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1.  Structural brain lesions and restless legs syndrome: a cross-sectional population-based study 
BMJ Open  2014;4(11):e005938.
Objective
To evaluate the association between white matter lesion (WML) volume, silent infarcts and restless legs syndrome (RLS) in a population-based study of elderly individuals.
Design
Cross-sectional study.
Setting
Population-based Three-City study.
Participants
1035 individuals from the Dijon, France, centre of the Three-City study who had available information on volume of WMLs from MRIs and who answered questions about the prevalence of RLS.
Primary outcome measure
Prevalence of RLS.
Results
WML volume was measured using an automated tissue segmentation method. Logistic regression was used to evaluate adjusted associations between tertiles of WML volume and RLS and between silent infarcts and RLS. 218 individuals (21.1%) were determined to have RLS. Compared with those in the first tertile of WML volume, individuals in the second tertile (OR=1.09; 95% CI 0.75 to 1.60) or third tertile (OR=1.17; 95% CI 0.79 to 1.74) did not have an increased prevalence of RLS. We also did not observe associations between the volume of deep or periventricular WML and RLS; nor did we observe an association between silent brain infarcts and RLS (OR=0.74; 95% CI 0.40 to 1.39). These findings were not modified by age or gender.
Conclusions
Higher volume of WML and the presence of silent infarcts were not associated with an increased prevalence of RLS in this population-based cohort of elderly individuals.
doi:10.1136/bmjopen-2014-005938
PMCID: PMC4244423  PMID: 25421338
restless legs syndrome; MRI
2.  Migraine, Headache and the Risk of Depression: Prospective Cohort Study 
Background
While cross-sectional studies have shown associations between migraine and depression, few studies have been able to evaluate the association between migraine and incident depression.
Methods
Prospective cohort study among 36,016 women without a history of depression enrolled in the Women’s Health Study who provided information about migraine and headache at baseline. Women were classified as either having non-migraine headache, migraine with aura, migraine without aura, past history of migraine or no history of headache. Cox proportional hazards models were used to evaluate the association between migraine and headache status and incident depression.
Results
At baseline, 5115 women reported a history of non-migraine headache, 1805 reported migraine with aura, 2723 reported migraine without aura and 1896 reported a past history of migraine. During 13.8 mean years of follow-up, 3833 new cases of depression occurred. The adjusted relative risks of incident depression were 1.44 (95% CI: 1.32, 1.56) for non-migraine headache, 1.53 (95% CI: 1.35, 1.74) for migraine with aura, 1.40 (95% CI: 1.25, 1.56) for migraine without aura and 1.56 (95% CI: 1.37, 1.77) for past history of migraine compared to no history of headache.
Conclusions
Middle-aged women with migraine or non-migraine headache are at increased risk of incident depression.
doi:10.1177/0333102413483930
PMCID: PMC3720737  PMID: 23588795
Migraine; depression; epidemiology
3.  Baseline cognitive function, recurrent stroke, and risk of dementia in stroke patients 
Background and purpose
To determine the interrelationships between baseline MMSE and risk of overall dementia, post-recurrent stroke dementia and dementia without recurrent stroke among patients with a history of stroke.
Methods
Prospective cohort study among participants enrolled in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) for whom baseline Mini-Mental State Examination (MMSE) score was available. Baseline MMSE was divided into four categories: 30, 29–27, 26–24, or <24. Participants were followed for incident dementia and recurrent stroke. Logistic regression models were used to examine the association between MMSE and dementia.
Results
Of the 6080 participants included in this analysis, 2493 had MMSE=30, 1768 had MMSE=29–28, 1369 had MMSE=26–24 and 450 had MMSE<24. Average follow-up time was 3.8 years. There were 407 cases of dementia, 106 of which were preceded by a recurrent stroke. The risk of overall dementia increased with decreasing MMSE score. However, the impact of MMSE on risk of dementia without recurrent stroke was much stronger than the impact of MMSE on the risk of post-recurrent stroke dementia. For those with MMSE<24, the risk of dementia without recurrent stroke was 47.89 (95% CI: 28.57–80.26) while the risk of post-recurrent stroke dementia was only 7.17 (95% CI: 3.70–13.89). Higher MMSE scores were even less strongly associated with the risk of post-recurrent stroke dementia.
