Risk Profile of Patients with Spontaneous Cervical Artery Dissection.

OBJECTIVE: Epidemiological data to characterize the individual risk profile of patients with spontaneous cervical artery dissection (sCeAD) are rather inconsistent. METHODS AND RESULTS: In the setting of the Italian Project on Stroke in Young Adults Cervical Artery Dissection (IPSYS CeAD), we compared the characteristics of 1,468 patients with sCeAD (mean age = 47.3 ± 11.3 years, men = 56.7%) prospectively recruited at 39 Italian centers with those of 2 control groups, composed of (1) patients whose ischemic stroke was caused by mechanisms other than dissection (non-CeAD IS) selected from the prospective IPSYS registry and Brescia Stroke Registry and (2) stroke-free individuals selected from the staff members of participating hospitals, matched 1:1:1 by sex, age, and race. Compared to stroke-free subjects, patients with sCeAD were more likely to be hypertensive (odds ratio [OR] = 1.65, 95% confidence interval [CI] = 1.37-1.98), to have personal history of migraine with aura (OR = 2.45, 95% CI = 1.74-3.34), without aura (OR = 2.67, 95% CI = 2.15-3.32), and family history of vascular disease in first-degree relatives (OR = 1.69, 95% CI = 1.39-2.05), and less likely to be diabetic (OR = 0.65, 95% CI = 0.47-0.91), hypercholesterolemic (OR = 0.75, 95% CI = 0.62-0.91), and obese (OR = 0.41, 95% CI = 0.31-0.54). Migraine without aura was also associated with sCeAD (OR = 1.81, 95% CI = 1.47-2.22) in comparison with patients with non-CeAD IS. In the subgroup of patients with migraine, patients with sCeAD had higher frequency of migraine attacks and were less likely to take anti-migraine preventive medications, especially beta-blockers, compared with the other groups. INTERPRETATION: The risk of sCeAD is influenced by migraine, especially migraine without aura, more than by other factors, increases with increasing frequency of attacks, and seems to be reduced by migraine preventive medications, namely beta-blockers. ANN NEUROL 2023;94:585-595.

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.

Genetic Imbalance Is Associated With Functional Outcome After Ischemic Stroke.

Background and Purpose- We sought to explore the effect of genetic imbalance on functional outcome after ischemic stroke (IS). Methods- Copy number variation was identified in high-density single-nucleotide polymorphism microarray data of IS patients from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) and SiGN (Stroke Genetics Network)/GISCOME (Genetics of Ischaemic Stroke Functional Outcome) networks. Genetic imbalance, defined as total number of protein-coding genes affected by copy number variations in an individual, was compared between patients with favorable (modified Rankin Scale score of 0-2) and unfavorable (modified Rankin Scale score of ≥3) outcome after 3 months. Subgroup analyses were confined to patients with imbalance affecting ohnologs-a class of dose-sensitive genes, or to those with imbalance not affecting ohnologs. The association of imbalance with outcome was analyzed by logistic regression analysis, adjusted for age, sex, stroke subtype, stroke severity, and ancestry. Results- The study sample comprised 816 CADISP patients (age 44.2±10.3 years) and 2498 SiGN/GISCOME patients (age 67.7±14.2 years). Outcome was unfavorable in 122 CADISP and 889 SiGN/GISCOME patients. Multivariate logistic regression analysis revealed that increased genetic imbalance was associated with less favorable outcome in both samples (CADISP: P=0.0007; odds ratio=0.89; 95% CI, 0.82-0.95 and SiGN/GISCOME: P=0.0036; odds ratio=0.94; 95% CI, 0.91-0.98). The association was independent of age, sex, stroke severity on admission, stroke subtype, and ancestry. On subgroup analysis, imbalance affecting ohnologs was associated with outcome (CADISP: odds ratio=0.88; 95% CI, 0.80-0.95 and SiGN/GISCOME: odds ratio=0.93; 95% CI, 0.89-0.98) whereas imbalance without ohnologs lacked such an association. Conclusions- Increased genetic imbalance was associated with poorer functional outcome after IS in both study populations. Subgroup analysis revealed that this association was driven by presence of ohnologs in the respective copy number variations, suggesting a causal role of the deleterious effects of genetic imbalance.

Genetic Imbalance in Patients with Cervical Artery Dissection.

