Skip to main content

Comorbid neuropathologies in migraine: an update on cerebrovascular and cardiovascular aspects

Abstract

Several conditions are comorbid with migraine; our review is focused on the relation between migraine, and cerebrovascular and cardiovascular diseases. Despite many studies showed an association between migraine and patent foramen ovale, it is still not known whether its presence might be causal for the migraine pathogenesis and currently its closure cannot be recommended for migraine prevention. On the contrary, conflicting epidemiological data link migraine to arterial hypertension and the use of antihypertensive agents acting on the renin-angiotensin system sounds promising in migraine prevention. A complex bidirectional relation exists between migraine and stroke, and new evidences show a clear association between migraine and coronary heart disease. In both conditions, migraine represents a defined risk factor although the magnitude of the risk varies across the different studies. However, since the risk is low in the general population, it is not possible to identify which migraineurs will develop a cardiovascular or a cerebrovascular event making difficult to apply preventive measures.

As reported in the literature, comorbidity may be defined as the presence of any additional coexistent condition in a patient with an index disease or as an association between two different disorders that is more than coincidental [1]. According to Lipton and Silberstein [2] comorbidity may arise by coincidence or selection bias, one condition may cause the other, both conditions may be related to shared environmental genetic risk factors, and the same environmental or genetic risk factors may determine a brain state that gives rise to both conditions. The presence of a comorbidity may complicate the diagnosis because of the overlapping symptoms [2].

We already reviewed the comorbid neuropathologies in migraine [3]; this update includes the most recent advances on cerebrovascular and cardiovascular comorbidities.

Migraine and patent foramen ovale

Patent foramen ovale (PFO), an interatrial communication remnant of the fetal circulation, is due to the failure in the fusion of the septum primum with the septum secundum. Anatomically, the PFO comprises overlapping portions of septum primum and septum secundum, acting as a 1-way flap valve allowing right-to-left shunt when the pressure in the right atrium is superior to the pressure in the left atrium [4, 5]. The prevalence of PFO in the healthy adult population is around 25%. Since the last decade evidences cumulated showing that migraine and PFO are associated to an extent that goes beyond what would be predicted by the chance co-occurrence of two common conditions. In case–control studies, migraine with aura has been found to be associated with PFO in nearly 50% of cases that is twice the figure usually reported in non-migraineurs [6–10] and in patients with PFO migraine has been found twice as frequently as in patients without PFO [11–13]. Right-to-left cardiac shunt at rest through a PFO is more common in migraineurs with aura than in non-migraineurs control patients with PFO [6] and patients with migraine tend to have greater right-to-left shunts with respect to the non-migrainous population [10] suggesting that interatrial communication may play a role in the pathogenesis of migraine. The mechanisms underlying this possible association have been postulated but never demonstrated. Venous blood contains agents normally removed by passage through the lungs that can trigger an attack of migraine if they reach the brain in sufficient concentrations; alternatively, long-term shunting of those agents may reduce the threshold for migraine generation in the brain [14]. Such observations do not obviously imply that PFO is the cause of migraine, as only 50% of patients with migraine with aura exhibit PFO and not all subjects with PFO have migraine. However, patients with migraine who have large right-to-left shunts tend to recognize those activities that increase the extent of the shunt as a trigger of their migraine attacks suggesting that the PFO might play a relevant role in subjects with a constitutional susceptibility to migraine [15]. Not all studies, however, support this hypothesis. The recent Shunt-Associated Migraine (SAM) study showed that the effect of right-to-left shunt on migraine features is not relevant but patients with shunt-associated migraine had a higher likelihood to have at least one first degree relative affected by migraine suggesting a possible genetic linkage between migraine and PFO [16]. Clarifying if a PFO plays any role in migraine pathogenesis or if the association is caused by a common inheritance but is not causal for migraine is crucial. If the former hypothesis will be proved, trials of PFO closure for migraine prevention would have a rationale, in the latter case there will be no reason to close the PFO to prevent migraine.

Closure of the PFO for migraine prevention

A variable proportion of patients who underwent PFO closure for non-migraine indications reported cessation or improvement of their migraine attacks after the procedure [17–29] (Table 1). The effect was evident for patients with migraine with (frequency reduced by 54%) or without (frequency reduced by 62%) aura but not for patients with non-migraine headaches [27]. Those studies are limited by being predominantly retrospective, non-randomized, and conducted in highly selected populations of patients. Furthermore, the highly variable course of migraine and the known placebo effect in previous migraine trials preclude any conclusion.

Table 1 Effect of patent foramen ovale closure on migraine in non-randomized studies in which the closure was performed for other reasons than migraine

The Migraine Intervention with STARFlex Technology (MIST) trial was the first randomized controlled study designed to assess the effect of PFO closure on migraine headache in patients with frequent, disabling, and drug-resistant migraine with aura [30]. In the trial, patients who suffered from migraine with aura, experienced frequent migraine attacks, had previously failed 2 or more classes of prophylactic treatments, and had moderate or large right-to-left shunts consistent with the presence of a PFO, were randomized to transcatheter PFO closure with the STARFlex implant or to a sham procedure. Patients were followed up for 6 months. The primary efficacy end point was cessation of migraine headache 91 to 180 days after the procedure. One hundred forty-seven patients were randomized. No significant difference was observed in the primary end point of migraine headache cessation between implant and sham groups (3 of 74 versus 3 of 73, respectively; P = 0.51). Secondary end points also were not achieved. On exploratory analysis, excluding two outliers, the implant group demonstrated a greater reduction in total migraine headache days (P = 0.027). As expected, the implant arm experienced more procedural serious adverse events; all events were transient. However, the results of the MIST trial did not allow to definitely exclude any benefit of the PFO closure. In fact, the included patients were selected because they had particularly severe and refractory migraine that is less amenable to treat than mild or moderate migraine; the continued use of prophylactic migraine medication throughout the trial in both treatment arms may have limited the impact of PFO closure; and the primary study end point of migraine cessation may have been unrealistic and less clinically relevant than reduction in migraine frequency since even the best-designed studies of preventive medications show a responder rate (reduction of migraine frequency ≥50%) of only around 50% [31]. According to the SAM study the presence of a right-to-left shunt reduced the susceptibility to develop a migraine attack following exposure to other triggers but enhanced the likelihood of initiating an attack with an aura [16]; consequently, it should be tested the hypothesis whether PFO closure may benefit auras rather than pain in migraineurs. Finally, in the MIST trial, the benefits of PFO closure were analyzed from 3 to 6 months after device implant. The effect of PFO closure during this relatively early analysis phase may have been confounded by clopidogrel use, incomplete closure of the defect, concomitant pulmonary shunt, and a possible early transient adverse effect of device implant. Therefore, a longer analysis phase might have demonstrated additional benefit accrued over time. Residual shunts were assessed by the investigators using contrast transthoracic echocardiography at 6 months. However, it is likely that more residual shunts persisted earlier during the analysis phase and atrial or pulmonary shunts below the detection threshold of this technique might have had an impact on the treatment effect in this population.

Thus, there is insufficient evidence on the hypothesis that migraine frequency is reduced by PFO closure. Further properly conducted, prospective studies in migraine patients including control groups with other or no headaches are underway in Europe and USA. Until then PFO closure should not be used for the prophylaxis of migraine [32].

Migraine and arterial hypertension

Despite the possible association between migraine and arterial hypertension is an old issue, data still do not prove an univocal interpretation of the co-occurrence of these two conditions. In fact, several studies have explored a possible association between migraine and hypertension, with contradictory results. Some studies have shown a positive association between migraine and hypertension [33–37], others found no association while others found a negative association between migraine and hypertension [38–47] (Table 2). This fact may be attributed to differences in methodology, the small sample size of some studies and to some diagnostic inaccuracy in the characterization of the various headache forms including migraine. Confusion may arise also from the fact that hypertension may be an epiphenomenon of acute pain while, headache may be associated with hypertensive encephalopathy as a consequence of increased intracranial pressure, or may be reported as a side effect of some antihypertensive treatments.