Conclusions
Stroke patients with low MMSE scores are at high risk of dementia over time, even in the absence of a recurrent stroke, and should therefore be followed closely for further cognitive decline.
doi:10.1161/STROKEAHA.111.680728
PMCID: PMC3695012  PMID: 23686974
cerebrovascular disease; cognitive functioning; dementia; epidemiology
4.  Migraine and cognitive decline: A topical review 
Headache  2013;53(4):589-598.
Migraine has been linked with an increased risk of stroke and an increased prevalence of clinically silent brain lesions and white matter hyperintensities. As it is known that stroke and structural brain lesions are associated with an increased risk of cognitive decline, it has been hypothesized that migraine may be a progressive brain disorder and associated with an increased risk of cognitive impairment. Given the prevalence of migraine in the population, especially among women, and the aging of the population, an association between migraine and cognitive impairment would have substantial public health implications. In this review, we will summarize the existing evidence evaluating the association between migraine and cognitive function. Additionally, we will discuss methodological issues in migraine and cognitive function assessment and elaborate on study design strategies to address this important question.
doi:10.1111/head.12046
PMCID: PMC3618490  PMID: 23405909
migraine; cognitive decline; epidemiology
5.  Biomarkers and functional outcomes from ischemic cerebral events in women: a prospective cohort study 
Introduction
Several biomarkers have been associated with increased risk of ischemic stroke. However, the association between these biomarkers and functional outcome from cerebral ischemic events is unclear. We aimed to assess the patterns of association between cardiovascular disease biomarkers and functional outcomes after incident ischemic cerebral events in women.
Methods
Prospective cohort study among 27,728 women enrolled in the Women’s Health Study who provided information blood samples and were free of stroke or transient ischemic attack (TIA) at baseline. Multinomial logistic regression was used to determine the association between elevated biomarker levels and functional outcomes from ischemic cerebral events. Possible functional outcomes included TIA and ischemic stroke with mRS (modified Rankin scale) score of 0–1, 2–3 or 4–6.
Results
After a mean follow-up of 15.1 years, 461 TIAs and 380 ischemic strokes occurred. Elevated levels of total cholesterol were associated with the highest risk of poor functional outcome (mRS 4–6) after incident cerebral ischemic events (relative risk=2.02 95%CI=1.18–3.46). We observed significant associations between elevated levels of total cholesterol, Lp(a), C-reactive protein, and triglyercides and mild or moderate functional outcomes after ischemic cerebral events. Elevations in all other biomarkers were not significantly associated with functional outcomes.
Conclusions
While total cholesterol was associated with highest risks of poor functional outcome after stroke, we overall observed an inconsistent pattern of association between biomarkers linked with increased risk of vascular events and more impaired functional outcomes from stroke.
doi:10.1111/j.1468-1331.2012.03874.x
PMCID: PMC3538088  PMID: 23034002
stroke; epidemiology; biomarkers
6.  Effect of Low Dose Aspirin on Functional Outcome from Cerebral Vascular Events in Women 
Background and Purpose
While aspirin is effective in prevention of stroke, fewer studies have examined the impact of aspirin on stroke morbidity.
Methods
The Women’s Health Study is a completed randomized, placebo-controlled trial designed to test the effect of low-dose aspirin and vitamin E in the primary prevention of cardiovascular disease and cancer which enrolled 39,876 women. We used multinomial logistic regression to evaluate the relationship between randomized aspirin assignment and functional outcomes from stroke. Possible functional outcomes were no stroke nor TIA, modified Rankin scale (mRS) score 0–1, mRS 2–3 and mRS 4–6.
Results
After a mean of 9.9 years of follow-up, 460 confirmed strokes (366 ischemic, 90 hemorrhagic and 4 unknown type) and 405 confirmed transient ischemic attacks (TIAs) occurred. With regard to total and ischemic stroke, women who were randomized to aspirin had a non-significant decrease in risk of any outcome compared to women not randomized to aspirin. This decrease in risk only reached statistical significance for those experiencing TIA compared to participants without stroke or TIA (OR=0.77; 95% CI: 0.63, 0.94). For hemorrhagic stroke, a non-significant increase in the risk of achieving a modified Rankin Scale (mRS) score 2–3 or mRS 4–6 compared to no stroke or TIA was observed for the women randomized to aspirin compared to those randomized to placebo.
