Pamela M. Rist

Migraine and cardiovascular disease: systematic review and meta-analysis.

Objective To evaluate the association between migraine and cardiovascular disease, including stroke, myocardial infarction, and death due to cardiovascular disease. Design Systematic review and meta-analysis. Data sources Electronic databases (PubMed, Embase, Cochrane Library) and reference lists of included studies and reviews published until January 2009. Selection criteria Case-control and cohort studies investigating the association between any migraine or specific migraine subtypes and cardiovascular disease. Review methods Two investigators independently assessed eligibility of identified studies in a two step approach. Disagreements were resolved by consensus. Studies were grouped according to a priori categories on migraine and cardiovascular disease. Data extraction Two investigators extracted data. Pooled relative risks and 95% confidence intervals were calculated. Results Studies were heterogeneous for participant characteristics and definition of cardiovascular disease. Nine studies investigated the association between any migraine and ischaemic stroke (pooled relative risk 1.73, 95% confidence interval 1.31 to 2.29). Additional analyses indicated a significantly higher risk among people who had migraine with aura (2.16, 1.53 to 3.03) compared with people who had migraine without aura (1.23, 0.90 to 1.69; meta-regression for aura status P=0.02). Furthermore, results suggested a greater risk among women (2.08, 1.13 to 3.84) compared with men (1.37, 0.89 to 2.11). Age less than 45 years, smoking, and oral contraceptive use further increased the risk. Eight studies investigated the association between migraine and myocardial infarction (1.12, 0.95 to 1.32) and five between migraine and death due to cardiovascular disease (1.03, 0.79 to 1.34). Only one study investigated the association between women who had migraine with aura and myocardial infarction and death due to cardiovascular disease, showing a twofold increased risk. Conclusion Migraine is associated with a twofold increased risk of ischaemic stroke, which is only apparent among people who have migraine with aura. Our results also suggest a higher risk among women and risk was further magnified for people with migraine who were aged less than 45, smokers, and women who used oral contraceptives. We did not find an overall association between any migraine and myocardial infarction or death due to cardiovascular disease. Too few studies are available to reliably evaluate the impact of modifying factors, such as migraine aura, on these associations.

Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials.

Objective To evaluate the effect of vitamin E supplementation on incident total, ischaemic, and haemorrhagic stroke. Design Systematic review and meta-analysis of randomised, placebo controlled trials published until January 2010. Data sources Electronic databases (Medline, Embase, Cochrane Central Register of Controlled Trials) and reference lists of trial reports. Selection criteria Randomised, placebo controlled trials with ≥1 year of follow-up investigating the effect of vitamin E on stroke. Review methods and data extraction Two investigators independently assessed eligibility of identified trials. Disagreements were resolved by consensus. Two different investigators independently extracted data. Risk ratios (and 95% confidence intervals) were calculated for each trial based on the number of cases and non-cases randomised to vitamin E or placebo. Pooled effect estimates were then calculated. Results Nine trials investigating the effect of vitamin E on incident stroke were included, totalling 118 765 participants (59 357 randomised to vitamin E and 59 408 to placebo). Among those, seven trials reported data for total stroke and five trials each for haemorrhagic and ischaemic stroke. Vitamin E had no effect on the risk for total stroke (pooled relative risk 0.98 (95% confidence interval 0.91 to 1.05), P=0.53). In contrast, the risk for haemorrhagic stroke was increased (pooled relative risk 1.22 (1.00 to 1.48), P=0.045), while the risk of ischaemic stroke was reduced (pooled relative risk 0.90 (0.82 to 0.99), P=0.02). There was little evidence for heterogeneity among studies. Meta-regression did not identify blinding strategy, vitamin E dose, or morbidity status of participants as sources of heterogeneity. In terms of absolute risk, this translates into one additional haemorrhagic stroke for every 1250 individuals taking vitamin E, in contrast to one ischaemic stroke prevented per 476 individuals taking vitamin E. Conclusion In this meta-analysis, vitamin E increased the risk for haemorrhagic stroke by 22% and reduced the risk of ischaemic stroke by 10%. This differential risk pattern is obscured when looking at total stroke. Given the relatively small risk reduction of ischaemic stroke and the generally more severe outcome of haemorrhagic stroke, indiscriminate widespread use of vitamin E should be cautioned against.

