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
Migraine as a risk factor for stroke | A clearly clinically defined stroke syndrome must occur remotely in time from a typical attack of migraine |
Migraine caused by stroke (symptomatic migraine) | An acute vascular event in the central nervous system (ischemic or hemorrhagic stroke or TIA) produces episodes of headache with the characteristics of migraine with or without aura; to be coded as ICHD-II 6.1 |
Migraine as a cause of stroke (migrainous infarction) | A documented infarct in a relevant area during the course of an attack of migraine with aura, in a patient with a history of migraine with aura, with symptoms that are those of the aura and in the absence of other possible causes at an extensive workup; to be coded as ICHD-II 1.5.4 |
Migraine and stroke sharing a common cause | A syndrome (usually of genetic origin) in which both migraine and stroke are major clinical features (e.g. CADASIL [ICHD-II 6.7.1] or MELAS [ICHD-II 6.7.2]) |
Migraine associated with subclinical stroke | Evidence at brain neuroimaging of small areas compatible with brain ischemia in patients without a history of any clinical symptom indicating a stroke syndrome |
Migraine mimicking stroke (and viceversa: stroke mimicking migraine) | Symptoms of migraine attacks (particularly aura without headache) and of stroke (particularly TIAs) may overlap causing problems in the differential diagnosis |
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
| 40–84 | M | 22,071 | 2.0, 1.1–3.6 | NR | NR |
| 15–44 | M, W | 899 | 1.3, 0.7–2.4 | 8.6, 1.0–75 | 1.0, 0.5–2.0 |
| 20–44 | W | 1,027 | 3.5, 1.3–9.6 | 3.8, 1.3–11.5 | 3.0, 0.7–13.5 |
| 15–65 | M, W | 267 | 1.8, 0.9–3.6 | 2.6, 1.1–6.6 | 1.3, 0.5–3.6 |
| ≥45 | W | 39,754 | 1.4, 1.0–1.9 | 1.7, 1.1–2.7 | 1.1, 0.7–1.8 |
| 15–49 | W | 1,000 | NR | 1.5, 1.1–2.0 | 1.0, 0.6–1.5 |
| 15–44 | M, W | 616 | NR | 14.8, 1.8–124 | 1.6, 0.9–3.0 |
| 25–74 | M, W | 12,220 | 2.1, 1.5–2.9 | NR | NR |
| 15–49 | W | 1,319 | 2.3, 1.0–5.2 | NR | NR |
| ≤45 | M, W | 320 | 2.1, 1.2–3.8 | NR | NR |
| 45–64 | M, W | 12,750 | NR | 2.7, 1.6–4.6 | 0.8, 0.4–1.5 |
| 18–80 | M, W | 424 | 1.3, 0.8–2.3 | 1.3, 0.5–3.8 | 0.8, 0.4–1.5 |
| <45 | W | 245 | 3.5, 1.8–6.4 | 6.2, 2.1–18.0 | 3.0, 1.5–5.8 |
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]
Major cardiovascular event | 1 | 2.15 (1.58–2.92) P < 0.001 | 1.23 (0.88–1.73) P = 0.23 | 1 | 1.24 (1.06–1.46) P = 0.008 |
Ischemic stroke | 1 | 1.91 (1.17–3.10) P = 0.01 | 1.27 (0.77–2.09) P = 0.36 | 1 | 1.12 (0.84–1.50) P = 0.43 |
Myocardial infarction | 1 | 2.08 (1.30–3.31) P = 0.002 | 1.22 (0.73–2.05) P = 0.45 | 1 | 1.42 (1.15–1.77) P < 0.001 |
Coronary revascularization | 1 | 1.74 (1.23–2.46) P = 0.002 | 0.98 (0.67–1.42) P = 0.90 | 1 | 1.05 (0.89–1.24) P = 0.54 |
Angina | 1 | 1.71 (1.16–2.53) P = 0.007 | 1.12 (0.75–1.66) P = 0.58 | 1 | 1.15 (0.99–1.33) P = 0.07 |
Cardiovascular death | 1 | 2.33 (1.21–4.51) P = 0.01 | 1.06 (0.46–2.45) P = 0.89 | 1 | 1.07 (0.80–1.43) P = 0.65 |
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 B
100 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].