Conclusions
Results from this large randomized clinical trial provide evidence that 100mg of aspirin every other day may reduces the risk of ischemic cerebral vascular events, but does not have differential effects on functional outcomes from stroke.
doi:10.1161/STROKEAHA.112.672451
PMCID: PMC3552068  PMID: 23306328
cerebrovascular disease; epidemiology; aspirin
7.  Migraine and risk of incident diabetes in women: prospective study 
Background
Previous cross-sectional studies evaluating the relationship between diabetes prevalence and migraine status have found conflicting results. We examined the relationship between migraine and incident type 2 diabetes (T2D) in a cohort of adult women.
Methods
Prospective cohort study conducted among participants in the Women’s Health Study who provided information on migraine and did not have diabetes at baseline. Our four exposure groups were migraine with aura, migraine without aura, past history of migraine and no history of migraine. Cox proportional hazards models were used to determine the hazard ratio for incident T2D.
Results
Among the 38,620 women included in this study, 5062 (13.1%) women had migraine, of whom 2014 (39.8%) reported migraine with aura, and 2,087 (5.4%) women had a past history of migraine. During a mean of 14.6 years of follow-up, there were 3,032 cases of incident T2D. After adjustment for confounders, the hazard ratio (95% confidence interval) for developing diabetes was 1.06 (0.91–1.24) for women with migraine with aura, 1.01 (0.89–1.16) for women with migraine without aura, 1.13 (0.98–1.30) for women with a past history of migraine compared to women with no history of migraine.
Conclusion
Results of this prospective study in women do not support an association between migraine and incident T2D.
doi:10.1177/0333102412453954
PMCID: PMC3460043  PMID: 22807568
migraine; diabetes; epidemiology
8.  Physical Activity and Functional Outcomes from Cerebral Vascular Events in Men 
Background/Purpose
In studies enrolling stroke patients, higher levels of pre-stroke physical activity are associated with better functional outcomes. However, prospective studies evaluating this association are sparse. Using a cohort of initially healthy men, we aimed to prospectively assess the association between physical activity and functional outcomes from cerebral vascular events.
Methods
Prospective cohort study among 21,794 men enrolled in the Physician's Health Study who provided information on physical activity at baseline and who did not have a history of stroke or transient ischemic attack (TIA). Baseline levels of physical activity were categorized as: vigorous exercise <1, 1, 2–4 and ≥5 times/week. Possible functional outcomes included TIA and stroke with mRS score of 0–1, 2–3 or 5–6. Multinomial logistic regression was used to determine the association between physical activity and functional outcomes from cerebral vascular events.
Results
After a mean of 20.2 years of follow-up, 761 TIAs, 1146 ischemic strokes, 221 hemorrhagic strokes and 11 strokes of unknown type occurred. Compared with men who did not experience a stroke or TIA and who exercise vigorously <1 time/week, men who exercise vigorously ≥5 times/week had adjusted relative risk (95% CIs) of 0.67 (0.53–0.86) for TIA, 0.84 (0.61–1.14) for stroke with mRS 0–1, 0.85 (0.67–1.08) for mRS 2–3, and 1.12 (0.78–1.60) for mRS 5–6 after total stroke. Other levels of physical activity did not have a significant impact on the risk of our outcomes.
Conclusions
Physical activity prior to TIA or stroke does not appear to influence functional outcomes after cerebral vascular events.
doi:10.1161/STROKEAHA.111.619544
PMCID: PMC3226877  PMID: 21940956
9.  Associations Between Lipid Levels and Migraine: Cross-sectional Analysis in the EVA Study 
Cephalalgia  2011;31(14):1459-1465.
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 Aging 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 to participants without headache, we observed strong associations between increasing tertiles of total cholesterol and migraine with aura. The OR (95% CI) 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 (OR for 3rd tertile:4.42 (1.32–14.77).) We did not see significant associations between increased biomarkers 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.
doi:10.1177/0333102411421682
PMCID: PMC3303216  PMID: 21926156
migraine; cholesterol; epidemiology
10.  Tumor Necrosis Factor Gene Polymorphisms and Migraine: A Systematic Review and Meta-Analysis 
Cephalalgia  2011;31(13):1381-1404.
Background
Data on the association between TNF-alpha and TNF-beta gene polymorphisms and migraine are conflicting.