BACKGROUND: Genetic and environmental risk factors are assumed to contribute to the susceptibility to cervical artery dissection (CeAD). To explore the role of genetic imbalance in the etiology of CeAD, copy number variants (CNVs) were identified in high-density microarrays samples from the multicenter CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) study and from control subjects from the CADISP study and the German PopGen biobank. Microarray data from 833 CeAD patients and 2040 control subjects (565 subjects with ischemic stroke due to causes different from CeAD and 1475 disease-free individuals) were analyzed. Rare genic CNVs were equally frequent in CeAD-patients (16.4%; n=137) and in control subjects (17.0%; n=346) but differed with respect to their genetic content. Compared to control subjects, CNVs from CeAD patients were enriched for genes associated with muscle organ development and cell differentiation, which suggests a possible association with arterial development. CNVs affecting cardiovascular system development were more common in CeAD patients than in control subjects (p=0.003; odds ratio (OR) =2.5; 95% confidence interval (95% CI) =1.4-4.5) and more common in patients with a familial history of CeAD than in those with sporadic CeAD (p=0.036; OR=11.2; 95% CI=1.2-107). CONCLUSION: The findings suggest that rare genetic imbalance affecting cardiovascular system development may contribute to the risk of CeAD. Validation of these findings in independent study populations is warranted.

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.

Serum cholesterol levels, HMG-CoA reductase inhibitors and the risk of intracerebral haemorrhage. The Multicenter Study on Cerebral Haemorrhage in Italy (MUCH-Italy).

OBJECTIVE: Although a concern exists that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) might increase the risk of intracerebral haemorrhage (ICH), the contribution of these agents to the relationship between serum cholesterol and disease occurrence has been poorly investigated. METHODS: We compared consecutive patients having ICH with age and sex-matched stroke-free control subjects in a case-control analysis, as part of the Multicenter Study on Cerebral Haemorrhage in Italy (MUCH-Italy), and tested the presence of interaction effects between total serum cholesterol levels and statins on the risk of ICH. RESULTS: A total of 3492 cases (mean age, 73.0±12.7 years; males, 56.6%) and 3492 control subjects were enrolled. Increasing total serum cholesterol levels were confirmed to be inversely associated with ICH. We observed a statistical interaction between total serum cholesterol levels and statin use for the risk of haemorrhage (Interaction OR (IOR), 1.09; 95% CI 1.05 to 1.12). Increasing levels of total serum cholesterol were associated with a decreased risk of ICH within statin strata (average OR, 0.87; 95% CI 0.86 to 0.88 for every increase of 0.26 mmol/l of total serum cholesterol concentrations), while statin use was associated with an increased risk (OR, 1.54; 95% CI 1.31 to 1.81 of the average level of total serum cholesterol). The protective effect of serum cholesterol against ICH was reduced by statins in strictly lobar brain regions more than in non-lobar ones. CONCLUSIONS: Statin therapy and total serum cholesterol levels exhibit interaction effects towards the risk of ICH. The magnitude of such effects appears higher in lobar brain regions.

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 ß-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.

Obesity and the risk of intracerebral hemorrhage: the multicenter study on cerebral hemorrhage in Italy.

BACKGROUND AND PURPOSE: The effect of obesity on the risk of intracerebral hemorrhage (ICH) may depend on the pathophysiology of vessel damage. To further address this issue, we investigated and quantified the correlations between obesity and obesity-related conditions in the causal pathways leading to ICH. METHODS: A total of 777 ICH cases ≥ 55 years of age (287 lobar ICH and 490 deep ICH) were consecutively enrolled as part of the Multicenter Study on Cerebral Hemorrhage in Italy and compared with 2083 control subjects by a multivariate path analysis model. Separate analyses were conducted for deep and lobar ICH. RESULTS: Obesity was not independently associated with an increased risk of lobar ICH (odds ratio [OR], 0.76; 95% confidence interval [CI], 0.58-1.01) or deep ICH (OR, 1.18; 95% CI, 0.95-1.45) when compared with control subjects. The path analysis confirmed the nonsignificant total effect of obesity on the risk of lobar ICH (OR, 0.77; 95% CI, 0.58-1.02) but demonstrated a significant indirect effect on the risk of deep ICH (OR, 1.28; 95% CI, 1.03-1.57), mostly determined by hypertension (OR, 1.07; 95% CI, 1.04-1.11) and diabetes mellitus (OR, 1.04; 95% CI, 1.01-1.07). Obesity was also associated with an increased risk of deep ICH when compared with lobar ICH (OR, 1.62; 95% CI, 1.14-2.31). CONCLUSIONS: Obesity increases the risk of deep ICH, mostly through an indirect effect on hypertension and other intermediate obesity-related comorbidities, but has no major influence on the risk of lobar ICH. This supports the hypothesis of different, vessel-specific, biological mechanisms underlying the relationship between obesity and cerebral hemorrhage.

Complications of acute stroke and the occurrence of early seizures.

