CURRENT LITERATURE: CLINICAL SCIENCE

Headache Currents

Migraine and ischaemic heart disease and stroke: potential mechanisms and treatment options
INTRODUCTION ultiple epidemiological studies cited in this issue of Headache Currents support the link of migraine and a higher risk for vascular disease, especially ischaemic stroke in women with migraine with aura before age 45 years. The precise mechanism by which migraine predisposes to stroke has not been clearly delineated, although studies show that the risk of stroke in women with migraine is increased with oral contraceptive use and smoking. Other potential factors increasing the risk of stroke in migraineurs include endothelial dysfunction, prothrombotic factors, vasospasm, hyperhomocysteinaemia and possible embolic mechanisms such as paradoxical embolus via a patent foramen ovale (PFO) or related to mitral valve prolapse. Migraine has also been associated with an increased risk of cervicocephalic dissection, which may lead to ischaemic stroke, and migraine frequently occurs years before clinical ischaemic brain disease in individuals with Notch 3 gene mutations associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). If these potential mechanisms were not complex enough, there is concern that medications such as triptans and ergots, used to treat migraine headaches, may potentially cause ischaemic brain or heart disease (angina and myocardial infarction). Results: Compared with controls, migraineurs were more likely to smoke [odds ratio (OR) 1.43; 1.1, 1.8}, less likely to consume alcohol (OR 0.58; 0.5, 0.7) and more likely to report a parental history of early myocardial infarction. Migraineurs with aura were more likely to have an unfavourable cholesterol prole [TC 240 mg/dl (OR 1.43; 0.97, 2.1), TC:HDL ratio > 5.0 (OR 1.64; 1.1, 2.4)], have elevated BP [systolic BP > 140 mmHg or diastolic BP > 90 mmHg (OR 1.76; 1.04, 3.0)] and report a history of early-onset CHD or stroke (OR 3.96; 1.1, 14.3); female migraineurs with aura were more likely to be using oral contraceptives (OR 2.06; 1.05, 4.0). The odds of having an elevated Framingham risk score for CHD were approximately doubled for the migraineurs with aura. Conclusions: Migraineurs, particularly with aura, have a higher cardiovascular risk prole than individuals without migraine.