Methods
We performed a systematic review and meta-analysis of studies published until January 2011. We used data from published papers and as provided after contact with the authors. We calculated study specific odds ratios (OR) and 95% confidence intervals (CI) assuming additive, dominant, and recessive genetic models as well as pooled effect estimates.
Results
Among the ten studies identified the best evidence is available for the TNF-alpha -308G>A and TNF-beta 252A>G polymorphisms indicating no overall association with migraine. Subgroup analyses suggested that the A allele of the TNF-alpha -308G>A variant more than doubles the risk for migraine among populations with a heterogeneous ethnic background, which was driven by associations for MO (additive model: pooled OR=2.87; 95% CI 1.86–4.43). Further, the risk for MA was increased among Asian populations (additive model: pooled OR=1.71; 95% CI 1.07–2.71). Both observed effects were stronger among females than males.
Conclusions
Our results indicate no overall association between TNF-alpha and TNF-beta gene variants. However, associations differed among specific populations. Our findings need to be treated with caution and further targeted research is warranted to evaluate population-specific effects including population stratification.
doi:10.1177/0333102411419022
PMCID: PMC3303222  PMID: 22001640
migraine; tumor necrosis factor; lymphotoxin; polymorphism; meta-analysis
11.  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 for migraine subtypes and cause-specific mortality. For any migraine pooled analysis does not suggest an association with all-cause (five studies; pooled relative risk [RR]=0.90, 95%CI 0.71–1.16), cardiovascular (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 each 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 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 migraine prevalence a definitive answer to the question if migraine or a subtype alters risk for mortality is of high public health importance; hence, further studies are needed.
doi:10.1177/0333102411415879
PMCID: PMC3175288  PMID: 21803936
migraine; migraine aura; mortality; cardiovascular disease; meta-analysis
12.  Migraine and Cognitive Decline in the Population-Based EVA Study 
Background
Previous studies on migraine and cognition have shown mixed results. However, many could not assess the relationship between migraine and change in cognitive function or only used a limited number of cognitive tests.
Methods
Prospective cohort study among 1170 participants of the Epidemiology of Vascular Aging Study who provided information about migraine status and completed cognitive testing. Participants were classified as having no severe headache, non-migraine headache and migraine. Cognitive functioning was measured at up to four time points using nine different cognitive functioning tests. Linear mixed effects models were used to evaluate the relationship between migraine status and change in cognitive function.
Results
Of the 1170 participants, 938 had no severe headache, 167 had migraine, and 65 had non-migraine headache. After adjusting for age, gender, education, and smoking status, people with migraine or non-migraine headache did not experience a greater rate of cognitive decline than those without headache or migraine in any domain (for the MMSE, p-values were 0.68 for the non-migraine headache and time interaction and 0.85 for the migraine and time interaction) during 4-5 years of follow-up. For the Wechsler, those with migraine declined less over time (p-value=.02).
Conclusion
Migraine was not associated with faster cognitive decline over time.
doi:10.1177/0333102411417466
PMCID: PMC3175294  PMID: 21816772
Migraine; cognitive function; epidemiology
13.  Migraine, Migraine Aura, and Cervical Artery Dissection: A Systematic Review and Meta-Analysis 
Cephalalgia  2011;31(8):886-896.
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 until 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% 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=0.58). 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.
doi:10.1177/0333102411401634
PMCID: PMC3303220  PMID: 21511950
migraine; migraine aura; cervical artery dissection; carotid artery dissection; vertebral artery dissection; meta-analysis
14.  Migraine and Functional Outcome from Ischemic Cerebral Events in Women 
Circulation  2010;122(24):2551-2557.
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
Prospective cohort study among 27,852 women enrolled in the Women’s Health Study for whom we had information on migraine and measured cholesterol values and who had no prior stroke or transient ischemic attack (TIA). 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 0–1, mRS 2–3, and mRS 4–6. 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 (1.03–2.36) for TIA, 2.33 (1.37–3.97) for stroke with mRS 0–1, 0.82 (0.30–2.24) for mRS 2–3, and 1.18 (0.28–4.97) for mRS 4–6. The risk of any outcome was not significantly elevated for women who experienced migraine without aura or who had a past history of migraine.