Table 2 Selected studies evaluating the association between blood pressure, arterial hypertension and migraine

Antihypertensives for migraine prophylaxis

Beta-blockers that are drugs capable of lowering blood pressure have been extensively used for migraine prevention. More recently, drugs acting on the renin-angiotensin system such as the angiotensin converting enzyme inhibitors and the angiotensin II receptor blockers, have been tested in migraine prophylaxis.

A double blind, placebo controlled, crossover study of lisinopril 10 mg/day in 60 patients with migraine aged 19–59 years with two to six episodes per month showed that active treatment had a clinically important prophylactic effect in migraine [48]. Hours with headache, days with headache, days with migraine, and headache severity index were reduced by 20, 17, 21, and 20%, respectively, with lisinopril compared with placebo. Days with migraine were reduced by at least 50%.

A randomized, double-blind, placebo-controlled crossover study of candesartan 16 mg/day in 60 migrainous patients showed that the angiotensin II receptor blocker provided effective migraine prophylaxis, with a tolerability profile comparable with that of placebo. In detail, candesartan reduced the number of days with headache including hours with headache, days with migraine, hours with migraine, headache severity index, levels of disability and days of sick leave although there were no differences in health-related quality of life [49].

Another small, open-label study showed that patients with migraine and arterial hypertension or prehypertension treated with olmesartan (10–40 mg/day) for at least 3 months reported an 82.5% average reduction in the frequency of migraine attacks [50]. Patients also experienced a 45% average reduction in the severity of migraine attacks measured on a numeric pain scale of 1–10 [50]. Further studies are needed to confirm the possible benefits of olmesartan in patients with migraine.

The mechanisms underlying the benefits of drugs acting on the renin–angiotensin system for migraine prophylaxis are unknown. Whether the prevention of migraine is attributable to the blood pressure reduction or to separate pharmacological actions of the drugs other than lowering blood pressure is still an unresolved issue. Angiotensin II is a vasoconstrictor agent, increases sympathetic discharge and adrenal medullary catecholamine release. Angiotensin is also involved in local brain functions mediated by the type I receptors that include modulation of the cerebrovascular flow, effects on fluids and electrolyte homeostasis, autonomic pathways, and neuroendocrine systems.

Migraine and cerebrovascular and cardiovascular diseases

There are evidences that link migraine with ischemic stroke and ischemic heart disease and potential mechanisms accounting for their association. The association between migraine and vascular disease of the retina has been also reported.

Migraine and stroke

A complex bidirectional relation exists between migraine and stroke including migraine as a risk factor for stroke, migraine caused by stroke, migraine as a cause of stroke, migraine and stroke sharing a common cause, migraine mimicking stroke, and migraine associated with subclinical stroke [3, 51]. Such possibilities were already extensively reviewed and are summarized in Table 3 [3].

Table 3 Possible comorbidities between migraine and stroke

Numerous studies evaluated the association between migraine and risk of stroke (Table 4) [51–72]. There is good evidence that migraine with aura is associated with an increased risk of ischemic stroke while data do not support an univocal association between migraine without aura and ischemic stroke [53]. The risk of stroke among migraineurs is especially increased in young women with migraine with aura, but is also apparent in older individuals. The increased severity of the migraine attack is not associated with an increased risk of ischemic stroke; on the contrary, high frequency of attacks (>12 attacks per year) and a recent onset of migraine (lifetime duration of <1 year before the stroke event) are related to an increased risk [62]. The risk of stroke in migraineurs is increased of more than three times in the presence of cigarette smoking and of more than four times in the presence of oral contraceptive use [54, 72]. The combination of migraine, oral contraceptives, and smoking further increases the risk [54]. More recent findings suggest that neither oral contraceptive use nor smoking alone substantially increase the odds ratio of ischemic stroke among women with migraine with aura [62]. However, the combination of both, results in a ten-fold increased risk of ischemic stroke when compared with women without migraine who did not smoke and did not use oral contraceptives [62], which is consistent with previous observations. Those data strongly indicate that women with migraine with aura who use oral contraceptives should be strictly advised to quit smoking. Although limited by small numbers, data indicate that the presence of a PFO did not substantially increase the risk of ischemic stroke among women with migraine with aura [62], suggesting that its presence is unlikely to explain a large amount of strokes in migraineurs. With regard to ischemic stroke subtypes, the proportion of lacunar infarction and of ischemic stroke of undetermined origin but not of atherosclerotic and cardioembolic strokes was higher among women with migraine with aura than in non-migraine stroke patients [62] suggesting possible alternative pathogenic mechanisms in migraineurs.

Table 4 Selected studies reporting the risk of stroke in migraineurs

Migraine may directly cause a cerebral ischemic event (migrainous infarction, ICHD-II 1.5.4) [73]. This condition is very rare and vastly over diagnosed [73]. Migrainous infarction is considered a direct consequence of an unusually severe hypoperfusion during the aura. To diagnose migraine-induced stroke the neurological deficit must exactly mimic the migrainous symptoms of previous attacks; the stroke must occur during the course of a typical migraine attack; all other causes of stroke must be excluded although stroke risk factors may be present [73]. Since most strokes in migraineurs do not occur during the course of migraine attack, this condition may account only for a minority of strokes in migraineurs and may not account for the increased risk of non cerebral events.

Migraine has also been associated with subclinical vascular brain lesions [74, 75]. These lesions appear as infarcts on magnetic resonance imaging even in the absence of a clinical history of stroke. Lesions are particularly common in the posterior circulation vascular territory [76–79]. Even in the absence of differences between patients with migraine and controls in the overall infarct prevalence (8.1 vs. 5.0%; P = 0.23), 8.1% of patients with migraine with aura compared with 2.2% of patients with migraine without aura and 0.7% of controls (P = 0.05) had one or more lesions in the cerebellar region [74]. Participants at the highest risk were those with migraine with aura and at least one attack per month compared with controls [74]. Traditional cardiovascular risk factors and specific antimigraine medications did not modify the association between structural brain changes and migraine [74]. Specific small cerebellar border zone infarct-like lesions were those mostly represented [75]. Patients with and without posterior circulation territory infarct-like lesions did not present differences in cardiovascular risk factors [75] suggesting that, when present, such lesions are not atherosclerotic in origin or reflect small-vessel disease and that a combination of (possibly migraine-related) hypoperfusion and embolism is the likeliest etiological mechanism, although other mechanisms could also play a role.

Migraine and retinal vascular disease

Case reports have linked retinal vein occlusions [80, 81] and retinal infarctions [82, 83] to migraine. A population-based study in a white Australian population (age 49 years and older) reported smaller retinal arteriolar calibers among persons with a history of migraine without aura as compared with those without a history of migraine [84]. Recent results from the Atherosclerosis Risk in Communities (ARIC) Study indicate that middle-aged persons with migraine and other headaches and without arterial hypertension and diabetes mellitus were more likely to have retinopathy signs including retinal hemorrhages (blot or flame shaped), microaneurysms, soft or hard exudates, macular edema, intraretinal microvascular abnormalities, venous beading, swelling, or laser photocoagulation scars [85]. The association was stronger in patients with migraine with aura.

The retinal and cerebral microcirculations share similar anatomy, embryology, and physiology. Since the retina is more accessible than cerebral vessels, understanding the mechanisms of the vascular disease of the retina might provide important clues to clarify the relation between stroke and migraine.

Migraine and coronary heart disease

While increased risk of ischemic stroke among persons with migraine, and particularly with migraine with aura, has been well established, the association between migraine with aura and overall cardiovascular disease including coronary heart disease has been long debated [86–94]. Only recently, a clear association between migraine and cardiovascular disease became evident [88, 89, 92].

