Curr Neurol Neurosci Rep (2015) 15:5 DOI 10.1007/s11910-015-0530-8 HEADACHE (RB HALKER, SECTION EDITOR) Dissecting the Association Between Migraine and Stroke Andrea M. Harriott & Kevin M. Barrett # Springer Science+Business Media New York 2015 Abstract Migraine is a common disabling neurological dis- Introduction order resulting from excessive cortical excitation and trigeminovascular afferent sensitization. In addition to aber- Migraine is a common neurological condition characterized rant neuronal processing, migraineurs are also at significant by recurrent unilateral headaches of moderate to severe inten- risk of vascular disease. Consequently, the impact of mi- sity lasting 4–72 h in duration. The pain is often pulsatile in graine extends well beyond the ictal headache and includes quality and associated with nausea, vomiting, and sensitivity a well-documented association with acute ischemic stroke, to light and sound. Migraines can be heralded by visual aura in particularly in young women with a history of migraine with addition to other somatosensory, vestibular, motor, and aura. The association between migraine and stroke has been speech-related disturbances [1–4]. Migraine impacts 15 to acknowledged for 40 years or more. However, examining 20 % of the general adult population, including approximately the pathobiology of this association has become a more 17 to 25 % of women and 6 to 10% of men [5–7]. Starting as recent and critically important undertaking. The diversity early as 12 years of age, the highest prevalence of migraine is of mechanisms underlying the association between migraine amongst persons 20 to 50 years of age [6, 8]. The social, and stroke likely reflects the heterogenous nature of this economic, and psychological burden of migraine alone can disorder. Vasospasm, endothelial injury, platelet aggregation be devastating. In addition to the medical costs related to and prothrombotic states, cortical spreading depression, ca- emergency room visits, indirect costs related to reduced work rotid dissection, genetic variants, and traditional vascular capacity and disability amplify the economic burden associat- risk factors have been offered as putative mechanisms in- ed with migraine [6, 9, 10]. volved in migraine-related stroke risk. Assimilating these Comorbid conditions accompanying migraine are worthy seemingly divergent pathomechanisms into a cogent under- of clinical and scientific attention because they contribute to standing of migraine-related stroke will inform future studies significant disability and death in the migraine population. A and the development of new strategies for the prevention number of epidemiologic studies support the observation that and treatment of migraine and stroke. migraine is independently associated with acute ischemic stroke. Stroke is a major disabling neurological event with 795,000 new and recurrent cases diagnosed yearly, and is Keywords Migraine . Acute ischemic stroke . Migraine the fourth leading cause of death in the USA [11]. The average genetics . Cortical spreading depression . Endothelial age of stroke onset is 60 to 70 years [12, 13]. However, a dysfunction minority of strokes occur in young individuals less than 45 years of age and with fewer modifiable vascular risk factors This article is part of the Topical Collection on Headache (e.g., hypertension, hyperlipidemia, and diabetes mellitus). While this population appears to have fewer identified modi- * : A. M. Harriott ( ) K. M. Barrett fiable risks, the rate of long-term mortality is higher than Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA would be expected [14] and they remain at risk of recurrent e-mail: [email protected] stroke [15, 16]. That migraine, particularly migraine with au- K. M. Barrett ra, has been identified as a non-modifiable risk factor for e-mail: [email protected] stroke in this otherwise relatively healthy younger population 5 Page 2 of 14 Curr Neurol Neurosci Rep (2015) 15:5 raises important fundamental questions about the cerebrovas- 44 years was associated with acute ischemic stroke with an cular, metabolic, and neurobiological mechanisms underlying odds ratio (OR) of 3.5 (95 % confidence interval (CI) 1.8–64). this association. The purpose of this article is to review the The association was greater in the migraine with aura (OR 6.2, relationship between migraine and acute ischemic stroke, the 95 % CI 2.1–18.0) group compared to the migraine without potential mechanisms underlying this relationship, therapeutic aura (OR 3.0, 95 % CI 1.5–5.8) group [25]. The association options, and future research directions. between migraine with and without aura and stroke was rep- licated in another case-control study enrolling