Several studies have also addressed the possible association between migraine and hemorrhagic stroke [1, 8, 11–13, 23, 24, 27, 35, 41, 93]. The pooled analysis of comparable studies [8, 11–13, 27, 35, 41, 93] by Sacco et al. indicated that subjects with any migraine had a 1.5-fold increased risk of hemorrhagic (including intracerebral and subarachnoid hemorrhage) stroke (Table 1.1) [84]. Subgroup analyses showed that female migraineurs had a 1.6-fold increased risk of hemorrhagic stroke as compared with female non-migraineurs (pooled adjusted effect estimate [PAEE] 1.6; 95 % CI 1.2–2.1) as female migraineurs aged less than 45 years (PAEE 1.6; 95 % CI 1.1–2.2) when compared with female non-migraineurs in the same age group [84]. However, solid conclusions could not be made for the different migraine types (with and without aura) because of insufficient data as only three studies [12, 35, 41] collected data on the risk of hemorrhagic stroke according to migraine type (Table 1.1). Two of them [35, 41] showed an association between migraine with aura and hemorrhagic stroke, while only one showed an association between migraine without aura and hemorrhagic stroke [35]. Regarding hemorrhagic stroke type, available data suggested that the association between migraine and hemorrhagic stroke is driven by an increase of intracerebral but not subarachnoid events [11, 41]. Thereafter, Gaist et al. performed a case–control study using data from 1,797 subjects with intracerebral hemorrhage and 1,340 subjects with subarachnoid hemorrhage and frequency matched controls from a large epidemiological dataset, The Health Improvement Network (THIN) [23]. In this study authors were unable to demonstrate an increased risk of overall hemorrhagic stroke or of intracerebral hemorrhage or subarachnoid hemorrhage in subjects with migraine compared with non-migraineurs. Analysis according to migraine type showed that neither migraine with aura nor migraine without aura were associated with an increased risk of hemorrhagic stroke. Only subjects with a long history (≥20 years) of migraine had an increased risk of intracerebral hemorrhage as compared to control subjects. Gelfand et al., in a further study including 1,566,952 children aged 2–17 years, were unable to demonstrate an association between migraine and hemorrhagic stroke in this age group [24]. Recently, the study by Albieri et al., did not demonstrate an increased risk of hemorrhagic stroke in migraineurs; however, in this study sub-analysis by gender suggested an increased risk for hemorrhagic stroke in women migraineurs (RR 1.4; CI 1.1–1.8) as compared to non-migraineurs but no difference by migraine status in men [1]. Notably, data from the Nationwide Inpatient Sample indicated also that, during pregnancy, a diagnosis of migraine was associated with an increased risk of intracerebral (OR 9.1; 95 % CI 3.0–27.8) but not subarachnoid hemorrhage [9].

Some studies have identified migraine also as a possible risk factor for cardiac vascular events [37, 38, 59], while others were unable to prove this association [27, 98, 104]. The pooled analysis of available data [27, 37, 38, 98, 104] by Schürks et al. did not indicate an increased risk of myocardial infarction in subjects with any migraine versus no migraine (Table 1.1) [91], but subsequently, data has pointed to an association between any migraine with cardiac ischemic disease [107] and between migraine with and without aura and myocardial infarction [7]. A further meta-analysis by Schurks et al., by pooling data from comparable studies [14, 25, 51], showed that the presence of any migraine did not alter the risk of coronary artery disease mortality (Table 1.1) [92]. A more recent meta-analysis by Sacco et al., pooling data from comparable studies [7, 27, 37, 38, 59, 98, 104], indicated a 30 % increase in the risk of myocardial infarction in subjects with migraine as compared to non-migraineurs (Table 1.1) [87]. An analysis stratified according to aura status indicated an increased risk of myocardial infarction in subjects with migraine with aura as compared to non-migraineurs while the meta-analysis was unable to show an increased risk of myocardial infarction in subjects with migraine without aura (Table 1.1) [87]. This same meta-analysis also indicated that migraineurs as compared with non-migraineurs had an increased risk of angina (Table 1.1) [87]. In the case of angina, the risk was increased in both migraineurs with migraine with and without aura (Table 1.1) [87]. Both for myocardial infarction and angina, the meta-analysis indicated that the overall increased risk was mostly driven by the association in women while the meta-analysis was unable to demonstrate the association in men [87]. Notably, data from the Nationwide Inpatient Sample indicated also that, during pregnancy, a diagnosis of migraine was associated with an increased risk of myocardial infarction (OR 4.9; 95 % CI 1.7–14.2) [9].