A large cohort of more than 12,000 individuals participating in the ARIC study found an association between migraine, and particularly migraine with aura, with Rose angina that in the absence of a corresponding association with coronary artery disease suggested that the association between migraine and angina was not mediated by coronary artery disease [92]. However, the ARIC study did not allow any conclusive evidence mostly due to a possible bias related to the assessment of the headaches.

A prospective cohort of the Women’s Health Study which included 27,840 US women aged 45 years or older and that were free of cardiovascular disease and angina at study entry showed that, after a mean of 10 years of follow-up, active migraine with aura was associated with an increased risk of cardiovascular events while the association was not evident for patients suffering from migraine without aura [88]. In detail, compared with women without migraine history, women who reported active migraine with aura had an increased risk for major cardiovascular disease, ischemic stroke, myocardial infarction, coronary revascularization, angina, and death due to ischemic cardiovascular disease (Table 5) [88]. Patients who had prior migraine were at increased risk only of coronary revascularization and angina with respect to patients without migraine [88].

Table 5 Multivariable-adjusted hazard ratios for ischemic vascular events according to migraine status in men and women according to data from the Women’s Health Study [88] and the Physician’s Health Study [89]

A further prospective cohort study of 20,084 men aged 40 to 84 years participating in the Physicians’ Health Study showed, with a mean follow-up of 16 years, that migraine (any migraine including migraine with or without aura) was associated also in the male sex to an increased risk of cardiovascular disease. However, the detailed analysis of the end-point events showed that this overall increased risk was mainly driven by myocardial infarction while the risk of ischemic stroke, coronary revascularization, angina, and death due to ischemic cardiovascular disease was similar in migraineurs and non-migraineurs (Table 5) [89]. However, the association between migraine and ischemic stroke was modified by age (P = 0.03), indicating an increased risk of ischemic stroke for men with migraine who were 40–54 years of age but not for those in the older age groups. In this study, information on aura was not available hindering any definitive conclusion about the possible different risk between male patients suffering from migraine with or without aura. A previous analysis of data from the same population [86] did not reveal the positive association found later [88, 89].

Mechanism linking migraine to cardiovascular and cerebrovascular diseases

Accordingly, solid evidence supports the concept that migraine, particularly migraine with aura is associated with ischemic stroke and ischemic heart disease. Although it is possible that in some individuals transient ischemic attacks were misclassified as aura, this seems unlikely to account for the increased risk. Moreover, triptan-induced chest pain might have been misdiagnosed with angina in some cases inducing a possible bias.

The mechanisms by which migraine either causes or co-occurs with cerebrovascular and cardiovascular disorders have remained cryptic and probably are rather complex. In the past, mechanisms relying on protracted cerebral vasoconstriction were postulated. Thereafter, an association between migraine with aura and congenital heart defects, particularly PFO, has been proposed as another potential mechanism accounting for the increased risk of stroke in migraineurs. Those possibilities, however, are unlikely to explain the association between migraine and coronary vascular events since they may explain the increased risk at the cerebral level only. More correctly, migraine can be considered a marker of a more wide systemic vascular disorder. In fact, there is increasing evidence that in migraineurs the vascular system not just in the brain but outside as well is impaired [95, 96]. Brachial artery diameter as brachial and femoral artery compliance were decreased while aortic augmentation index (a parameter of arterial stiffness that can be obtained from the central arterial waveform as the ratio of augmentation pressure by the reflection pressure wave to the pulse pressure) was increased in migraineurs [96]. Subjects with migraine had greater arterial stiffness than migraine-free subjects independently of other confounding factors including age, sex, body height, blood pressure, and heart rate [97]. However, the precise mechanisms by which migraine may lead to cerebrovascular and cardiovascular events remain unclear. Several possibilities can be postulated to explain the increased risk in migraineurs.

The first hypothesis relies on the fact that the increased risk of vascular events can be due to a worst profile in terms of vascular risk factors of migraineurs, and particularly of migraineurs with aura, with respect to controls. The Genetic Epidemiology of Migraine (GEM) study reported that, compared to controls, migraineurs were more likely to smoke, less likely to consume alcohol, and more likely to report a parental history of early myocardial infarction [98]. Migraineurs with aura were more likely to have an unfavorable cholesterol profile, to have elevated blood pressure, to report a history of early onset coronary heart disease or stroke, and had an elevated Framingham risk score; female migraineurs with aura were more likely to be using oral contraceptives [98]. Moreover, migraine frequency and severity have been associated with increased body mass index [99] and migraine, particularly migraine with aura, has been associated with the methylenetetrahydrofolate reductase C677T genotype [100, 101], which may lead to hyperhomocysteinemia. Recently, compared with women with no migraine history, women who reported any history of migraine had modestly increased adjusted odds ratios for elevated total cholesterol, for non-HDL cholesterol, for apolipoprotein B100 and for C-reactive protein [102]. The increase did not differ according to migraine aura status and migraine frequency. The same study did not find any association between migraine and LDL cholesterol, HDL cholesterol, apolipoprotein A-1, fibrinogen, soluble intercellular adhesion molecule-1, homocysteine, and creatinine [102]. However, the main limitation to the risk factors hypothesis is that in the above reported studies as in other studies most of the vascular risk factors were present in the multivariate model which showed the association between migraine and cerebrovascular and cardiovascular diseases [70, 88, 89, 103]. In addition, several studies indicated that the migraine–stroke association was present in the absence of traditional vascular risk factors and that the type of stroke was less frequently a large-vessel stroke or a small-vessel stroke with respect to the general stroke population [62, 104].

Migraine has also been associated to an increase in prothrombotic factors, including prothrombin factor [105, 106], factor V Leiden [107], and von Willebrand factor [108]. The role of those uncommon vascular risk factors remains to be clarified but probably they can be associated only with a minority of vascular events.

The second hypothesis postulates that migraine pathophysiology may affect the endothelial function and by this alone or in combination with existing local vascular pathologies may increase the vascular risk outside of a migraine attack. The dysfunction of the endothelium, a mechanical and biological barrier between the blood and the vascular wall, implies a change of its homeostatic properties in turn of procoagulatory, proinflammatory and proliferative state which predisposes to atherogenesis [109]. Endothelial dysfunction is characterized by reduction in bioavailability of vasodilators (such as nitric oxide), increase in endothelial-derived contracting factors, and consequent impairment of the reactivity of the vasculature, including the microvasculature; it represents the first step in the development of atherothrombosis that finally leads to vascular events [109]. Traditional risk factors are known to cause endothelial dysfunction. There is also increasing evidence that migraine may be a non-traditional risk factor for endothelial dysfunction [95]. In fact, prothrombotic, proinflammatory, or other vasoactive peptides released during migraine may damage the endothelium, leading to an increased risk of atherosclerosis and vascular events. Endothelial dysfunction is mediated by increased oxidative stress, an important promotor of inflammatory processes [110]. Clinical investigation of markers of oxidative stress in a migraine population during, after, and between migraine attacks has yielded support for the association [111]. Moreover, cortical spreading depression, a self-propagating wave of neuronal and glial depolarization that has been implicated in the genesis of aura [112] might be responsible of cellular and molecular events, resulting in transient loss of membrane ionic gradients, as well as massive surges of extracellular potassium, neurotransmitters, and intracellular calcium. Cortical spreading depression may mediate its effects in part by altering the permeability of the blood–brain barrier via activation of matrix metalloproteinases, a family of neutral metalloproteases [113]. Their activation causes direct cellular damage and the release of vasoactive neuropeptides during migraine attacks that may stimulate inflammatory responses within and outside the brain [114]. Reduced endothelial repair capacity has emerged as another possible connection between migraine and vascular disease [115]. Levels of endothelial progenitor cells, measured using flow cytometry, were lower in migraineurs, and particularly in those with aura, with respect to healthy controls and to patients with tension-type headache; migraineurs presented also increased markers of senescence and decreased migratory capacity of endothelial progenitor cells. Endothelial progenitor cells derive from bone marrow, circulate in peripheral blood, are capable of proliferation and differentiation into endothelial cells, and play a role in neoangiogenesis after ischemia [116, 117]. Although it is not known if the reduction of endothelial progenitor cells represents a primary alteration in migraine or the consequence of migraine attacks, it might be possible that their alteration mediates the increased vascular risk.