Scher AI, Terwindt GM, Picavet HS, Verschuren WM, Ferrari MD, Launer LJ, Cardiovascular risk factors and migraine: the GEM population-based study. Neurology 2005; 64:61420. Background: Migraine, particularly with aura, is a risk factor for early-onset ischaemic stroke. The underlying mechanisms are unknown, but may in part be due to migraineurs having an increased risk prole for cardiovascular disease. In this study, the authors compare the cardiovascular risk prole of adult migraineurs with that of non-migraineurs. Methods: Participants (n = 5755, 48% men, age 20 65 years) were from the Genetic Epidemiology of Migraine (GEM) study, a population-based study in the Netherlands. A total of 620 current migraineurs were identied: 31% with aura (MA), 64% without aura (MoA) and 5% unclassied. Controls were 5135 individuals without lifetime migraine. Measured cardiovascular risk factors included blood pressure (BP), serum total and high-density lipoprotein cholesterol (TC, HDL), smoking, oral contraceptive use and the Framingham risk score for myocardial infarction or coronary heart disease (CHD) death.
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COMMENTARY This population-based casecontrol study from the Netherlands examines the cardiovascular risk prole of individuals with MA, MoA and control subjects. Its ndings are that migraineurs, especially those with aura, are more likely to have a higher-risk cardiovascular risk prole than individuals who do not have migraine. This includes a higher likelihood of smoking, reported family history (parents) of early myocardial infarction, unfavourable cholesterol prole, elevated BP and a history of early-onset CHD or stroke. In addition, women with aura were more likely to be using oral contraceptives than women with no history of migraine. The latter have been associated with hypercoagulability. This study also shows that individuals with MA were approximately twice as likely to have an elevated risk of coronary artery disease using the Framingham coronary heart disease risk score. Women with migraine were more likely to have received a diagnosis of gestational hypertension, and there is evidence to link this with hypertension later in life. As the authors point out, it is not possible to determine if migraine modies cardiovascular risk factors or if cardiovascular risk factors modify the clinical expression of migraine. Nevertheless, this study does show that individuals with migraine (especially MA) are more likely to have risk factors that have been associated with cardiovascular disease. It will be important for the ndings in this Dutch population be conrmed in other populations. Meanwhile, those who care for patients with migraine, especially those in primary care, should be aware that there is a likelihood of cardiovascular risk factors being higher than in those individuals without migraine and should appropriately screen these patients for modiable risk
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Headache Currents
Although these results suggest that signicant right-to-left shunts contribute to the increased stroke risk in individuals with migraine, there are shortcomings in this study. Clearly, peripherally located large vessel cerebral infarctions are more likely to be of embolic origin, but deep small infarctions are often due to small vessel disease. The authors provide no information regarding localization and, indeed, it is not clear whether the patients underwent neuroimaging. The authors do not detail other risk factors for ischaemic stroke such as diabetes mellitus, hypercholesterolaemia and hypertension which might predispose to ischaemic strokes via other mechanisms. In addition, the authors included patients who were > 50 years old, when atherosclerotic mechanisms play a larger role in symptomatic cerebrovascular disease than at younger ages. All of these shortcomings may have led to misattribution of strokes to a paradoxical embolism. Despite the shortcomings, the study lends credence to the hypothesis that paradoxical embolism is likely to account for some of the excess stroke risk in patients with migraine. Anzola GP, Morandi E, Casilli F, Onorato E. Different degrees of right-to-left shunting predict migraine and stroke: data from 420 patients. Neurology 2006; 66: 7657. The authors analyse the extent of right-to-left shunting in patients with migraine, patients with cryptogenic stroke and controls. Patients with both migraine and stroke had larger shunts than those with migraine without stroke (P = 0.038), patients with no migraine with stroke (P = 0.007) and control patients (P < 0.0001). Patients with migraine have overall larger shunts than nonmigraineurs, particularly if they have had a stroke. Rightto-left shunting may be causally related to migraine and to the increased stroke risk of migraine. COMMENTARY The authors of this retrospective study used contrast-enhanced transcranial Doppler studies to identify evidence of right-to-left shunts in patients and, as in the study by Wilmshurst et al., found that patients with migraine had larger shunts than nonmigraineurs, particularly if they had suffered a stroke. They also conclude that large right-to-left shunts are more likely to be associated with stroke in patients with migraine. However, just as in the Wilmshurst study, the study can be criticized for lack of characterization of strokes and lack of control for other stroke risk factors. Nevertheless, the overall ndings suggest that some of the excess stroke risk in migraineurs is attributable to larger right-to-left shunts. Even though this study and that of Wilmshurst et al. suggest that right-to-left shunts may contribute to increased stroke risk in migraine, there have been no randomized controlled trials that have demonstrated that closure of a PFO prevents ischaemic stroke in patients with migraine or is an effective treatment for migraine attacks.

factors. When hypertension, elevated cholesterol and smoking are present, intervention should be undertaken to modify them to reduce the future risk of vascular events. Wilmshurst P, Nightingale S, Pearson M, Morrison L, Walsh K. Relation of atrial shunts to migraine in patients with ischemic stroke and peripheral emboli. Am J Cardiol 2006; 98:8313. This study investigated whether the increased incidence of stroke in young subjects with migraine is because they have an increased prevalence of atrial right-to-left shunts. The investigators report the prevalence of clinically relevant atrial shunts in those with stroke and migraine compared with those with stroke but without migraine, and also in historic control groups of subjects who had MA but no stroke and in population controls. Of 60 consecutive stroke patients, 42 (70%) had large- or medium-sized atrial shunts. Transcatheter shunt closure was performed in 39 patients, of whom 35 had a PFO (mean diameter 9.8 4.1 mm) and four had atrial septal defects. If atrial shunts were unrelated to stroke in patients with migraines, shunt prevalence in those with migraine and stroke would be the same as in those with migraine but without stroke. However, a much greater shunt prevalence was found in those with stroke and MA (84%) than in those with MA but no stroke (38.1%, P < 0.001), population controls (12.2%, P < 0.001) and those with stroke but no migraine (55.6%, P < 0.05). Shunt prevalence was also signicantly greater in patients who had stroke and MoA (75%) than in population controls (P < 0.001) and in those with MA but no stroke (P < 0.05). In conclusion, the increased incidence of stroke in subjects with migraine compared with the general population is because they have a higher prevalence of large atrial shunts and hence an increased risk for paradoxic embolism. COMMENTARY Several studies have demonstrated a higher occurrence of PFO in patients with MA. This study included 60 consecutive patients who presented with ischaemic stroke and underwent contrast echocardiography to seek evidence of possible paradoxic embolism. All patients were <66 years old at the time of presentation or, for those with more than one stroke, the rst stroke was at < 66 years (mean age 42.7 13.3 years and an age range of 11 65). Patients were excluded if carotid Doppler showed signicant carotid artery disease, if transthoracic echocardiography showed a left-sided cardiac source of emboli, or 24-h ambulatory electrocardiography showed atrial brillation or utter. As outlined above, shunt prevalence was greater in patients with stroke who had migraine, both MA and MoA, compared with population controls.
Blackwell Publishing Ltd Cephalalgia, 2007, 27, 988990