Data from the WHS cohort showed that the association with myocardial infarction was evident among women in the highest Framingham risk score group and this pattern of association was driven by a particularly increased risk of myocardial infarction in women with migraine with aura who had high total cholesterol levels [39]. In contrast to the findings for ischemic stroke, this same study reported and association between low migraine frequency (< monthly) and myocardial infarction (HR 2.4; 95 % CI 1.6–3.7) and angina (HR 1.9; 95 % CI 1.3–2.9) among women with active migraine with aura, while the study was unable to demonstrate an association between higher migraine frequency (monthly and ≥ weekly) and those same cardiac end points [40].

Several studies have also indicated that compared to non-migraineurs, migraineurs have a higher burden of asymptomatic white matter brain lesions and, according to some studies, infarct-like lesions on brain magnetic resonance imaging (MRI) [4, 28, 42, 60]. Those lesions may suggest chronic ischemic disease, but their nature still remains elusive because of the lack of neuropathological correlation.

White matter abnormalities in migraineurs have an uncertain pathological significance and may correspond to gliosis, demyelination, and loss of axons; this set of findings has been attributed to microvascular damage. According to a systematic review of studies published up to January 2013, prevalence of white matter abnormalities in migraineurs ranged from 4 to 59 % [4]. A meta-analysis of studies published up to November 2003, of pooled data from 7 studies [16, 22, 30, 67, 74, 77, 109] suggested an increased risk of white matter hyperintensities in migraineurs (OR 3.9; 95 % CI 2.3–6.7) [99]. According to the Cerebral Abnormalities in Migraine an Epidemiological Risk Analysis (CAMERA) study, a population-based study including 134 migraineurs without aura, 161 migraineurs with aura, and 140 controls aged 30–60 years reported that migraine was associated with deep white matter abnormalities in women (OR, 2.1; 95 % CI, 1.0–4.1) [33]. This association was independent of the presence or absence of aura, and the risk increased with attack frequency (highest in those with ≥1 attack per month: OR, 2.6; 95 % CI, 1.2–5.7) [33]. A subsequent analysis from the CAMERA study indicated an increased risk of infratentorial (mostly pontine) hyperintensities in migraine with and without aura [34]. By contrast, this same study showed that in men, deep white matter abnormalities were not influenced by the presence, subtype, or frequency of migraine. The Epidemiology of Vascular Ageing (EVA) study, a population-based cross-sectional study involving 780 participants, confirmed the association of migraine with white matter abnormalities (OR 1.8; 95 % CI 1.0–2.9) [42]. The association between migraine and white matter hyperintensities was evident only for deep located lesions and migraine with aura (OR 12.4; 95 % CI 1.6–99.4) but not for periventricular lesions and migraine without aura [42]. A meta-analysis by Bashir et al., pooling data from 4 comparable studies [17, 33, 42, 77] published up to January 2013, showed an increased risk of white matter abnormalities in subjects with migraine with aura (PAEE 1.7; 95 % CI 1.1–2.7) and no association with migraine without aura [4]. More recently, data from the NOMAS indicated no association between migraine with or without aura and white matter hyperintensity volume [60]. Recently, an analysis of data from a subset of 506 subjects included in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) study, a placebo-controlled trial assessing effects by pravastatin on cardiovascular disease, was unable to demonstrate an association between migraine either with and without aura and white matter hyperintensities [2].

Two studies addressing the impact of migraine on white matter hyperintensities progression over time provided conflicting results [28, 66]. Data from the CAMERA study indicated that, after a mean follow-up of 8.5 years, migraine was associated with white matter hyperintensities progression (OR 2.1; 95 % CI 1.0–4.1) [66]. In contrast, data from the Atherosclerosis Risk in Communities (ARIC) cohort study involving 1,028 participants who received 2 magnetic resonance imaging 8–12 years apart was unable to demonstrate any difference in white matter hyperintensity progression over the time between individuals with and without migraine [28]. The available studies did not support the hypothesis that migraineurs with white matter abnormalities are at risk of cognitive impairment [42, 66, 73].