The third hypothesis is that a vasospastic disorder may give rise to both conditions. The finding in the ARIC study that migraine was associated with Rose angina but not with coronary artery disease suggests a further possible mechanism relying on a generalized vasospastic disorder underlying both migraine and angina [92]. This possibility is further supported by the finding that in women with indications for coronary angiography, those with migraine had less severe angiographic coronary artery disease than those without migraine [118]. Moreover, cases of non-atherosclerotic vasospam of the coronary arteries have been documented in migraineurs with cardiac symptoms [87, 89, 119].

The last hypothesis relies on an increased risk attributable to the different pharmacologic agents used to treat migraine. Concerns have been raised regarding the cardiovascular safety of the use of migraine medications, especially triptans and compounds containing ergotamine, due to their vasoconstrictive properties. However, recent reviews of the clinical, pharmacological and post-marketing cardiovascular safety data of triptans currently do not support a direct association of these drugs with ischemic vascular events [120, 121]. Moreover, data referring to the association between migraine and stroke date to the pre-triptans era. As migraine with and without aura is similarly treated, this hypothesis seems unlikely [122, 123].

Conclusion

Although migraine represents a clear vascular risk factor the odds of risk can be considered small, especially in the absence of concurrent vascular risk factors. To date, among the huge population of migraineurs it is not possible to recognize the subjects who will develop a vascular event. It is currently unclear whether specific migraine features, such as frequency or intensity, are associated with further high risk of vascular events. In addition, it is currently unknown if the treatment of migraine reduces the risk of ischemic vascular events.

Nonetheless, for patients with migraine with aura, we recommend heightened vigilance for and active control of cardiovascular risk factors such as hypertension, hyperlipidemia, and smoking. Particular caution should be applied in prescribing combined oral contraceptives in patients with migraine with aura especially when they have additional risk factors which cannot easily be controlled [124]. Future studies should investigate the possibility that preventive medications for migraine or antiplatelet treatments might modify the risk of vascular disease in subjects with migraine and whether there are subgroups most likely to benefit [123].

References

  1. Feinstein AR (1970) The pre-therapeutic classification of comorbidity in chronic disease. J Chronic Dis 23:455–468

    CAS  PubMed  Google Scholar 

  2. Lipton RB, Silberstein SD (1994) Why study the comorbidity of migraine? Neurology 44(suppl 7):S4–S5 7969946, 1:STN:280:DyaK2M%2FlvF2kug%3D%3D

    CAS  PubMed  Google Scholar 

  3. Sacco S, Olivieri L, Bastianello S, Carolei A (2006) Comorbid neuropathologies in migraine. J Headache Pain 7:222–230 16767530

    PubMed Central  PubMed  Google Scholar 

  4. Meier B, Lock JE (2003) Contemporary management of patent foramen ovale. Circulation 107:5–9 12515733

    PubMed  Google Scholar 

  5. Sommer RJ, Hijazi ZM, Rhodes JF (2008) Pathophysiology of congenital heart disease in the adult. Part I: shunt lesions. Circulation 117:1090–1099 18299514

    PubMed  Google Scholar 

  6. Anzola GP, Magoni M, Guindani M, Rozzini L, Dalla Volta G (1999) Potential source of cerebral embolism in migraine with aura: a transcranial Doppler study. Neurology 52:1622–1625 10331688, 1:STN:280:DyaK1M3mtVGgsw%3D%3D

    CAS  PubMed  Google Scholar 

  7. Dalla Volta G, Guindani M, Zavarise P, Griffini S, Pezzini A, Padovani A (2005) Prevalence of patent foramen ovale in a large series of patients with migraine with aura, migraine without aura and cluster headache, and relationship with clinical phenotype. J Headache Pain 6:328–330 16362702

    PubMed Central  PubMed  Google Scholar 

  8. Del Sette M, Angeli S, Leandri M, Ferriero G, Buzzone GL, Finocchi C, Gandolfo C (1998) Migraine with aura and right-to-left shunt on transcranial Doppler: a case–control study. Cerebrovasc Dis 8:327–330 9774749, 1:STN:280:DyaK1M%2FmtlyhtQ%3D%3D

    CAS  PubMed  Google Scholar 

  9. Ferrarini G, Malferrari G, Zucco R, Gaddi O, Norina M, Pini LA (2005) High prevalence of patent foramen ovale in migraine with aura. J Headache Pain 6:71–76 16362645

    PubMed Central  PubMed  Google Scholar 

  10. Jesurum JT, Fuller CJ, Velez CA, Spencer MP, Krabill KA, Likosky WH, Gray WA, Olsen JV, Reisman M (2007) Migraineurs with patent foramen ovale have larger right-to-left shunt despite similar atrial septal characteristics. J Headache Pain 8:209–216 17901924

    PubMed Central  PubMed  Google Scholar 

  11. Lamy C, Giannesini C, Zuber M, Arquizan C, Meder JF, Trystram D, Coste J, Mas JL (2002) Clinical and imaging findings in cryptogenic stroke patients with and without patent foramen ovale. The PFO-ASA study. Stroke 33:706–711 11872892, 1:STN:280:DC%2BD387jsl2ktw%3D%3D

    CAS  PubMed  Google Scholar 

  12. Mas JL, Arquizan C, Lamy C, Zuber M, Cabanes L, Derumeaux G, Coste J, for the Patent Foramen Ovale, Atrial Septal Aneurysm Study Group (2001) Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm or both. N Engl J Med 345:1740–1746 11742048, 1:STN:280:DC%2BD38%2FivFajsA%3D%3D

    CAS  PubMed  Google Scholar 

  13. Sztajzela R, Genouda D, Rotha S, Mermillodb B, Le Floch-Rohra J (2002) Patent foramen ovale, a possible cause of symptomatic migraine. A study of 74 patients with acute ischemic stroke. Cerebrovasc Dis 13:102–106

    Google Scholar 

  14. Wilmshurst P, Nightingale S (2006) The role of cardiac and pulmonary pathology in migraine: a hypothesis. Headache 46:429–434 16618259

    PubMed  Google Scholar 

  15. Tembl J, Lago A, Sevilla T, Solis P, Vilchez J (2007) Migraine, patent foramen ovale and migraine triggers. J Headache Pain 8:7–12 17361381

    PubMed Central  PubMed  Google Scholar 

  16. Anzola GP, Meneghetti G, Zanferrari C, Adami A, Dinia L, Del Sette M, for the SAM Study Group (2008) Is migraine associated with right-to-left shunt a separate disease? Results of the SAM study. Cephalalgia 28:360–366 18279428, 1:STN:280:DC%2BD1c7ls1GktA%3D%3D

    CAS  PubMed  Google Scholar 

  17. Anzola GP, Frisoni GB, Morandi E, Casilli F, Onorato E (2006) Shunt associated migraine responds favorably to atrial septal repair: a case control study. Stroke 37:430–434 16373630

    PubMed  Google Scholar 

  18. Anzola GP, Morandi E, Casilli F, Onorato E (2006) Different degrees of right-to-left shunting predict migraine and stroke: data from 420 patients. Neurology 66:765–767 16534123

    PubMed  Google Scholar 

  19. Azarbal B, Tobis J, Suh W, Chan V, Dao C, Gaster R (2005) Association of interatrial shunts and migraine headaches: impact of transcatheter closure. J Am Coll Cardiol 45:489–492 15708691

