Migraine and the menopause transition

WHAT IS THE EFFECT OF MIGRAINE IN MIDLIFE WOMEN? Migraine is a neurologic disorder affecting approximately 42 million people in the United States, with women being three times more likely to experience migraine than men.1 This higher incidence in women is thought to arise from hormone fluctuations2—most notably the “estrogen drop” associated with the menstrual cycle—as well as possible neuroanatomic differences such as a thicker insular cortex in women. This sex-linked discrepancy remains incompletely understood. The peak prevalence of migraine coincides with the reproductive years. Many women, however, report changes in migraine characteristics and severity during perimenopause, with a significant number experiencing increased migraine frequency and intensity.3 A previously stable migraine pattern, triggered by hormone fluctuations in the menopause transition, may become erratic and more refractory to treatment. Phenotypic changes such as the development of migraine aura—including visual and sensory symptoms, sometimes without headache—can also arise during this stage. Although migraine prevalence begins to decline after age 60, approximately 50% of women affected in midlife continue to experience migraine postmenopause.2,3 WHAT IS MIGRAINE VERSUS MIGRAINE WITH AURA? Migraine, a chronic neurologic disorder, is characterized by recurrent attacks of moderate to severe headache lasting 4 to 72 hours, typically accompanied by nausea, vomiting, photophobia, and phonophobia.4 A subset of patients experience migraine with aura, typified by transient neurologic symptoms such as visual disturbances (eg, shimmering lights, scotoma, or visual field cuts), sensory symptoms, or speech disturbances that typically precede the headache phase and last from 5 to 60 minutes. Aura can also occur without subsequent headache.4 WHAT IS THE PATHOPHYSIOLOGY OF MIGRAINE? Alterations in brain excitability and neurotransmitter release—particularly involving calcitonin gene-related peptide (CGRP) and serotonin—play significant roles in triggering the neuroinflammatory migraine cascade. Calcitonin gene-related peptide levels are highest during periods of lowest estrogen in menstruating women, which may help explain menstrual migraine.5 A positive family history is common, suggesting a hereditary component. Environmental and endogenous factors serve as triggers, including dietary factors, poor sleep, altitude fluctuations, and psychological stress. The ensuing neurovascular process can result in the spectrum of migraine-related symptoms. HOW IS MIGRAINE DIAGNOSED? Migraine remains a clinical diagnosis because there are no definitive biomarkers or imaging findings. Diagnosis is established by the criteria in the International Classification of Headache Disorders, third edition (ICHD-3).4 Migraine without aura requires at least five attacks, with headache lasting 4 to 72 hours; at least two specific pain characteristics (unilateral, pulsating, moderate to severe intensity, or aggravation by activity); and at least one associated symptom (nausea or vomiting or both photophobia and phonophobia). For migraine with aura, at least two attacks are required for diagnosis, with one or more fully reversible aura symptoms and at least three of six specific characteristics: gradual spread over 5 minutes or more; symptom duration of 5 to 60 minutes; one symptom unilateral; one symptom is positive (eg, scintillations); headache within 60 minutes; or two or more aura symptoms in succession.4 Positive (additive) neurologic symptoms in migraine with aura represent active neuronal excitation, manifesting as scintillations (flashing lights, zigzag patterns) or paresthesia (pins and needles tingling), whereas negative symptoms reflect neuronal dysfunction or suppression, presenting as scotomas, visual field loss, or numbness. Evaluating new-onset recurrent headache in women aged older than 50 years warrants particular vigilance to exclude secondary causes such as tumors, stroke, or giant cell arteritis. Neuroimaging (magnetic resonance imaging or magnetic resonance angiogram) in addition to laboratory tests (C-reactive protein and erythrocyte sedimentation rate) may be indicated. Retinal migraine, uniquely characterized by monocular visual loss, is a rare diagnosis of exclusion, and requires urgent initial investigation to rule out other causes including retinal vasospasm, embolic phenomena, optic neuritis, and other vascular disorders. The condition most commonly presents with monocular visual symptoms (blindness, scotoma, or scintillations), typically lasting less than 1 hour and occurring ipsilateral to the subsequent headache. Although ICHD-3 criteria require reversible visual loss, nearly half of patients with recurrent attacks may eventually experience permanent monocular visual loss, representing a potential ocular form of migrainous infarction.6 WHAT ARE THE CEREBROVASCULAR RISKS ASSOCIATED WITH MIGRAINE? Migraine with aura is independently associated with an approximately two-fold increased risk of ischemic stroke compared with no migraine.7 Cardiovascular risk factors are prevalent in patients with migraines, even at younger ages, and increasing age increases cardiovascular disease risk, so early vascular risk factor screening and modification is recommended. When treated with combined hormone contraceptives (CHCs), stroke