MTHFR 677C>T and ACE D/I Polymorphisms in Migraine: A Systematic Review and Meta-Analysis

(Headache 2010;50:588‐599)

Migraine, Migraine Aura, and Cervical Artery Dissection: A Systematic Review and Meta-Analysis

Objective: We evaluated the current evidence on the association between migraine, including aura status, and cervical artery dissection. Methods: We performed a systematic review and meta-analysis of studies investigating the association between migraine or migraine subtypes (e.g. migraine with aura) and cervical artery dissection published through October 2010. Results: We identified five case-control studies investigating the association between migraine and cervical artery dissection. In pooled analysis, migraine doubled the risk of cervical artery dissection (pooled odds ratio [OR] = 2.06, 95% confidence interval [CI] 1.33–3.19). All studies allowed evaluation of migraine aura status. While the effect estimate for migraine without aura (pooled OR = 1.94, 95% CI 1.21–3.10) was similar to overall migraine, the association was weaker for migraine with aura (pooled OR = 1.50, 95% CI 0.76–2.96). However, there is no evidence that aura status significantly modifies the association between migraine and cervical artery dissection (meta-regression on aura status p = .58). The risk does not appear to differ between women and men; however, only few studies presented gender-specific data. Heterogeneity among studies was low to moderate. Conclusion: In this meta-analysis migraine is associated with a two-fold increased risk of cervical artery dissection. This risk does not appear to significantly differ by migraine aura status or gender.

Migraine and mortality: A systematic review and meta-analysis

Objective: To evaluate the evidence on the association between migraine and mortality. Methods: Systematic review and meta-analysis of studies investigating the association between any migraine (all forms of migraine collectively) or migraine subtypes (e.g. migraine with aura) and mortality published until March 2011. Results: We identified ten cohort studies. Studies differed regarding the types of mortality investigated and only four presented aura-stratified results, limiting pooled analyses with regard to migraine subtypes and with regard to cause-specific mortality. For any migraine pooled analyses do not suggest an association with all-cause mortality (five studies; pooled relative risk (RR) = 0.90, 95% confidence interval (CI) 0.71–1.16), cardiovascular disease mortality (CVD; six studies; pooled RR = 1.09, 95% CI 0.89–1.32), or coronary heart disease mortality (CHD; three studies; pooled RR = 0.95, 95% CI 0.57–1.60). Heterogeneity among studies is moderate to high. Two studies suggest that migraine with aura increases risk for CVD and CHD mortality. Conclusion: This meta-analysis does not suggest that any migraine is associated with increased risk of mortality from all causes, CVD, or CHD. However, there is heterogeneity among studies and suggestion that migraine with aura increases CVD and CHD mortality. Given the high prevalence of migraine in the general population a definitive answer to the question of whether migraine or a subtype alters risk for mortality is of high public health importance and further targeted research implicated.

Migraine and Functional Outcome From Ischemic Cerebral Events in Women

Background— Studies have linked migraine with aura to an increased risk of ischemic stroke, particularly among women. Data on the relationship of migraine and functional outcome from ischemic cerebral events are sparse. Methods and Results— This was a prospective cohort study among 27 852 women enrolled in the Womens Health Study for whom we had information on migraine and measured cholesterol values and who had no prior stroke or transient ischemic attack (TIA) at baseline. Migraine was classified into no history of migraine, active migraine with aura, active migraine without aura, and past history of migraine. Possible functional outcomes were no stroke or TIA, TIA, and stroke with modified Rankin Scale (mRS) score 0 to 1, mRS 2 to 3, and mRS 4 to 6. We used multinomial logistic regression to evaluate the relationship of migraine with functional outcomes after ischemic stroke. During a mean of 13.5 years of follow-up, 398 TIAs and 345 ischemic strokes occurred. Compared with women without history of migraine and who did not experience a TIA or stroke, women who reported migraine with aura had adjusted relative risk (95% confidence interval) of 1.56 (1.03 to 2.36) for TIA, 2.33 (1.37 to 3.97) for stroke with mRS 0 to 1, 0.82 (0.30 to 2.24) for mRS 2 to 3, and 1.18 (0.28 to 4.97) for mRS 4 to 6. The risk of any outcome was not significantly elevated for women who experienced migraine without aura or who had a past history of migraine. Conclusions— Results of this large prospective cohort suggest that women with migraine with aura are at increased risk of experiencing TIA or ischemic stroke with good functional outcome.

Sex Hormone Receptor Gene Polymorphisms and Migraine: A Systematic Review and Meta-Analysis

Background: Data on the association between sex hormone receptor polymorphisms and migraine are conflicting. Methods: We performed a systematic review and meta-analysis on this topic searching for studies published until August 2009. For each study, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) assuming additive, dominant, and recessive genetic models. We then calculated pooled ORs and 95% CIs. Results and Conclusion: Among the seven genes targeted, four variants were investigated in multiple studies. Effect estimates from an additive model suggest that the ESR-1 594 G > A (pooled OR 1.37; 95% CI 1.02–1.83) and ESR-1 325 C > G (pooled OR 1.16; 95% CI 1.03–1.32) variants are associated with any migraine. This pattern does not differ between migraine with and without aura. In contrast, the ESR-1 Pvu II C > T and PGR PROGINS insert polymorphism do not appear to be associated with migraine. Results were driven by studies among Caucasians and may differ in other ethnic groups.