    PubMed  Google Scholar 

  20. Giardini A, Donti A, Formigari R, Salomone L, Prandstraller D, Bonvicini M, Palareti G, Guidetti D, Gaddi O, Picchio FM (2006) Transcatheter patent foramen ovale closure mitigates aura migraine headaches abolishing spontaneous right-to-left shunting. Am Heart J 151:922e1–922e5

    Google Scholar 

  21. Kimmelstiel C, Gange C, Thaler D (2007) Is patent foramen ovale closure effective in reducing migraine symptoms? A controlled study. Catheter Cardiovasc Interv 69:740–746 17295330

    PubMed  Google Scholar 

  22. Morandi E, Anzola GP, Angeli S, Melzi G, Onorato E (2003) Transcatheter closure of patent foramen ovale: a new migraine treatment? J Interv Cardiol 16:39–42 12664816

    PubMed  Google Scholar 

  23. Post MC, Thijs V, Herroelen L, Budts WI (2004) Closure of a patent foramen ovale is associated with a decrease in prevalence of migraine. Neurology 62:1439–1440 15111695

    PubMed  Google Scholar 

  24. Reisman M, Christofferson RD, Jesurum J, Olsen JV, Spencer MP, Krabill KA, Diehl L, Aurora S, Gray WA (2005) Migraine headache relief after transcatheter closure of patent foramen ovale. J Am Coll Cardiol 45:493–495 15708692

    PubMed  Google Scholar 

  25. Rigatelli G, Cardaioli P, Braggion G, Giordan M, Fabio D, Aggio S, Roncon L, Chinaglia M (2007) Resolution of migraine by transcatheter patent foramen ovale closure with Premere Occlusion System in a preliminary series of patients with previous cerebral ischemia. Catheter Cardiovasc Interv 70:429–433 17722021

    PubMed  Google Scholar 

  26. Schwedt T, Dodick D (2006) Patent foramen ovale and migraine: bringing closure to the subject. Headache 46:663–671 16643562

    PubMed  Google Scholar 

  27. Schwerzmann M, Wiher S, Nedeltchev K, Mattle HP, Wahl A, Seiler C, Meier B, Windecker S (2004) Percutaneous closure of patent foramen ovale reduces the frequency of migraine attacks. Neurology 62:1399–1401 15111681, 1:STN:280:DC%2BD2c3htlyitw%3D%3D

    CAS  PubMed  Google Scholar 

  28. Wilmshurst P, Bryson P (2000) Relationship between the clinical features of neurological decompression illness and its causes. Clin Sci (Lond) 99:65–75 1:STN:280:DC%2BD3M7kvVGiuw%3D%3D

    CAS  Google Scholar 

  29. Wilmshurst PT, Nightingale S, Walsh KP, Morrison WL (2000) Effect on migraine of closure of cardiac right-to-left shunts to prevent recurrence of decompression illness or stroke or for haemodynamic reasons. Lancet 356:1648–1651 11089825, 1:STN:280:DC%2BD3M%2FltlOktw%3D%3D

    CAS  PubMed  Google Scholar 

  30. Dowson AJ, Mullen M, Peatfield R, Muir K, Khan A, Wells C, Lipscombe S, Rees T, De Giovanni J, Morrison W, Hildick-Smith D, Elrington G, Hillis W, Malik I, Rickards A (2008) Migraine Intervention with STARFlex Technology trial: a prospective, multicentre, double-blind, sham-controlled trial to evaluate the effectiveness of patent foramen ovale closure with STARFlex septal repair implant to resolve refractory migraine headache. Circulation 117:1397–1404 18316488

    PubMed  Google Scholar 

  31. Silberstein SD (2005) Topiramate in migraine prevention. Headache 45(suppl 1):S57–S65 15833091

    PubMed  Google Scholar 

  32. Diener HC, on behalf of the Council of the European Headache Federation (2007) Patent foramen ovale and migraine: no reason to intervene. J Headache Pain 8:3–6 17221341

    PubMed Central  PubMed  Google Scholar 

  33. Cirillo M, Stellato D, Lombardi C, De Santo NG, Covelli V (1999) Headache and cardiovascular risk factors: positive association with hypertension. Headache 39:409–416 11279918, 1:STN:280:DC%2BD3M7ovFWruw%3D%3D

    CAS  PubMed  Google Scholar 

  34. Franceschi M, Colombo B, Rossi P, Canal N (1997) Headache in a population-based elderly cohort. An ancillary study to the Italian Longitudinal Study of Aging (ILSA). Headache 37:79–82 9074291, 1:STN:280:DyaK2s3ivVaisQ%3D%3D

    CAS  PubMed  Google Scholar 

  35. Marcoux S, Berube S, Brisson J, Fabia J (1992) History of migraine and risk of pregnancy-induced hypertension. Epidemiology 3:53–56 1554810, 1:STN:280:DyaK383gvVSrsQ%3D%3D

    CAS  PubMed  Google Scholar 

  36. Markush RE, Karp HR, Heyman A, O’Fallon WM (1975) Epidemiologic study of migraine symptoms in young women. Neurology 25:430–435 1169701, 1:STN:280:DyaE2M7nsFeqtw%3D%3D

    CAS  PubMed  Google Scholar 

  37. Merikangas KR, Fenton BT (1994) Comorbidity of migraine with somatic disorders in a large-scale epidemiologic study in the United States. In: Olesen J (ed) Headache classification and epidemiology. Raven Press, New York, pp 301–314

    Google Scholar 

  38. Chen TC, Leviton A, Edelstein S, Ellenberg JH (1987) Migraine and other diseases in women of reproductive age. The influence of smoking on observed associations. Arch Neurol 44:1024–1028 3632373, 1:STN:280:DyaL2szisFOhtw%3D%3D

    CAS  PubMed  Google Scholar 

  39. Gudmundsson LS, Thorgeirsson G, Sigfusson N, Sigvaldason H, Johannsson M (2005) Migraine patients have lower systolic but higher diastolic blood pressure compared with controls in a population-based study of 21,537 subjects. The Reykjavik Study. Cephalalgia 26:436–444

    Google Scholar 

  40. Hagen K, Stovner LJ, Vatten L, Holmen J, Zwart J-A, Bovim G (2002) Blood pressure and risk of headache: a prospective study of 22,685 adults in Norway. J Neurol Neurosurg Psychiatry 72:463–466 11909904, 1:STN:280:DC%2BD383itlGitw%3D%3D

    PubMed Central  CAS  PubMed  Google Scholar 

  41. Muiesan ML, Padovani A, Salvetti M, Monteduro C, Poisa P, Bonzi B, Paini A, Cottini E, Agosti C, Castellano M, Rizzoni D, Vignolo A, Agabiti-Rosei E (2006) Headache: prevalence and relationship with office or ambulatory blood pressure in a general population sample (the Vobarno Study). Blood Press 15:14–19 16492611

    PubMed  Google Scholar 

  42. Prudenzano MP, Monetti C, Merico L, Cardinali V, Genco S, Lamberti P, Livrea P (2005) The comorbidity of migraine and hypertension. A study in a tertiary care headache centre. J Headache Pain 6:220–222 16362669

    PubMed Central  PubMed  Google Scholar 

  43. Rasmussen BK, Olesen J (1992) Symptomatic and nonsymptomatic headaches in a general population. Neurology 42:1225–1231 1603351, 1:STN:280:DyaK383ptlGntQ%3D%3D

    CAS  PubMed  Google Scholar 

  44. Tronvik E, Stovner LJ, Hagen K, Holmen J, Zwart JA (2008) High pulse pressure protects against headache: prospective and cross-sectional data (HUNT study). Neurology 70:1329–1336 18413586, 1:STN:280:DC%2BD1c3ltlGmsQ%3D%3D