Conclusion
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.
doi:10.1161/CIRCULATIONAHA.110.977306
PMCID: PMC3058846  PMID: 21126968
Migraine; stroke; epidemiology; women
15.  Sex Hormone Receptor Gene Polymorphisms and Migraine: A Systematic Review and Meta-Analysis 
Data on the association between sex hormone receptor polymorphisms and migraine are conflicting. 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. Among the 7 genes targeted 4 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.
doi:10.1177/0333102410364155
PMCID: PMC3055237  PMID: 20959426
migraine; sex hormone receptors; polymorphisms; meta-analysis
16.  5-HTTLPR Polymorphism in the Serotonin Transporter Gene and Migraine: A Systematic Review and Meta-Analysis 
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 until 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. 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). 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.
doi:10.1177/0333102410362929
PMCID: PMC3055240  PMID: 20959425
migraine; serotonin transporter gene; SLC6A4; 5-HTTLPR; meta-analysis
17.  STin2 VNTR Polymorphism in the Serotonin Transporter Gene and Migraine: A Pooled and Meta-Analysis 
The journal of headache and pain  2010;11(4):317-326.
Data on the association between the SLC6A4 STin2 VNTR polymorphism and migraine are conflicting. To perform a pooled and meta-analysis, we searched for studies published until September 2009 using electronic databases (MEDLINE, EMBASE, Science Citation Index) and reference lists of studies. Assessment for eligibility and extraction of data was performed by two independent investigators. We extracted allele and genotype frequencies for each study. We then calculated study-specific and pooled odds ratios (OR) and 95% confidence intervals (CI) assuming allele and genotype models. We also calculated pooled ORs and 95% CIs based on study-specific effect estimates for the allele model. We included five studies investigating the association between the STin2 VNTR polymorphism and migraine. Results from the allele model suggested a protective effect against migraine for the STin2.9 and STin2.10 alleles compared to the STin2.12 allele among populations of European descent, which however, was not significant. Results from the genotype model indicated a significant ~25% reduced risk for migraine among carriers of the 10/12 genotype compared with carriers of the 12/12 genotype among all study populations (OR=0.76, 95% CI 0.60–0.97) for any migraine, which was more pronounced among populations of European descent (OR=0.68, 95% CI 0.53–0.87). Results for migraine with and without aura were of similar magnitude, however not statistical significant. Our results suggest a protective effect of non-STin2.12 alleles compared to STin2.12 alleles, respectively 10/12 and 10/10 genotypes compared to the 12/12 genotype against migraine among populations of European descent. Associations in non-European populations may differ.
doi:10.1007/s10194-010-0230-3
PMCID: PMC3026586  PMID: 20585826
migraine; serotonin transporter; SLC6A4; STin2 VNTR; meta-analysis
18.  MTHFR 677C>T and ACE D/I Polymorphisms in Migraine: A Systematic Review and Meta-Analysis 
Headache  2009;50(4):588-599.
Background
Data on the association between the MTHFR 677C>T and ACE D/I polymorphisms and migraine including aura status are conflicting.
Objective
To perform a systematic review and meta-analysis on this topic.
Methods
We searched for studies published until March 2009 using electronic databases (MEDLINE, EMBASE, Science Citation Index) and reference lists of studies and reviews on the topic. Assessment for eligibility of studies and extraction of data was performed by two independent investigators. For each study we calculated the odds ratios (OR) and 95% confidence intervals (CI) assuming additive, dominant, and recessive genetic models. We then calculated pooled ORs and 95% CIs.
Results
Thirteen studies investigated the association between the MTHFR 677C>T polymorphism and migraine. The TT genotype was associated with an increased risk for any migraine, which only appeared for migraine with aura (pooled OR=1.48, 95% CI 1.02–2.13), but not migraine without aura. Nine studies investigated the association of the ACE D/I polymorphism with migraine. The II genotype was associated with a reduced risk for migraine with (pooled OR=0.71, 95% CI 0.55–0.93) and without aura (pooled OR=0.84, 95% CI 0.70–0.99). Results for both variants were driven by studies in non-Caucasian populations. Results among Caucasians did not suggest an association. Extractable data did not allow investigation of gene-gene-interactions.
