12/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate CADASIL [112,113] (see "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)", section on 'Migraine with aura') Some of these conditions may present with headaches that have migrainous features. Patients with cerebral AVMs may present with migraine-like attacks that lateralize to the same cerebral hemisphere [105,106,114]. Migraine-like headaches are a frequent and early manifestation of both SMART syndrome and CADASIL and may be the sole symptom in some patients. Other conditions in the differential diagnosis of stroke are reviewed elsewhere. (See "Differential diagnosis of transient ischemic attack and acute stroke".) Migraine coincidental with stroke Migraine or other headache may occur coincidentally with stroke since both are common conditions. With advancing age, the prevalence of migraine decreases, while that of stroke increases. In addition, stroke risk factors such as hypertension, diabetes, and heart disease are more common in older age groups. Migraine and stroke may occur together as presenting features of or covariables for other conditions such as antiphospholipid antibody syndrome and CADASIL. (See 'Mechanisms' above.) Management The general approach to the acute stroke treatment of patients with migraine is similar to other patients without migraine. Acute stroke management is discussed in detail separately. (See "Initial assessment and management of acute stroke", section on 'Ischemic stroke management'.) Treatment aimed at primary or secondary stroke prevention in patients with migraine or nonspecific headache is not well studied, but an approach combining stroke risk factor control with migraine prophylaxis seems most reasonable. Patients with additional stroke risk factors such as hypertension, tobacco use, or high-estrogen-containing oral contraception should be informed about the increased stroke risk, and efforts should be taken to minimize risks. Education Patients with migraine should be taught to recognize the early warning signs of stroke to prevent confusion between migraine aura and TIA ( table 1) and to seek appropriate intervention. Similarly, clinicians should be aware of the potentially increased risk of stroke in the migraine population and should not dismiss focal symptoms in their evaluation of these patients. (See "Differential diagnosis of transient ischemic attack and acute stroke", section on 'Distinguishing transient attacks'.) Managing medications Specific medication management strategies for patients with stroke and migraine are discussed below. (See 'Managing medications that impact stroke risk' below.) https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 13/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate General preventive therapy for stroke and treatment of migraine are discussed in greater detail separately. (See "Overview of primary prevention of cardiovascular disease".) (See "Overview of secondary prevention of ischemic stroke".) (See "Acute treatment of migraine in adults".) (See "Preventive treatment of episodic migraine in adults".) OTHER MIGRAINE-ASSOCIATED CEREBROVASCULAR MANIFESTATIONS Intracerebral hemorrhage Most studies have reported on the association between migraine and ischemic stroke. However, migraine has been identified as a possible risk factor for other cerebrovascular conditions, including intracerebral hemorrhage [23]. The relationship of migraine with intracerebral hemorrhage is supported by a meta-analysis of eight studies (four case-control and four cohort), which found that the overall pooled effect estimate of hemorrhagic stroke was 1.48 (95% CI 1.16-1.88) for subjects with any migraine [115]. Subclinical brain lesions Several prospective population-based studies have found an association between migraine with aura and silent infarct-like lesions on brain MRI [11,60,116- 118]. However, the etiology, nature, and clinical significance of the MRI lesions reported in these studies remains unclear [118,119]. Two patterns of brain lesions have been associated with migraine with aura: Infarct-like lesions in the posterior circulation territory In a population-based study of 4689 subjects from Iceland, subjects were evaluated at a mean age of 51 years and then reevaluated at a mean age of 76 years by interview and brain MRI. Those subjects who reported migraine with aura at the initial evaluation had an increased risk of infarct-like lesions 25 years later (adjusted odds ratio [aOR] 1.4, 95% CI 1.1-1.8) [117]. This result was driven mainly by an increased risk of cerebellar infarct-like lesions in the subgroup of females who had migraine with aura (odds ratio [OR] 1.9, 95% CI 1.4-2.6). Migraine with (but not without) aura was also associated with an increased risk for subclinical posterior circulation territory infarct-like lesions in a cross-sectional study of Dutch adults aged 30 to 60 years [116]. Most lesions were in the cerebellum. In another study report, patients with migraine had a significantly increased prevalence of small infratentorial hyperintense lesions, most located in the mid-pons [120]. White matter lesions - A 2013 systematic review and meta-analysis of four clinic-based case-control studies found that white matter lesions were more common in subjects with https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 14/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate migraine compared with controls [118]. The association was significant for migraine with aura (OR 1.68, 95% CI 1.07-2.65) but not for migraine without aura (OR 1.34, 95% CI 0.96- 1.87). By contrast, a subsequent population-based study found that severe white matter disease was associated with migraine without aura (OR 1.87, 95% CI 1.04-3.37) but not with migraine with aura (OR 0.55, 95% CI 0.17-1.83) [121]. In this study, a history of migraine was not associated with white matter lesion progression over time [121]. MANAGING MEDICATIONS THAT IMPACT STROKE RISK Indications for antithrombotic therapy The indications for antithrombotic therapy are not impacted by migraine, either with or without aura. Primary prevention Primary prevention of stroke with aspirin or other antiplatelet therapy is not warranted for patients with migraine with or without aura in the absence of cardiovascular risk