    CAS  PubMed  Google Scholar 

  45. Waters WE (1971) Headache and blood pressure in the community. BMJ 1:142–143 5539420, 1:STN:280:DyaE3M%2FnvFGksw%3D%3D

    PubMed Central  CAS  PubMed  Google Scholar 

  46. Tzourio C, Gagniere B, El Amrani M, Alperovitch A, Bousser MG (2003) Relationship between migraine, blood pressure and carotid thickness. A population-based study in the elderly. Cephalalgia 23:914–920 14616934, 1:STN:280:DC%2BD3srjs12itQ%3D%3D

    CAS  PubMed  Google Scholar 

  47. Wiehe M, Fuchs SC, Moreira LB, Stoll Moraes R, Fuchs FD (2002) Migraine is more frequent in individuals with optimal and normal blood pressure: a population-based study. J Hypertens 20:1303–1306 12131526, 1:CAS:528:DC%2BD38Xlt1Kmt7w%3D

    CAS  PubMed  Google Scholar 

  48. Schrader H, Stovner LJ, Helde G, Sand T, Bovim G (2001) Prophylactic treatment of migraine with angiotensin converting enzyme inhibitor (lisinopril): randomised, placebo controlled, crossover study. BMJ 322:19–23 11141144, 1:CAS:528:DC%2BD3MXps1WgtQ%3D%3D

    PubMed Central  CAS  PubMed  Google Scholar 

  49. Tronvik E, Stovner LJ, Helde G, Sand T, Bovim G (2003) Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled trial. JAMA 289:65–69 12503978, 1:CAS:528:DC%2BD3sXmsVak

    CAS  PubMed  Google Scholar 

  50. Charles JA, Jotkowitz S, Byrd LH (2006) Prevention of migraine with olmesartan in patients with hypertension/prehypertension. Headache 46:503–507 16618270

    PubMed  Google Scholar 

  51. Bousser MG, Welch KMA (2005) Relation between migraine and stroke. Lancet Neurol 4:533–542 16109360

    PubMed  Google Scholar 

  52. Buring JE, Hebert P, Romero J, Kittross A, Cook N, Manson J, Peto R, Hennekens C (1995) Migraine and subsequent risk of stroke in the Physicians’ Health Study. Arch Neurol 52:129–134 7848119, 1:STN:280:DyaK2M7ltVynuw%3D%3D

    CAS  PubMed  Google Scholar 

  53. Carolei A, Marini C, De Matteis G, the Italian National Research Council Study Group of Stroke in the Young (1996) History of migraine and risk of cerebral ischaemia in young adults. Lancet 347:1503–1506 8684100, 1:STN:280:DyaK283ivVWgsg%3D%3D

    CAS  PubMed  Google Scholar 

  54. Chang CL, Donaghy M, Poulter N (1999) Migraine and stroke in young women: case-control study. The World Health Organisation Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. BMJ 318:13–18 9872876, 1:STN:280:DyaK1M%2FptFCmug%3D%3D

    PubMed Central  CAS  PubMed  Google Scholar 

  55. Collaborative Group for the Study of Stroke in Young Women (1975) Oral contraceptives and stroke in young women. JAMA 231:718–722

    Google Scholar 

  56. Donaghy M, Chang CL, Poulter N (2002) Duration, frequency, recency, and type of migraine and the risk of ischaemic stroke in women of childbearing age. J Neurol Neurosurg Psychiatry 73:747–750 12438482, 1:STN:280:DC%2BD38nnvVGrtg%3D%3D

    PubMed Central  CAS  PubMed  Google Scholar 

  57. Etminan M, Takkouche B, Isorna FC, Samii A (2005) Risk of ischaemic stroke in people with migraine: systematic review and meta-analysis of observational studies. BMJ 330:63–65 15596418

    PubMed Central  PubMed  Google Scholar 

  58. Haapaniemi H, Hillbom M, Juvela S (1997) Life-style associated risk factors for acute brain infarction among persons of working age. Stroke 28:26–30 8996483, 1:STN:280:DyaK2s7kvFKktw%3D%3D

    CAS  PubMed  Google Scholar 

  59. Henrich JB, Horwitz RI (1989) A controlled study of ischemic stroke risk in migraine patients. J Clin Epidemiol 42:773–780 2760669, 1:STN:280:DyaL1MzktFyksg%3D%3D

    CAS  PubMed  Google Scholar 

  60. Kurth T, Slomke MA, Kase CS, Cook NR, Lee IM, Gaziano JM, Diener HC, Buring JE (2005) Migraine, headache, and the risk of stroke in women: a prospective study. Neurology 64:1020–1026 15781820, 1:STN:280:DC%2BD2M7ltlCisQ%3D%3D

    CAS  PubMed  Google Scholar 

  61. Lidegaard O (1995) Oral contraceptives, pregnancy and the risk of cerebral thromboembolism: the influence of diabetes, hypertension, migraine and previous thrombotic disease. Br J Obstet Gynaecol 102:153–159 7756208, 1:STN:280:DyaK2M3nsFOluw%3D%3D

    CAS  PubMed  Google Scholar 

  62. MacClellan LR, Giles W, Cole J, Wozniak M, Stern B, Mitchell BD, Kittner SJ (2007) Probable migraine with visual aura and risk of ischemic stroke: The Stroke Prevention in Young Women Study. Stroke 38:2438–2445 17690308

    PubMed  Google Scholar 

  63. Marini C, Carolei A, Roberts RS, Prencipe M, Gandolfo C, Inzitari D et al (1993) Focal cerebral ischemia in young adults: a collaborative case–control study. Neuroepidemiology 12:70–81 8232706, 1:STN:280:DyaK2c%2FltVehtA%3D%3D

    CAS  PubMed  Google Scholar 

  64. Merikangas KR, Fenton BT, Cheng SH, Stolar MJ, Risch N (1997) Association between migraine and stroke in a large-scale epidemiological study of the United States. Arch Neurol 54:362–368 9109736, 1:STN:280:DyaK2s3mtlyltg%3D%3D

    CAS  PubMed  Google Scholar 

  65. Milhaud D, Bogousslavsky J, van Melle G, Liot P (2001) Ischemic stroke and active migraine. Neurology 57:1805–1811 11723268, 1:STN:280:DC%2BD3MnnslegtA%3D%3D

    CAS  PubMed  Google Scholar 

  66. Mosek A, Marom R, Korczyn AD, Bornstein N (2001) A history of migraine is not a risk factor to develop an ischemic stroke in the elderly. Headache 41:399–401 11318887, 1:STN:280:DC%2BD3M3jtFSjtA%3D%3D

    CAS  PubMed  Google Scholar 

  67. Nightingale AL, Farmer RD (2004) Ischemic stroke in young women: a nested case–control study using the UK general practice research database. Stroke 35:1574–1578 15143296

    PubMed  Google Scholar 

  68. Schwaag S, Nabavi DG, Frese A, Husstedt IW, Evers S (2003) The association between migraine and juvenile stroke: a case–control study. Headache 43:90–95 12558760

    PubMed  Google Scholar 

  69. Sochurkova D, Moreau T, Lemesle M, Menassa M, Giroud M, Dumas R (1999) Migraine history and migraine-induced stroke in the Dijon stroke registry. Neuroepidemiology 18:85–91 10023131, 1:STN:280:DyaK1M7kvVSqsg%3D%3D

    CAS  PubMed  Google Scholar 

  70. Stang PE, Carson AP, Rose KM, Mo J, Ephross SA, Shahar E, Szklo M (2005) Headache, cerebrovascular symptoms, and stroke: the Atherosclerosis Risk in Communities Study. Neurology 64:1573–1577 15883318, 1:STN:280:DC%2BD2M3ksFWntw%3D%3D