a similar num- ber of patients [27]. A study enrolling both men and women Migraine and Stroke: Defining the Clinical Problem (308 stroke cases and 591 age- and gender-matched controls) found a significant association between migraine with aura The Epidemiology of Migraine-Associated Stroke Risk and stroke (OR 8.6, 95 % CI 1.0–75) but not migraine without aura (OR 1.0, 95 % CI 0.5–2.0) [26]. A differential association Multiple cohort [17–20] and case-control [21–31] studies sub- between stroke and migraine with aura was replicated in a stantiate an association between migraine and acute ischemic study enrolling a similar number of cases and controls al- stroke. Migraine is an independent risk factor for acute ische- though the effect size in the latter study was more modest as mic stroke. A large cohort study of 63,575 individuals with a compared to other studies (migraine with aura OR 1.5, 95 % documented history of migraine and 76,936 individuals with- CI 1.1–2.0) [23, 28]. out migraine followed over a 33–35-month period found that The variability in the strength of association across individ- those with migraine were at 2.5 times greater risk of developing ual studies may reflect differences in sample size and head- acute ischemic stroke compared to those without migraine [17]. ache classification. Additionally, there may be differences in A consistent association between migraine and stroke has patient selection and diagnostic criteria for stroke. Despite been observed in multiple case-control studies, particularly in these limitations, the consistent association in multiple study the cryptogenic stroke population aged less than 45 years with populations is compelling. Multiple meta-analyses estimate a a gender-based predilection for women (Table 1)[17, 19, pooled adjusted twofold risk of stroke in migraineurs as com- 23–28, 32–37]. In a case-control study that included 72 stroke pared to non-migraineurs [32, 38–39, 40•]. It is important to cases and 173 matched controls, migraine in women aged 18– mention that the strokes migraineurs suffer can have a Table 1 Case-control studies: the association between migraine and acute ischemic stroke in the young Study AIS (n)Ctrl(n) Gender Age Migraine Migraine and other variables All migraine MwA MwoA OCP Smoking OR 95 % CI OR 95 % CI OR 95 % CI OR 95 % CI OR 95 % CI [22] 140 451 Women 15–44 2.0 (1.2–3.3) 5.9 (2.9–12.2) [23] 89 178 Both 15–65 1.8 (0.9–3.6) 2.6 (1.1–6.6) 1.3 (0.5–3.6) [24] 212 212 Both 18–80 1.3 (0.8–2.3) Women <45 4.3 (1.2–16.3) 10.2 (1.1–93.3) [25]72173Women18–44 3.5 (1.8–6.4) 6.2 (2.1–18.0) 3.0 (1.5–5.8) 13.9 (5.5–35.1) 10.2 (3.5–29.9) [26] 308 591 Both 15–44 1.3* (0.7–2.4) 8.6 (1.0–75) 1.0 (0.5–2.0) [29] 366 219 Men 16–60 2.12 (1.05–2.95) [27]87220Women20–44 3.54 (1.30–9.61) 3.81 (1.26–11.5) 3.0 (0.66–13.5) 16.9 (2.72–106.0) 7.39 (2.14–25.5) [21]86214Women20–44 4.61a (1.27–16.8) [30] 626 4054 Women 15–44 3.2b (2.5–4.2) [31] 190 1129 Women 15–49 2.33 (1.04–5.21) [28] 386 614 Women 15–49 1.5 (1.1–2.0) 1.0 (0.6–1.5) 7.0 (1.3–22.8)c *p>0.05 a Migraine for greater than 12 years duration b Includes transient ischemic attack c Combined effect of smoking and oral contraceptive, either alone did not produce a significant effect. OR and CI were not available for smoking alone and oral contraceptive use alone Curr Neurol Neurosci Rep (2015) 15:5 Page 3 of 14 5 significant impact on morbidity and mortality [41]. However, contraceptive use on migraine-associated stroke risk requires in a prospective cohort study of 27,852 women aged added investigation. >45 years, women with a history of migraine with aura and stroke had a two times greater likelihood of having a modified Migraine-Related Stroke Versus Migrainous Infarction Rankin Scale score between 0 and 1, suggesting the possibility for good functional outcomes in this population [42]. Migraine-associated stroke can be subdivided into two general categories: migraine-related stroke and migrainous infarction (See Fig. 1a, b). Migraine-related stroke is defined as an Influence of Oral Contraceptive Use and Cigarette Smoking interictal stroke occurring in a person with a history of mi- graine. In contrast, migrainous infarction is diagnosed in There appears to be a substantial influence of cigarette migraineurs that experience prolonged aura lasting >60 min smoking and oral contraceptive use on the association be- with neuroimaging confirming an acute infarction in the brain tween migraine and stroke. Multiple studies have demonstrat- region likely responsible for the aura symptoms [53, 54]. One ed that smoking produces a greater than multiplicative in- example of migrainous infarction is a prolonged visual aura crease in the association between migraine and stroke.