factors. (See "Aspirin in the primary prevention of cardiovascular disease and cancer", section on 'Assessing benefits and risks'.) Secondary prevention Secondary stroke prevention with antiplatelet or anticoagulant medications is warranted for patients with and without migraine who have a history of transient ischemic attack (TIA) or stroke. (See "Overview of secondary prevention of ischemic stroke", section on 'Antithrombotic therapy'.) Use of estrogen-containing therapies While estrogen-containing therapies are associated with an increased risk of venous thromboembolism and ischemic stroke, these medications can be used safely in many patients with migraine depending on the migraine characteristics (no aura), estrogen indication (contraception or therapy for menopause symptoms), dose, delivery (oral, transdermal), and relative benefits compared with risks. However, estrogen-containing medications are typically avoided in patients with migraine with aura who have a history of stroke or are at elevated risk for cardiovascular disease, including stroke. The cardiovascular impact of estrogen-containing contraceptives is reviewed separately. (See "Combined estrogen- progestin contraception: Side effects and health concerns", section on 'Cardiovascular effects'.) Hormonal contraception The decision to start or continue estrogen-containing contraceptive therapy in patients with migraine involves shared decision making after discussing individual risks and benefits of therapy and alternative options. Estrogen-containing contraceptives include oral pills, transdermal patches, and vaginal rings ( figure 1). (See "Contraception: Counseling and selection".) https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 15/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate Without aura Patients experiencing migraine without aura who are otherwise candidates for estrogen-containing contraception can safely use estrogen-containing contraceptives, including oral pills, transdermal patches, and vaginal rings [122-124]. If contraceptive pills are selected, formulations containing 35 mcg of ethinyl estradiol, or the equivalent, are preferred ( table 2). Patients who elect estrogen-containing contraceptives should be younger than 35 years if they are smokers and do not have other cardiovascular, thromboembolism, or stroke risk factors [122-124]. Detailed discussions, including supporting data, on candidates and risks related to estrogen-containing contraception are presented separately. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use", section on 'Candidates'.) (See "Combined estrogen-progestin contraception: Side effects and health concerns".) With aura Individuals with aura are generally not candidates for estrogen-containing contraceptives [28,122-125]. However, high-quality studies specific to low-dose estrogen products are lacking [31]. Therefore, the use of estrogen-containing contraception in patients with aura should be individualized. For those with a clear indication for estrogen- containing contraceptives, such as endometriosis or those who desire this method after a clear discussion of the risks, their use may be reasonable. Presentation of the data regarding candidates for estrogen-containing contraception, contraindications, and risks associated with use are discussed separately. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use".) (See "Combined estrogen-progestin contraception: Side effects and health concerns".) Consideration of other medical conditions We and other experts use comprehensive tables of medical conditions and personal characteristics from the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) to counsel patients regarding safe use of the various hormonal methods of contraception [122,123]. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use", section on 'Candidates'.) Menopausal hormone therapy Concerns have been raised that estrogen-containing hormone therapy for symptoms of menopause may increase stroke risk. However, available data conflict, in part because of variables such as patient age and medical comorbidities as well as https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 16/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate estrogen dose and route of administration. These issues are reviewed in detail in related content. (See "Menopausal hormone therapy and cardiovascular risk".) The safety of menopausal hormone therapy, either estrogen alone or estrogen plus progestin, in patients with migraine varies by migraine type and the patient s thromboembolic risk. Patients who should avoid estrogen We avoid estrogen-containing menopausal hormone therapy for patients with migraine with aura and a history of stroke or those at high risk (eg, >10 percent 10-year risk) for cardiovascular disease including stroke (calculator 1). For these patients, we use nonhormonal options that are not associated with an elevated risk of thromboembolic complications. (See "Menopausal hot flashes", section on 'Nonhormonal pharmacotherapy'.) Estrogen use acceptable Menopausal estrogen therapy is acceptable for patients with migraine with or without aura and otherwise at low risk of cardiovascular disease (ie, 10 percent 10-year risk). The rationale is that the estrogen therapy for menopausal symptoms is not a supraphysiologic dose (as it is with estrogen-containing contraceptives). (See "Menopausal hormone therapy: Benefits and risks".) (See "Treatment of menopausal symptoms with hormone therapy".) Additional discussion on use of estrogen therapy in peri- and postmenopausal patients with migraine is discussed separately. (See "Estrogen-associated migraine headache, including menstrual migraine", section on 'Peri- and postmenopause'.) Medications to avoid Some medications are avoided in those who have migraine with aura and a history of stroke, TIA, or cardiovascular disease due the risk of cerebral ischemia. These include vasoconstrictive medications: Triptans Ergotamine derivatives Serotonin antagonists (eg, pizotifen and methysergide) In a case-control study of patients prescribed ergotamine or triptans, 188 patients hospitalized with ischemic events were age and sex-matched with 689 controls. Ergotamine overuse was a risk factor for ischemic complications (odds ratio [OR] 2.55, 95% CI 