    CAS  PubMed  Google Scholar 

  71. Tzourio C, Iglesias S, Hubert JB, Visy JM, Alpérovitch A, Tehindrazanarivelo A, Biousse V, Woimant F, Bousser MG (1993) Migraine and risk of ischaemic stroke: a case–control study. Br Med J 307:289–292 1:STN:280:DyaK3szosF2jug%3D%3D, 10.1136/bmj.307.6899.289

    CAS  Google Scholar 

  72. Tzourio C, Tehindrazanarivelo A, Iglesias S et al (1995) Case–control study of migraine and risk of ischaemic stroke in young women. Br Med J 310:830–833 1:STN:280:DyaK2M3islSntw%3D%3D

    CAS  Google Scholar 

  73. Headache Classification Subcommittee of the International Headache Society. The International Headache Classification of Headache Disorders, 2nd edn (2004) Cephalalgia 24(suppl 1):9–160

  74. Kruit MC, van Buchem MA, Hofman PA, Bakkers JT, Terwindt GM, Ferrari MD, Launer LJ (2004) Migraine as a risk factor for subclinical brain lesions. JAMA 291:427–434 14747499, 1:CAS:528:DC%2BD2cXos1Smsg%3D%3D

    CAS  PubMed  Google Scholar 

  75. Kruit MC, Launer LJ, Ferrari MD, van Buchem MA (2005) Infarcts in the posterior circulation territory in migraine. The population-based MRI CAMERA study. Brain 128:2068–2077 16006538

    PubMed  Google Scholar 

  76. Bogousslavsky J, Regli F, Van Melle G, Payot M, Uske A (1988) Migraine stroke. Neurology 38:223–227 3340283, 1:STN:280:DyaL1c7itlSrtw%3D%3D

    CAS  PubMed  Google Scholar 

  77. Broderick JP, Swanson JW (1987) Migraine-related strokes. Clinical profile and prognosis in 20 patients. Arch Neurol 44:868–871 3632398, 1:STN:280:DyaL2szisFOlsw%3D%3D

    CAS  PubMed  Google Scholar 

  78. Caplan LR (1991) Migraine and vertebrobasilar ischemia. Neurology 41:55–61 1781812, 1:STN:280:DyaK3M%2FovVSrug%3D%3D

    CAS  PubMed  Google Scholar 

  79. Milhaud D, Bogousslavsky J, Van Melle G, Liot P (2001) Ischemic stroke and active migraine. Neurology 57:1805–1811 11723268, 1:STN:280:DC%2BD3MnnslegtA%3D%3D

    CAS  PubMed  Google Scholar 

  80. Coppeto JR, Lessell S, Sciarra R, Bear L (1986) Vascular retinopathy in migraine. Neurology 36:267–270 3945397, 1:STN:280:DyaL287hvFWhsw%3D%3D

    CAS  PubMed  Google Scholar 

  81. Newman NJ, Lessell S, Brandt EM (1989) Bilateral central retinal artery occlusions, disk drusen, and migraine. Am J Ophthalmol 107:236–240 2923150, 1:STN:280:DyaL1M7msVektg%3D%3D

    CAS  PubMed  Google Scholar 

  82. Beversdorf D, Stommel E, Allen C, Stevens R, Lessell S (1997) Recurrent branch retinal infarcts in association with migraine. Headache 37:396–399 9237415, 1:STN:280:DyaK2szotVKnsg%3D%3D

    CAS  PubMed  Google Scholar 

  83. Glenn AM, Shaw PJ, Howe JW, Bates D (1992) Complicated migraine resulting in blindness due to bilateral retinal infarction. Br J Ophthalmol 76:189–190 1540572, 1:STN:280:DyaK387nt1ygsg%3D%3D

    PubMed Central  CAS  PubMed  Google Scholar 

  84. Liew G, Mitchell P, Wong TY, Wang JJ (2006) Retinal vascular caliber and migraine: the Blue Mountains Eye Study. Headache 46:997–1004 16732846

    PubMed  Google Scholar 

  85. Rose KM, Wong TY, Carson AP, Couper DJ, Klein R, Sharrett AR (2007) Migraine and retinal microvascular abnormalities: The Atherosclerosis Risk in Communities Study. Neurology 68:1694–1700 17502551, 1:STN:280:DC%2BD2s3ptFGjsA%3D%3D

    CAS  PubMed  Google Scholar 

  86. Cook NR, Benseñor IM, Lotufo PA (2002) Migraine and coronary heart disease in women and men. Headache 42:715–727 12390634

    PubMed  Google Scholar 

  87. Fournier JA, Fernandez-Cortacero JA, Granado C, Gascon D (1986) Familial migraine and coronary artery spasm in two siblings. Clin Cardiol 9:121–125 3948446, 1:STN:280:DyaL287jsVejug%3D%3D

    CAS  PubMed  Google Scholar 

  88. Kurth T, Gaziano JM, Cook NR, Logroscino G, Diener H, Buring JE (2006) Migraine and risk of cardiovascular disease in women. JAMA 296:283–291 16849661, 1:CAS:528:DC%2BD28XntVWqsLg%3D

    CAS  PubMed  Google Scholar 

  89. Kurth T, Gaziano JM, Cook NR, Bubes V, Logroscino G, Diener H, Buring JE (2007) Migraine and risk of cardiovascular disease in men. Arch Int Med 167:795–801

    Google Scholar 

  90. Lafitte C, Even C, Henry-Lebras F, de Toffol B, Autret A (1996) Migraine and angina pectoris by coronary artery spasm. Headache 36:332–334 8682678, 1:STN:280:DyaK283mslOqsA%3D%3D

    CAS  PubMed  Google Scholar 

  91. Mitchell P, Wang JJ, Currie J, Cumming RG, Smith W (1998) Prevalence and vascular associations with migraine in older Australians. Aust N Z J Med 28:627–632 9847952, 1:STN:280:DyaK1M%2FmsVCiug%3D%3D

    CAS  PubMed  Google Scholar 

  92. Rose KM, Carson AP, Sanford CP, Stang PE, Brown CA, Folsom AR, Szklo M (2004) Migraine and other headaches: associations with Rose angina and coronary heart disease. Neurology 63:2233–2239 15623679, 1:STN:280:DC%2BD2cnkslWjsg%3D%3D

    CAS  PubMed  Google Scholar 

  93. Sternfeld B, Stang P, Sidney S (1995) Relationship of migraine headaches to experience of chest pain and subsequent risk for myocardial infarction. Neurology 45:2135–2142 8848181, 1:STN:280:DyaK287gvFWgsQ%3D%3D

    CAS  PubMed  Google Scholar 

  94. Wayne VS (1986) A possible relationship between migraine and coronary artery spasm. Aust N Z J Med 16:708–710 3469972, 1:STN:280:DyaL2s7ls1eltA%3D%3D

    CAS  PubMed  Google Scholar 

  95. Tietjen GE (2007) Migraine and ischaemic heart disease and stroke: potential mechanisms and treatment implications. Cephalalgia 27:981–987 17661875

    PubMed  Google Scholar 

  96. Vanmolkot FH, Van Bortel LM, de Hoon JN (2007) Altered arterial function in migraine of recent onset. Neurology 68:1563–1570 17460157

    PubMed  Google Scholar 

  97. Nagai T, Tabara Y, Igase M, Nakura J, Miki T, Kohara K (2007) Migraine is associated with enhanced arterial stiffness. Hypertens Res 30:577–583 17785924

    PubMed  Google Scholar 

  98. Scher AI, Terwindt GM, Picavet HS, Verschuren WM, Ferrari MD, Launer LJ (2005) Cardiovascular risk factors and migraine: the GEM population-based study. Neurology 64:614–620 15728281, 1:STN:280:DC%2BD2M%2FpvVyjsg%3D%3D