BACKGROUND: Seizures are common neurological consequences of stroke. Although a number of factors including stroke severity on admission, cortical involvement, and stroke subtype have been consistently associated with post-stroke seizures, the effect that medical and neurological complications of stroke, occurring in the very acute phase, might have on such a risk has never been adequately explored. In the present study we aimed at determining the extent to which complications within the first week of stroke influence the risk of early seizures (ES). METHODS: Data of consecutive patients with first-ever acute stroke included in the Brescia Stroke Registry were analyzed. ES (≤7 days) were recorded and correlated with demographic data, disease characteristics, risk factors, and prespecified medical and neurological stroke complications in a multivariate path analysis model. RESULTS: 516 patients with first-ever acute stroke were eligible for inclusion in the present study. Of them, 436 patients had ischemic stroke (IS) [64 (14.6%) with hemorrhagic transformation (HT)] and 80 had intracerebral hemorrhage (ICH). Twenty patients (3.9%) developed ES. Patients with ES had a higher burden of complications compared with those without (30 vs. 4.2%, for patients with >6 complications). Lesion type, stroke complications, and lesion site were directly related to the risk of seizure occurrence (OR, 0.24; 95% CI, 0.07-0.80 for IS vs. ICH; OR, 1.57; 95% CI, 1.21-2.01 for any increase of 1 in the number of complications; OR, 0.15; 95% CI, 0.04-0.56 for subcortical lesions vs. cortical lesions). Complications appeared also to mediate the indirect effect of lesion type on the occurrence of ES (OR, 0.75; 95% CI, 0.60-0.94). No significant difference on the risk of ES was observed when HT and ICH were compared. The total effect of lesion type was 0.25 × 0.75 = 0.18, corresponding to (1-0.18) = 82% lower risk of ES for IS as compared to ICH. CONCLUSION: Although major determinants of ES are nonmodifiable, preventable and treatable medical and neurologic complications within the first week of stroke increase the risk of ES and mediate the effect of established predictors on the propensity to post-stroke epilepsy. Future epidemiologic studies aimed at investigating post-stroke seizures should include precise information on these complications.

Grange syndrome: an identifiable cause of stroke in young adults.

Grange syndrome is a disorder characterized by arterial occlusive disease, hypertension, congenital cardiac defects, bone fragility, brachysyndactyly, and learning disabilities. It was first described in four members of the same family and in two sporadic cases thereafter, suggesting the possibility of various patterns of inheritance. We report on the case of an 18-year-old female presenting with subarachnoid hemorrhage due to the rupture of a basilar artery aneurysm, and with distinctive systemic features including extensive vasculopathy, facial dysmorphisms and brachysyndactyly, consistent with the diagnosis of Grange syndrome. Although rare and not fully characterized, Grange syndrome should be included in the differential diagnosis of stroke at young age.

Headache due to spontaneous intracranial hypotension and subsequent cerebral vein thrombosis.

Cerebral vein thrombosis (CVT) is a rare complication of spontaneous intracranial hypotension (SIH). When to suspect a thrombotic disorder during the course of intracranial hypotension is not fully elucidated. A 48-year-old woman was admitted because of SIH with no signs of CVT on neuroimaging. The occurrence of diplopia and blurred vision 12 days later led to the performance of further investigations, which revealed thrombosis of the left lateral sinus, in the absence of variations in the headache characteristics. Among the other 4 cases of SIH clearly preceding the occurrence of CVT reported so far, only one had a change in the headache pattern related to CVT development. Although a change in the characteristics of headache is considered a marker of CVT in patients with SIH, this is not invariably part of the clinical scenario. Any new neurologic finding on exam in the disease course should raise a suspicion of venous thrombosis, thus prompting further specific investigations.

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.

Mutations in TGFBR2 gene cause spontaneous cervical artery dissection.

Mutations in the genes encoding transforming growth factor ß receptors 1 and 2 (TGFBR1 and TGFBR2) have recently been associated with hereditary connective tissue disorders with widespread vascular involvement, including arterial dissection. To determine whether mutations in these genes cause spontaneous cervical artery dissection (sCAD), all coding exons of TGFBR1 and TGFBR2 were sequenced in 56 consecutive patients with sCAD. Novel TGFBR2 disease causing mutations were found in two patients. The two mutations were the pK327R substitution affecting the kinase domain of TGFBR2 and the pC138R substitution falling in the extracellular domain of the protein, involved in TGFß binding and signalling. No TGFBR1 mutation was found. The findings indicate that TGFBR2 gene mutations are responsible for sCAD in 3.6% (95% CI 0.0 to 8.4) of cases, have implications in understanding the role of TGFß signalling in the pathogenesis of sCAD and emphasise the importance of considering molecular characterisation of the TGFBR2 gene in these patients, regardless of the presence of clinical features suggestive of hereditary connective tissue disorders.