1.22-5.36); but triptan overuse was not [126]. However, cases of cardiac arrest, cerebral infarcts, and spinal cord infarcts have been reported in the setting of triptan use [127-131]. https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 17/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate We also avoid long-term use of nonsteroidal antiinflammatory drugs (NSAIDs) in older patients and in patients with other uncontrolled risk factors for stroke due to the elevated risk of thrombotic cardiovascular events [132]. (See "NSAIDs: Adverse cardiovascular effects", section on 'NSAIDs and cardiovascular events'.) We suggest that beta blockers should not be used as initial therapy for migraine prophylaxis in patients over age 60 years and in patients who smoke. Compared with other antihypertensive drugs in the primary treatment of hypertension, beta blockers may be associated with a higher rate of stroke and other cardiovascular events. (See "Choice of drug therapy in primary (essential) hypertension".) The safety of calcitonin gene-related peptide antagonists has not been established for patients with a migraine with aura and a history of or uncontrolled risk factors for stroke [133,134]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Stroke (The Basics)" and "Patient education: Medicines after an ischemic stroke (The Basics)" and "Patient education: Migraines in adults (The Basics)") https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 18/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate Beyond the Basics topics (see "Patient education: Migraines in adults (Beyond the Basics)" and "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)" and "Patient education: Ischemic stroke treatment (Beyond the Basics)"). SUMMARY AND RECOMMENDATIONS Migraine-associated ischemic stroke Epidemiology The reported incidence of stroke due to migraine (migrainous stroke) ranges from 0.8 to 3.4 per 100,000 per year. Clinical factors associated with an elevated risk of stroke in patients with migraine include (see 'Modifiers of risk' above): - - - - Patients with migraine with aura Female patients Patients who smoke Patients who take estrogen-containing contraception Patients age <45 years Clinical and imaging findings Clinical symptoms of migraine-associated stroke are typically similar to previous migraine aura without new or atypical symptoms. However, the previously transient aura symptoms persist for longer duration. Infarction is frequently located in the posterior circulation and may be multifocal. (See 'Clinical and imaging findings' above.) Diagnosis Migrainous infarction occurs in a patient with migraine with aura that is typical of previous attacks except that one or more aura symptoms persists for >60 minutes. Neuroimaging demonstrates ischemic infarction in a relevant area. (See 'Diagnostic criteria' above.) Differential diagnosis Both cerebrovascular events and migraine attacks can present as acute transient neurologic events with similar symptoms ( table 1). In addition, acute neurologic symptoms that are persistent may also be caused by either migraine or stroke. Management The general approach to the acute stroke treatment of patients with migraine is similar to other patients without migraine. Treatment aimed at primary or secondary stroke prevention in patients with migraine involves combining stroke risk factor control with migraine prophylaxis. Patients should be taught to recognize the https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 19/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate early warning signs of stroke to prevent confusion between migraine aura and transient ischemic attack (TIA) ( table 1) and to seek appropriate intervention. (See 'Management' above.) Migraine and other stroke subtypes Migraine has been identified as a possible risk factor for other cerebrovascular conditions, including intracerebral hemorrhage and silent infarct-like lesions on brain MRI. (See 'Other migraine-associated cerebrovascular manifestations' above.) Managing medications that impact stroke risk Antithrombotic therapy Primary prevention of stroke with aspirin is not warranted for patients with migraine with or without aura in the absence of cardiovascular risk factors. Secondary stroke prevention with antiplatelet or anticoagulant medications is warranted for patients with and without migraine who have a history of TIA or stroke. (See 'Indications for antithrombotic therapy' above.) Estrogen-containing therapies While estrogen-containing therapies are associated with an increased risk of thromboembolism, these medications can be used safely in select patients with migraine depending on the migraine characteristics (no aura), estrogen dose, and relative benefits compared with risks. (See 'Use of estrogen- containing therapies' above.) Hormonal contraception We suggest that patients with migraine with aura avoid estrogen-containing contraceptives (Grade 2C). We give similar guidance to patients with other forms of migraine and an additional risk factor for stroke. Patients who are nonsmokers <35 years, without aura, and have no additional thromboembolic risk factors may consider estrogen-containing contraceptives. If oral contraceptives are selected, we prefer formulations containing 35 mcg or less of estrogen. (See 'Hormonal contraception' above.) Menopausal hormone therapy We suggest that patients with migraine with aura and a history of stroke or at high risk for future cardiovascular disease (calculator 1) avoid estrogen-containing menopausal hormone therapy (Grade 2C). Menopausal estrogen therapy is acceptable for patients with migraine with or without aura who are at low risk of cardiovascular disease, including stroke (ie, 10 percent 10-year risk). (See 'Menopausal hormone therapy' above.) Migraine medications to avoid We avoid triptans, ergotamine derivatives, serotonin antagonists, and long-term use of nonsteroidal antiinflammatory drugs (NSAIDs) for https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 20/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate patients with migraine with aura and a history of stroke or cardiovascular disease. We do not use beta blockers for patients over age 60 years and those who smoke. 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