Infarct-like lesions appear as small infarcts on brain magnetic resonance imaging mostly in the absence of a clinical history of stroke. Their exact nature still remains elusive and they might be of a different nature rather than ischemic. Data from the CAMERA study indicated that migraine with aura was associated with an increased risk of posterior circulation (mostly cerebellar) infarcts (OR 13.7; 95 % CI 1.7–112), while the study was unable to demonstrate an association between migraine without aura and posterior circulation infarcts [33, 34]. Another population-based study in Reykjavik involving 4,689 participants indicated that subjects with migraine with aura had an increased risk of late-life infarct-like lesions (OR 1.4; 95 % CI 1.1–1.8) that specifically reflected an association with cerebellar lesions in women (OR 1.9; 95 % CI, 1.4–2.6) [89]. Migraine without aura and non-migraine headache were not associated with an increased risk. Data from the EVA study further supported an increased risk of infarct-like lesions in subjects with migraine with aura (OR 3.4; 95 % CI 1.2–9.3) [42]. However, in contrast to other studies, the results of the EVA study indicated that most of the infarcts were located outside of the cerebellum or the brain stem [42]. Data from the NOMAS indicated that those reporting migraine overall had double the odds of infarct-like lesions (OR 2.1; 95 % CI 1.0–4.2) when compared with those reporting no migraine [60]. Recently, data from the PROSPER study showed no association between migraine either with or without aura and infarct-like lesions [2]. With regard to migraine progression, data from the CAMERA study also indicated that migraine was not associated with the progression of infarct-like lesions over time [66].

Recently, an analysis of data from the PROSPER study evaluated the possible association between migraine with cerebral microbleeds [2]. These authors were unable to demonstrate overall an association between overall migraine and cerebral microbleeds. However, analysis stratified by migraine type and microbleeds location (lobar, basal ganglia, infratentorial) indicated an association between migraine without aura with infratentorial microbleeds (OR 3.3; 95 % CI 1.0–11.0) [2].

Several monogenic diseases have been recognized that include both migraine and cerebrovascular disease in the disease spectrum, and this represents further evidence of shared mechanisms between the two conditions [81]. Those diseases are represented by cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), mitochondrial encephalopathy lactic acidosis with stroke-like episodes (MELAS), autosomal dominant retinal vasculopathy with cerebral leukodystrophy (AD-RVCL), and hereditary infantile hemiparesis, retinal arteriolar tortuosity and leukoencephalopathy (HIHRATL).

CADASIL is due to a mutation of the Notch3 gene on chromosome 19. It is characterized by migraine with or without aura, mood disturbances, TIA, or strokes (usually lacunar infarcts) and progressive cognitive decline; other less common clinical features are epilepsy, acute reversible encephalopathy, and myopathy. Migraine is very common in CADASIL and it is often the presenting symptom [103]. Subjects may have typical attacks of migraine with aura but atypical auras are particularly common [80].

MELAS is due to a mutation at position 3243 of the mitochondrial genome [95]. It is characterized by seizures, encephalopathy, stroke-like episodes, migraine mostly associated with vomiting and aura, short stature, cognitive impairment, depression, cardiomyopathy, cardiac conduction defects, and diabetes mellitus.

AD-RVCL is due to TREX1 mutation on chromosome 3 and is characterized by systemic microvasculopathy with adult-onset retinal vasculopathy and cerebrovascular disease variably associated with migraine, mainly without aura [32].

HIHRATL is due to a mutation in the COL4A1 gene on chromosome 13 [45]; the disease has some similarities with CADASIL and is characterized by features of cerebral small-vessel disease, including subcortical hemorrhagic and ischemic lacunar strokes and leukoaraiosis. Patients usually suffer also from migraine mostly with aura, seizures, infantile hemiparesis, developmental delay, neuropsychological abnormalities, and ocular, renal, and cardiac involvement.