The migraine-ischemic stroke connection: potential pathogenic mechanisms.

Strong epidemiological evidence indicates that migraine, especially migraine with aura, is associated with increased risk of ischemic stroke. However, the precise mechanisms of such a relation are currently not fully elucidated and are still a matter of speculation. Migraine may directly cause an ischemic event (i.e, migrainous infarct), by inducing cerebral microcirculatory vasoconstriction (cortical spreading depression-related oligemia), intracerebral large vessels spasm, and vascular endothelium-related hypercoagulability. On the other hand, migraine may predispose to cerebral ischemia outside of a migraine attack by affecting endothelial function, alone or in combination with traditional vascular risk factors, or by interacting with pre-existent stroke susceptibility conditions (i.e, patent foramen ovale). At least theoretically, the migraine-stroke link may be the consequence of the unfavourable effect of migraine-specific drugs (i.e, triptans or ergot alkaloids). Finally, migraine and ischemic vascular events may be linked via genetic pathways, certain genes playing a role on both diseases and influencing their relation. The coexistence of ischemic stroke and migraine in the context of specific syndromes (i.e, CADASIL) characterized by peculiar phenotype, proven inherited background and chronic alterations of the wall of cerebral small vessel arteries suggests that migraine and ischemic stroke may be the end phenotype of common pathogenic mechanisms. How to identify those migraineurs at highest risk of ischemic stroke and whether stroke can be prevented by specific therapeutic strategies are the goals of future research.

Development and implementation of a stroke rehabilitation integrated care pathway in an Italian no profit institution: an observational study.

BACKGROUND: To standardize assessment and coordinate processes in stroke rehabilitation, an integrated care pathway (ICP) was developed in an Italian Rehabilitation and Research Institution by a knowledge-translation interdisciplinary process, from evidence-based guidelines to rehabilitation practice. The ICP was implemented in two pilot Tuscan rehabilitation Centers. AIM: The purpose of this study was to describe ICP development and assess the ICP effects on postacute stroke inpatient rehabilitation outcomes. DESIGN: Prospective observational study, before and after comparison. SETTING: Two Tuscan inpatient rehabilitation centers. POPULATION: Patients accessing either centers for intensive rehabilitation after acute stroke. METHODS: Two cohorts were prospectively recruited before (2015-2017) and after (2018) implementation of the pathway. The primary outcome was change in activities of daily living disability, assessed by the modified Barthel Index (mBI) from admission to discharge. Secondary outcomes included length of stay (LOS), adverse outcomes, and changes in communication ability, trunk control, pain, ambulation, bladder catheter (Y/N), bedsores (Y/N). RESULTS: In 2015-2017, 443 postacute stroke patients (mean age 77±11 years, 47% women), while in 2018, 84 patients (mean age 76±13 years, 61% women) were admitted to the two facilities. Comparing the 2018 vs. the 2015-17 cohort, the mean mBI increase was not substantially different (26 vs. 24 points), nor were LOS (37±18 vs. 36±16 days), adverse outcomes, discharge destination, and improvement of ambulation, pain, and communication (P>0.05). Instead, a significantly higher improvement of trunk control (trunk control test: 69.6±33.2 vs. 79.0±31.3, P=0.019), and a higher percentage of bedsore resolution (13% vs. 5%, P=0.033), and bladder catheter removal (37% vs. 17% P<0.001) were observed in 2018 vs. 2015-2017. CONCLUSIONS: Compared to prior practice, ICP was associated to improvement of trunk control recovery, bladder catheter removal, and bedsores resolution. Further ICP implementation on a larger scale is needed to verify improvements of stroke inpatient rehabilitation outcomes. CLINICAL REHABILITATION IMPACT: An evidence-based stroke rehabilitation ICP was interdisciplinary developed and implemented in two rehabilitation centers of a multicenter Italian health group. ICP implementation as to inpatient intensive postacute stroke rehabilitation was associated to improved trunk control recovery, bladder catheter removal, and bedsore resolution. Further ICP implementation will allow multicenter studies and quality benchmarking.

New insights into the pleiotropic effects of statins for stroke prevention.

There is compelling evidence that treatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors - "statins" - the most important class of lipid lowering agents, reduces ischemic stroke incidence independent on their effect on serum cholesterol levels. In this review, the non-lipid-mediated - "pleiotropic" - effects of statins as well as their potential implication in developing new treatment strategies for stroke prevention will be discussed.

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.

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.