    CAS  PubMed  Google Scholar 

  99. Bigal ME, Liberman JN, Lipton RB (2006) Obesity and migraine: a population study. Neurology 66:545–550 16354886

    PubMed  Google Scholar 

  100. Lea RA, Ovcaric M, Sundholm J, Solyom L, Macmillan J, Griffiths LR (2005) Genetic variants of angiotensin converting enzyme and methylenetetrahydrofolate reductase may act in combination to increase migraine susceptibility. Brain Res Mol Brain Res 136:112–117 15893594, 1:CAS:528:DC%2BD2MXktVGmu7Y%3D

    CAS  PubMed  Google Scholar 

  101. Scher AI, Terwindt GM, Verschuren WM, Kruit MC, Blom HJ, Kowa H, Frants RR, van den Maagdenberg AM, van Buchem M, Ferrari MD, Launer LJ (2006) Migraine and MTHFR C677T genotype in a population-based sample. Ann Neurol 59:372–375 16365871, 1:CAS:528:DC%2BD28XhvVSksLo%3D

    CAS  PubMed  Google Scholar 

  102. Kurth T, Ridker PM, Buring JE (2007) Migraine and biomarkers of cardiovascular disease in women. Cephalalgia 28:49–56 17986270

    PubMed  Google Scholar 

  103. Rosamond W (2004) Are migraine and coronary heart disease associated? An epidemiologic review. Headache 44:S5–S12 15149488

    PubMed  Google Scholar 

  104. Yoon G, Baggaley S, Bacchetti P, Fu YH, Digre KB, Ptácek LJ (2005) Clinic-based study of family history of vascular risk factors and migraine. J Headache Pain 6:412–416 16362715

    PubMed Central  PubMed  Google Scholar 

  105. Goadsby PJ, Lipton RB, Ferrari MD (2002) Migraine - current understanding and treatment. N Engl J Med 346:257–270 11807151, 1:CAS:528:DC%2BD38XmslGgsQ%3D%3D

    CAS  PubMed  Google Scholar 

  106. Silberstein SD (2004) Migraine. Lancet 363:381–391 15070571, 1:CAS:528:DC%2BD2cXptVehsw%3D%3D

    CAS  PubMed  Google Scholar 

  107. Soriani S, Borgna-Pignatti C, Trabetti E, Casartelli A, Montagna P, Pignatti PF (1998) Frequency of factor V Leiden in juvenile migraine with aura. Headache 38:779–781 11279903, 1:STN:280:DC%2BD3M7ovFajuw%3D%3D

    CAS  PubMed  Google Scholar 

  108. Tietjen GE, Al-Qasmi MM, Athanas K, Dafer RM, Khuder SA (2001) Increased von Willebrand factor in migraine. Neurology 57:334–336 11468324, 1:STN:280:DC%2BD38%2Fis1ahsA%3D%3D

    CAS  PubMed  Google Scholar 

  109. Ross R (1999) Atherosclerosis—an inflammatory disease. Lancet 340:115–126 1:STN:280:DyaK1M%2FptFSqtQ%3D%3D

    CAS  Google Scholar 

  110. Bonetti PO, Lerman LO, Lerman A (2003) Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol 23:168–175 12588755, 1:CAS:528:DC%2BD3sXptFyrsw%3D%3D

    CAS  PubMed  Google Scholar 

  111. Ciancarelli I, Tozzi-Ciancarelli MG, Di Massimo C, Marini C, Carolei A (2003) Urinary nitric oxide metabolites and lipid peroxidation by-products in migraine. Cephalalgia 23:39–42 12534579, 1:STN:280:DC%2BD3s%2FivVSnsQ%3D%3D

    CAS  PubMed  Google Scholar 

  112. Moskowitz MA, Macfarlane R (1993) Neurovascular and molecular mechanisms in migraine headaches. Cerebrovasc Brain Metab Rev 5:159–177 8217498, 1:STN:280:DyaK2c%2FjtFCnuw%3D%3D

    CAS  PubMed  Google Scholar 

  113. Gursoy-Ozdemir Y, Qiu J, Matsuoka N, Bolay H, Bermpohl D, Jin H, Wang X, Rosenberg GA, Lo EH, Moskowitz MA (2004) Cortical spreading depression activates and up-regulates MMP-9. J Clin Invest 113:1447–1455 15146242, 1:CAS:528:DC%2BD2cXktlCltrY%3D

    PubMed Central  CAS  PubMed  Google Scholar 

  114. Waeber C, Moskowitz MA (2005) Migraine as an inflammatory disorder. Neurology 64(suppl 2):S9–S15 15911785

    PubMed  Google Scholar 

  115. Lee ST, Chu K, Jung KH, Kim DH, Kim EH, Choe VN, Kim JH, Im WS, Kang L, Park JE, Park HJ, Park HK, Song EC, Lee SK, Kim M, Roh JK (2008) Decreased number and function of endothelial progenitor cells in patients with migraine. Neurology 70:1510–1517 18354079

    PubMed  Google Scholar 

  116. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967 9020076, 1:CAS:528:DyaK2sXht1Clu7k%3D

    CAS  PubMed  Google Scholar 

  117. Werner N, Kosiol S, Schiegl T, Ahlers P, Walenta K, Link A, Böhm M, Nickenig G (2005) Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 353:999–1007 16148285, 1:CAS:528:DC%2BD2MXpvVOisbw%3D

    CAS  PubMed  Google Scholar 

  118. Ahmed B, Bairey Merz CN, McClure C, Johnson BD, Reis SE, Bittner V, Pepine CJ, Sharaf BL, Sopko G, Kelsey SF, Shaw L, WISE Study Group (2006) Migraines, angiographic coronary artery disease and cardiovascular outcomes in women. Am J Med 119:670–675 16887413

    PubMed  Google Scholar 

  119. Hoffmann M (2006) Stroke and chest pain in young people with migraine. Headache 46:208–211 16492229

    PubMed  Google Scholar 

  120. Dodick DW, Martin VT, Smith T, Silberstein S (2004) Cardiovascular tolerability and safety of triptans: a review of clinical data. Headache 44:S20–S30 15149490

    PubMed  Google Scholar 

  121. Hall GC, Brown MM, Mo J, MacRae KD (2004) Triptans in migraine: the risks of stroke, cardiovascular disease, and death in practice. Neurology 62:563–568 14981171, 1:CAS:528:DC%2BD2cXptVCqsg%3D%3D

    CAS  PubMed  Google Scholar 

  122. Lipton RB, Bigal ME (2006) Migraine and cardiovascular disease. JAMA 296:332–333 16849667, 1:CAS:528:DC%2BD28XntVaitL4%3D

    CAS  PubMed  Google Scholar 

  123. Lipton RB, Bigal ME (2007) Migraine and cardiovascular disease: is there a link? Nat Clin Pract Neurol 3:74–75 17228305

    PubMed  Google Scholar 

  124. Bousser MG, Conard J, Kittner S, de Lignières B, MacGregor EA, Massiou H, Silberstein SD, Tzourio C (2000) Recommendations on the risk of ischaemic stroke associated with use of combined oral contraceptives and hormone replacement therapy in women with migraine. Cephalalgia 20:155–156 10997767, 1:STN:280:DC%2BD3cvksF2qsA%3D%3D

    CAS  PubMed  Google Scholar 

Download references

Conflict of interest

None.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Antonio Carolei.

Rights and permissions

Open Access This is an open access article distributed under the terms of the Creative Commons Attribution Noncommercial License ( https://creativecommons.org/licenses/by-nc/2.0 ), which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

Reprints and permissions

About this article

Cite this article

Sacco, S., Cerone, D. & Carolei, A. Comorbid neuropathologies in migraine: an update on cerebrovascular and cardiovascular aspects. J Headache Pain 9, 237–248 (2008). https://doi.org/10.1007/s10194-008-0048-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10194-008-0048-4

Keywords