Conslusions
The MTHFR 677TT genotype is associated with an increased risk for migraine with aura, while the ACE II genotype is protective against both migraine with and without aura. Results for both variants appeared only among non-Caucasian populations. There was no association among Caucasians.
doi:10.1111/j.1526-4610.2009.01570.x
PMCID: PMC3071567  PMID: 19925624
Migraine; MTHFR 677C>T polymorphism; ACE D/I polymorphism; meta-analysis
19.  Alcohol Consumption and Functional Outcome after Stroke in Men 
Background and Purpose
Light-to-moderate alcohol consumption has been associated with reduced risk of total and ischemic stroke. However, data on the relationship between alcohol consumption and functional outcomes from stroke is sparse.
Method
Prospective cohort study among 21,862 men enrolled in the Physicians’ Health Study who provided information on alcohol consumption at baseline, had no prior history of stroke or transient ischemic attack (TIA). Alcohol consumption was divided into five categories: <1 drink/week, 1 drink/week, 2–4 drinks/week, 5–6 drinks/week and ≥1 drink/day. Possible functional outcomes included TIA, modified Rankin Scale (MRS)=0–1, MRS=2–3, and MRS=4–6. We used multinomial logistic regression to evaluate the relationship between levels of alcohol consumption and functional outcomes from stroke.
Results
During a mean of 21.6 years of follow-up, 767 TIAs and 1393 strokes (1157 ischemic, 222 hemorrhagic and 14 unknown type) occurred. Men who consumed 1 drink/week had lowest associated odds for any outcome. Compared with men who did not experience a TIA or stroke and who consumed <1 drink/week, men who consumed 1 drink/week had odds ratio (95% confidence interval) for total stroke of 0.85 (0.60–1.21) for MRS=0–1, 0.84 (0.64–1.10) for MRS=2–3, and 0.60 (0.37–0.97) for MRS=4–6. The OR for TIA was 0.95 (0.73–1.22). The pattern of association did not substantially differ for ischemic and hemorrhagic stroke. Higher alcohol consumption showed no association with functional outcome after stroke.
Conclusions
Our data do not show strong associations between alcohol consumption and functional outcome after stroke. Modest beneficial associations exist with low alcohol consumption.
doi:10.1161/STROKEAHA.109.562173
PMCID: PMC2818546  PMID: 19910548
Stroke; epidemiology; alcohol; men
20.  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.
doi:10.1136/bmj.c5702
PMCID: PMC2974412  PMID: 21051774
21.  STin2 VNTR polymorphism in the serotonin transporter gene and migraine: pooled and meta-analyses 
The Journal of Headache and Pain  2010;11(4):317-326.
Data on the association between the SLC6A4 STin2 VNTR polymorphism and migraine are conflicting. To perform pooled and meta-analyses, we searched for studies published until September 2009 using electronic databases (MEDLINE, EMBASE, Science Citation Index) and reference lists of studies. Assessment for eligibility and extraction of data was performed by two independent investigators. We extracted allele and genotype frequencies for each study. We then calculated study-specific and pooled odds ratios (OR) and 95% confidence intervals (CI) assuming allele and genotype models. We also calculated pooled ORs and 95% CIs based on study-specific effect estimates for the allele model. We included five studies investigating the association between the STin2 VNTR polymorphism and migraine. Results from the allele model suggested a protective effect against migraine for the STin2.9 and STin2.10 alleles compared to the STin2.12 allele among populations of European descent, which however was not significant. Results from the genotype model indicated a significant ~25% reduced risk for migraine among carriers of the 10/12 genotype compared with carriers of the 12/12 genotype among all study populations (OR = 0.76, 95% CI 0.60–0.97) for any migraine, which was more pronounced among populations of European descent (OR = 0.68, 95% CI 0.53–0.87). Results for migraine with and without aura were of similar magnitude, but were not statistically significant. Our results suggest a protective effect of non-STin2.12 alleles compared to STin2.12 alleles, respectively, 10/12 and 10/10 genotypes compared to the 12/12 genotype against migraine among populations of European descent. Associations in non-European populations may differ.
doi:10.1007/s10194-010-0230-3
PMCID: PMC3026586  PMID: 20585826
Migraine; Serotonin transporter; SLC6A4; STin2 VNTR; Meta-analysis
22.  Through the Clinician’s Lens: Objective and Subjective Views of Disability 
Qualitative health research  2008;19(1):17-29.