990 | Cephalalgia | August 2007

Headache Currents
dial infarction and stroke, or mortality. Consistent with previous studies, migraineurs in general have an elevated risk of stroke, but not myocardial infarction, compared with non-migraineurs.

Velentgas P, Cole JA, Mo J, Sikes CR, Walker AM. Severe vascular events in migraine patients. Headache 2004; 44:64251. Objective: To estimate rates of vascular events in relation to dispensing of triptans and ergot alkaloids among migraineurs, and to compare these rates with those of nonmigraineurs. Context: It has been speculated that the use of triptans or ergot alkaloid drugs might increase risk of ischaemic events through vasoconstriction. Design: A retrospective cohort study of 130 411 migraineurs and 130 411 age-, sex- and health planmatched non-migraineurs who were members of UnitedHealthcare during 19951999. The data source for this study was Ingenixs research database containing pharmacy and medical claims for UnitedHealthcare members, and the National Death Index. Main outcome measures: Incidence of cardiovascular and cerebrovascular events and mortality. Migraineurs and non-migraineurs had identical rates of myocardial infarction: 1.4 per 1000 person-years. Migraineurs were 67% more likely to suffer a stroke than non-migraineurs [adjusted relative risk (RR) 1.67, 95% condence interval (CI) 1.31, 2.13] and had higher rates of unstable angina and transient ischaemic attacks. There was no increase in risk of myocardial infarction with current (adjusted RR 0.80, 95% CI 0.58, 1.11) or recent (adjusted RR 1.15, 95% CI 0.71, 1.87) triptan use. Neither current (adjusted RR 0.90, 95% CI 0.64, 1.26) nor recent (adjusted RR 0.84, 95% CI 0.46, 1.55) triptan use was associated with risk of stroke. Current users of ergot alkaloids were somewhat more likely to have a stroke than other migraineurs (adjusted RR 1.49, 95% CI 0.93, 2.41), but there was no doseresponse relationship. Conclusions: Use of triptans is not associated with increased risk of any ischaemic events, including myocar-

COMMENTARY This large retrospective study of members of a healthcare company in USA assessed whether migraine was associated with stroke or myocardial infarction and found, as in other studies, that migraine is a stroke risk, but no association was found with myocardial infarction. It did not control for independent stroke or cardiovascular risk factors. Importantly, it did show that triptan use was not associated with stroke or myocardial infarction. On the other hand, use of ergots was associated with stroke risk. As clinicians, we are frequently faced with treatment of acute migraine headaches. Triptans, as a group, are the most useful group of agents yet developed for this purpose. The appropriate concern that triptans have been rarely associated with cardiac or cerebral ischaemia often causes hesitation in providing these agents. This study is reassuring that there is no signicant association of these agents with vascular events. This suggests that, in general, triptans can be prescribed safely. This should reassure clinicians regarding the safety of this class so that they will prescribe these agents, which have been shown to decrease migraine-related disability. Nevertheless, they are contraindicated in individuals with coronary artery disease, ischaemic cerebrovascular disease, uncontrolled hypertension, and those at high risk for such disorders. JW Swanson Mayo Clinic, Department of Neurology, Rochester, MN 55905, USA swanson.jerry@mayo.edu

Blackwell Publishing Ltd Cephalalgia, 2007, 27, 988990