5-HTTLPR polymorphism in the serotonin transporter gene and migraine: A systematic review and meta-analysis:

Background and methods: Data on the association between the SLC6A4 5-HTTLPR polymorphism and migraine are conflicting. We performed a systematic review and meta-analysis among studies published up to September 2009. For each study with genotype information, we calculated odds ratios (OR) and 95% confidence intervals (CI) assuming additive, dominant, and recessive genetic models. We then calculated pooled ORs and 95% CIs. Results: Among the ten studies identified there was no overall association between the polymorphism and any migraine for Europeans or Asians. However, European women carrying the S allele had an increased risk for any migraine (dominant model: pooled OR = 2.02; 95% CI 1.24–3.28). Results among Europeans further suggested an increased risk for migraine with aura among carriers of the S/S genotype (recessive model: pooled OR = 1.41; 95% CI 0.83–2.40). Conclusions: While our results indicate no overall association between the SLC6A4 5-HTTLPR polymorphism and migraine among Europeans and Asians, gender and migraine aura status may have modifying roles among Europeans.

Associations between lipid levels and migraine: Cross-sectional analysis in the Epidemiology of Vascular Ageing Study:

Background: Migraine with aura has been associated with increased prevalence of cardiovascular risk factors, including elevated levels of some vascular biomarkers. However, little research has been done on this association among the elderly. We examined the associations of lipid levels with headache and migraine in a cohort of elderly individuals. Methods: Cross-sectional study among 1155 participants enrolled in the Epidemiology of Vascular Ageing Study with available information on headache and blood biomarkers. We used multinomial logistic regression to evaluate the association between biomarker tertiles and headache categories. Results: 925 people had no severe headache, 64 people had non-migraine headache and 166 people had migraine, of whom 23 had aura. Compared with participants without headache, we observed strong associations between increasing tertiles of total cholesterol and migraine with aura. The odds ratio (95% confidence interval) was 4.67 (0.99–21.97) for the 2nd tertile and 5.97 (1.29–27.61) for the 3rd tertile. We also found strong associations between triglycerides and migraine with aura (odds ratio for 3rd tertile: 4.42 (1.32–14.77)). We did not see significant associations between increased biomarker levels and any other headache group. Conclusions: Elevated levels of total cholesterol and triglycerides are associated with migraine with aura but not other headache forms in the elderly.

Migraine and Cognitive Decline Among Women: Prospective Cohort Study

Objective To evaluate the association between migraine and cognitive decline among women. Design Prospective cohort study. Setting Women’s Health Study, United States. Participants 6349 women aged 65 or older enrolled in the Women’s Health Study who provided information about migraine status at baseline and participated in cognitive testing during follow-up. Participants were classified into four groups: no history of migraine, migraine with aura, migraine without aura, and past history of migraine (reports of migraine history but no migraine in the year prior to baseline). Main outcome measures Cognitive testing was carried out at two year intervals up to three times using the telephone interview for cognitive status, immediate and delayed recall trials of the east Boston memory test, delayed recall trial of the telephone interview for cognitive status 10 word list, and a category fluency test. All tests were combined into a global cognitive score, and tests assessing verbal memory were combined to create a verbal memory score. Results Of the 6349 women, 853 (13.4%) reported any migraine; of these, 195 (22.9%) reported migraine with aura, 248 (29.1%) migraine without aura, and 410 (48.1%) a past history of migraine. Compared with women with no history of migraine, those who experienced migraine with or without aura or had a past history of migraine did not have significantly different rates of cognitive decline in any of the cognitive scores: values for the rate of change of the global cognitive score between baseline and the last observation ranged from −0.01 (SE 0.04) for past history of migraine to 0.08 (SE 0.04) for migraine with aura when compared with women without any history of migraine. Women who experienced migraine were also not at increased risk of substantial cognitive decline (worst 10% of the distribution of decline). When compared with women without a history of migraine, the relative risks for the global score ranged from 0.77 (95% confidence interval 0.46 to 1.28) for women with migraine without aura to 1.17 (0.84 to 1.63) for women with a past history of migraine. Conclusion In this prospective cohort of women, migraine status was not associated with faster rates of cognitive decline.