with modifiable, age-specific risk factors. The IPSYS score may serve as a simple tool for risk estimation.

Homocysteine and Cerebral Ischemia: Pathogenic and Therapeutical Implications

Homocysteine is a thiol aminoacid synthesized during the metabolism of methionine. Increased plasma levels of homocysteine can be the result of mutations in the enzymes responsible for homocysteine metabolism, particularly cystathionine-beta synthase (CBS) and 5,10-methylenetetrahydrofolate reductase (MTHFR). Additionally, nutritional deficiencies in B vitamin cofactors required for homocysteine metabolism, including folic acid, vitamin B6 (pyridoxal phosphate), and/or vitamin B12 (methylcobalamin), can induce hyperhomocysteinemia. Over the last decade, following in vitro and in vivo observations of a homocysteine-associated vascular pathology, convincing epidemiological evidence has been gathered on the relation between moderate elevation of plasma homocysteine and vascular disease, including cerebral ischemia. However, causality has yet to be established. The association between homocysteine and ischemic stroke might be a spurious epidemiological finding because of confounding or it might reflect reverse causality. If this is the case, elevated levels of plasma homocysteine should be interpreted as an epiphenomenon secondary to the vascular disease itself. Thus, whether lowering homocysteine concentration prevents cerebral ischemia remains to be determined. The only method to answer the question of the causal relation between homocysteine and ischemic stroke is by intervention trials in which patients at high vascular risk, such as those who have had a recent cerebral ischemic event are randomly allocated to placebo or homocysteine-lowering multivitamin therapy, and followed prospectively. Some of these randomized controlled trials are currently ongoing. Their results should hopefully resolve the issue in the next future.

Do common prothrombotic mutations influence the risk of cerebral ischaemia in patients with patent foramen ovale? - Systematic review and meta-analysis

Conflicting results are available on the association of prothrombotic genetic abnormalities with patent foramen ovale (PFO)-related cerebral ischaemia. We comprehensively sought and identified studies of the association of both the factor V Leiden (FV(G1691A) mutation) and the prothrombin mutation (PT(G20210A) mutation) with PFO-related cerebral ischaemia and did meta-analyses to assess the evidence for such a relation. We analysed data from six eligible studies in 856 cases and 1,001 control subjects. Additional unpublished data from a new series including 463 subjects were also entered into the analysis. The PT(G20210A) variant was significantly associated with PFO-related stroke in comparison with both control subjects (odds ratio [OR] 3.85; 95% confidence interval [CI] 2.22 to 6.66) and non-PFO-associated stroke patients (OR 2.31; 95% CI 1.20 to 4.43), whereas a trend toward an association was observed for the FV(G1691A) mutation (OR 1.18; 95% CI 0.73 to 1.90, compared to control subjects; OR 1.14; 95% CI 0.62 to 2.09, compared to non-PFO-associated stroke patients). The status of carrier of either the FV(G1691A) mutation or the PT(G20210A) variant was associated with a risk for stroke of 1.98 (95% CI 1.38 to 2.83) and 1.62 (95% CI 1.03 to 2.57), as compared to control subjects and non-PFO-associated stroke patients, respectively. Addition of common prothrombotic genetic variants to standard initial screening may contribute to stratifying PFO-associated stroke patients at different risk of ischaemic events and targeting secondary prevention strategies.