In this study, we used recovery preference exploration (RPE) to explore how clinicians practicing in an inpatient medical rehabilitation facility assign meaning to alternative paths of recovery from profound disability. Through the RPE procedure, 33 clinicians ranked preference for recovery from 18 imagined activity limitations and provided narrative explanations for their choices. We used mixed methods, including grounded theory, to identify themes that expressed their recovery choices. Sixteen themes emerged that were classified into separate but linked procedural and conditional reasoning taxonomies. These theme taxonomies represented logical scientific inquiries vs. more phenomenological inquiries into lifeworld meanings, respectively. Just over two thirds (66.8%) of all quotes specified themes from the conditional reasoning taxonomy. The RPE procedure appeared to simulate a lived experience of imagined disability for the clinicians through which contexts and meanings began to emerge independent of the clinicians’ scientific attitudes.
doi:10.1177/1049732308327853
PMCID: PMC2896247  PMID: 19029242
disabled persons; grounded theory; health care professionals; moral perspectives; health concepts; imagination; mixed methods; phenomenology; recovery; rehabilitation; values
23.  Recovery From Disablement: What Functional Abilities Do Rehabilitation Professionals Value the Most? 
Objective
To determine whether rehabilitation clinicians representing different therapeutic disciplines would choose to recover from profound disability differently.
Design
Applying recovery preference exploration as a data-collection tool, clinicians imagined recovery from complete disability in each of the 18 activities assessed on the FIM instrument. We hypothesized that recovery-choice pathways would vary among the disciplines because of differences in training and practice focus. We compared each clinician’s preference for imagined recovery of the ability to perform each FIM activity relative to the other 17. Item-level preferences were explored by discipline. The mean absolute difference (MAD) in the medians of the 18 FIM recovery preference values between each of the disciplines was used to quantify overall differences.
Setting
Inpatient rehabilitation unit within a larger tertiary care urban hospital of an academic medical center.
Participants
Ninety-three clinicians actively providing care to patients in an inpatient rehabilitation setting classified into 5 groups anticipated to have similar types of practices: physicians and medical students (physician group), nurses, occupational and recreational therapists (occupational therapy [OT] group), physical therapists (physical therapy [PT] group), and neuropsychologists and social workers (psychology group).
Interventions
Not applicable.
Main Outcome Measures
Relative recovery preferences in 18 FIM activities.
Results
The MAD value between the 2 groups with the least similar recovery values (physician and psychology groups) was 1.78 times larger than the MAD value between the 2 groups with the most similar recovery values (PT and OT groups).
Conclusions
There were subtle differences in recovery choice pathways that may logically relate to differences in the cognitive processes used in clinical decision making among the therapeutic discipline groups.
doi:10.1016/j.apmr.2007.11.060
PMCID: PMC2884270  PMID: 18597736
Activity of daily living; Health knowledge, attitudes, practice; Learning; Patient care team; Rehabilitation
24.  Disability meanings according to patients and clinicians: imagined recovery choice pathways 
Objective
The purpose of this study was to explore how the meaning of disability varies between patients with acute-onset activity limitations and clinicians, and between males and females.
Methods
Seventy-nine patients undergoing inpatient rehabilitation and 93 practicing rehabilitation clinicians in the USA developed personal recovery choice pathways through recovery preference exploration (RPE). Imagining complete dependence in 18 activities as diverse as eating and expression, each individual determined an optimal sequence of recovery. This sequence was used to determine the relative value of each activity compared with the other 17. Three comparisons were made by calculating the mean absolute difference (MAD) in median utilities, including patients versus clinicians, male versus female patients, and male versus female clinicians. The MAD shows the relative magnitude of disparity between each pair.
Results
The MAD value between patients and clinicians was 3.4 times larger and 4.8 times larger than the MAD values between male and female patients and male and female clinicians, respectively.
Conclusions
The much larger difference in recovery preferences between patients and clinicians compared with differences between genders suggests that life contexts of being a patient with disabilities versus a clinician are more potent determinants of activity limitation perspectives than being a man or woman.
doi:10.1007/s11136-009-9441-y
PMCID: PMC2862634  PMID: 19190999
Activities of daily living; Decision making; Patient-centered care; Patient care team; Quality of life
25.  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.
doi:10.1136/bmj.b3914
PMCID: PMC2768778  PMID: 19861375

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