risk of migraine with aura amplifies considerably; in women aged 20 to 44 years, the absolute risk of ischemic stroke increases from 2.5 per 100,000 in those without migraine and without combined hormonal contraception to 36.9 per 100,000 in those with migraine with aura using CHCs.7 The Centers for Disease Control and Prevention-US Medical Eligibility Criteria for Contraceptive Use classifies CHCs as category 4 (unacceptable health risk) for women with migraine with aura. Progestin-only contraceptives remain safe (category 1) for all women with migraine, regardless of aura status. WHAT IS THE EFFECT OF HORMONE THERAPY ON MIGRAINE? Although observational data suggest that stabilizing estrogen levels can benefit migraine during the perimenopause transition, clinical trial data demonstrating efficacy and safety are scarce. For symptom relief of menopause symptoms, transdermal estradiol is recommended because in observational studies, it provides more stable hormone levels with less cardiovascular risk than oral preparations.7 The amount of estrogen in hormone therapy may not contribute to a meaningful increase in stroke risk in women with migraine, despite the established stroke risk associated with migraine with aura and the known increased stroke risk from estrogen in combined hormone contraception.8 Improving vasomotor and affective symptoms, however, might indirectly influence migraine frequency and severity. If patients experience new or changing aura (longer, different visual patterns) after starting hormone therapy, it should be stopped immediately with prompt medical consultation. WHAT ARE THE MANAGEMENT OPTIONS FOR MIGRAINE? Migraine management strategies are both acute and preventive. Preventive therapy is generally indicated when migraines occur at least four times per month. Available options include Traditional medications: Propranolol, topiramate, and valproic acid, which are FDA-approved for migraine prevention. Each has a unique side effect profile relevant for midlife women (eg, weight gain and hair loss with valproic acid; cognitive dysfunction with topiramate; fatigue with propranolol). Targeted therapies: Monoclonal antibodies targeting CGRP, administered monthly or quarterly, and oral CGRP antagonists (gepants) offer favorable efficacy and tolerability.9 Adverse events may include constipation, hypertension, or worsening Raynaud's disease, but these drugs are considered safe for those with cardiovascular histories. Integrative therapies: Acupuncture and other nonpharmacologic strategies may be beneficial adjuncts. It is essential to exclude pregnancy before starting newer antimigraine agents because safety in this population is undetermined. Acute therapies are used for aborting attacks at onset. These include triptans (eg, sumatriptan, eletriptan), new generation gepants, and nonsteroidal anti-inflammatory agents (eg, ibuprofen, celecoxib). The newer gepants provide rapid relief with fewer side effects compared with traditional triptans. Caution is necessary to avoid medication-overuse headache (“chronification”) with frequent use of acute medications.8 For chronic migraine (>15 headache days/mo, 8 of which are migrainous for ≥3 mo), onabotulinumtoxinA is FDA-approved for prevention and is generally safe and well-tolerated, including in those with vascular risk factors. KEY SUMMARY POINTS Migraine is a common neurologic disorder with disproportionate effect on women, including elevated stroke risk. Presentation characteristics may change over time, especially during perimenopause. Diagnosis of new-onset migraine requires exclusion of secondary causes, particularly in midlife and older women. There is no robust evidence supporting hormone therapy solely for migraine control in perimenopausal and postmenopausal women, although management of common menopause symptoms with hormone therapy might improve migraine. Safe and effective pharmacologic and integrative options are available to treat migraine. Migraine prevalence declines after age 60 but persists in approximately half of affected women. CLINICAL RECOMMENDATIONS Evaluate new or changing headache-associated symptoms in midlife and older women; educate regarding signs and symptoms of stroke and the ongoing need to manage concurrent cardiovascular risk factors such as hypertension, smoking, and excess weight. Investigate any change in pattern or severity of migraine during the menopause transition or thereafter with brain imaging and levels of inflammatory markers. Counsel patients that although transdermal estradiol (preferred therapy with micronized progesterone or a levonorgestrel intrauterine device) will not reliably treat migraine, it may provide symptom improvement by addressing other triggers. Educate that migraine is a complex neurobiologic disorder that can be effectively managed—patients are not at fault for their condition. Coming next in theStep-by-Stepseries: Chrisandra Shufelt, MD, MS, FACP, MSCP, professor and chair of the Division of General Internal Medicine at Mayo Clinic in Jacksonville, Florida, explains the various cardiometabolic changes that occur in the menopause transition and the effect of hormone therapy on those changes.This article is part of the ongoing series Menopause Step-by-Step, a monthly Menopause education feature.10 The Editors of this series are Dr. Cynthia Stuenkel, Dr. Cheryl Cox Kinney, and Dr. Isaac Schiff.