Describe the pathophysiology of migraine.

List diagnostic criteria for migraine without aura.

Identify patients with migraine with aura who may require a complete neurologic work-up.

Recognize tension headaches.

Select agents for migraine prevention and early intervention.

Roger K. Cady, MD
Adjunct Professor, Missouri State University, and Director and CEO, Headache Care Center, Springfield

Epidemiology of migraine: in general population, migraine occurs more commonly in women than in men (18% vs 5%-6%); 25 to 45 million migraine sufferers in United States; ≈50% of migraine inadequately diagnosed; ≈4 million Americans suffer from chronic daily headache; high cost (estimates up to $30 billion/yr), including indirect cost (eg, missed work or time spent with family); ≈37% of women who seek care at primary care practices have migraine; tension headache most common primary headache diagnosis, but people with episodic tension headache rarely seek medical care; headache that becomes medical concern, “almost inevitably is migraine”; diagnosis difficult because migraine often associated with other conditions (eg, fibromyalgia, anxiety)

Primary headache disorders: headaches with no identifiable cause (eg, tumor, vascular anomaly, trauma); migraine—with aura; without aura (episodic or chronic); tension—episodic (infrequent or frequent); chronic; cluster— episodic; chronic

Genetic predisposition: migraine triggered by factors that do not produce headache in general population (eg, alteration in weather, change in diet or sleep patterns); inheritance of sensitive (“very vigilant”) nervous system leaves patients prone to migraine; genetic factors remain unclear; 80% of people with migraine have first-degree relative with migraine; identical twins twice as likely as fraternal twins to have migraine; some rare types of migraine (eg, familial hemiplegic migraine) associated with gene mutations (in, eg, chromosomes 19 and 1) that affect ion channels and hyperexcitability of neurons and glial cells

“The migraine brain”: modulation occurs between excitatory and inhibitory neurotransmitters; migraineurs have particularly hyperexcitable brains; unique sensitivity to stimuli—studies of evoked potentials show lower threshold for and longer duration of activation; central nervous system (CNS) hyperexcitable during and between attacks of migraine (may be adaptive feature); approach to management—bring out patient’s assets and attributes (eg, conscientiousness, awareness of environment, problem-solving abilities) while controlling tendency to have attacks of migraine

Chronicity: attacks typically episodic; many migraineurs self-manage headaches (with, eg, over-the-counter [OTC] agents) and do not seek medical advice; some patients have lower threshold for headache (OTC agents in- effective); without proper management, migraine becomes chronic disease

Environmental factors: migraine threshold—environment exacerbates genetic vulnerability; nervous system affected by protective factors and risk factors; many patients understand concept of triggers (eg, chocolate); combination of factors creates environment that stimulates migraine; important to understand and modify interaction between environmental triggers and nervous system; risk factors—stress and letdown from stress; hormonal changes (eg, decreases in estrogen); diet (eg, nitrates, monosodium glutamate) and skipping meals; sleep disruption; weather change; minor head trauma; protective factors—regular healthy meals; regular wake and sleep times; daily exercise; stress management (eg, recreation, massage, exercise); menopause

Phases of migraine: preheadache (prodrome)—premonitory period; aura; events that occur in nervous system before onset of headache; headache—1) mild phase; highest benefit from treatment; 2) moderate to severe phase; postdrome—headache gone, but residual symptoms persist; sense of vulnerability (eg, fear of migraine returning); phase adds to disability of migraine; duration of phases—moderate to severe headache lasts 4 to 72 hr; premonitory period lasts 12 to 24 hr; aura lasts <60 min; postdrome lasts up to 24 hr; not uncommon for attack of migraine to last 4 to 5 days

Pathophysiology: genetically sensitive brain tries to adjust to interactions with environment; if brain cannot adjust sufficiently, symptoms emerge; premonitory symptoms—changes in mood (eg, anxiety, irritability, depression); changes in sensory processing (eg, lights appearing brighter than normal or greater awareness of noise or smell); fatigue; change in cognition (eg, forgetfulness); food cravings; muscle pain and tenderness (particularly in head and neck); autonomic symptoms (eg, nasal congestion); yawning; progression of migraine—activation in brainstem (“migraine generator”); changes in sensory processing and activation in areas of midbrain; electrical disruption; electrical instability moves across brain (spreading cortical depression) with associated vascular changes; gives rise to aura (theorized that electrical events activate trigeminal afferents in meninges during migraine)

Pain: branches of trigeminal nerve—ophthalmic branch (enervates forehead; integrates vasculature of meninges); maxillary branch (enervates midface and sinuses); mandibular branch (enervates jaw and temporalis muscles); all three branches have potential to contribute sensory information to brain during migraine; ophthalmic branch—most commonly associated with migraine; when meningeal blood vessels (wrapped in network of nerve cells and fibers) activated, vasoactive peptides (eg, calcitonin gene-related peptide [CGRP], substance P, neurokinins) released; release of inflammatory mediators leads to dilatation of blood vessels, extravasation of plasma, and lowering of sensory threshold of trigeminal afferent (ie, “sensory generator” created); extension of blood vessel by, eg, bending down to tie shoe, leads to intensification or awareness of pain; transmission travels through trigeminal nerve and enters brainstem and trigeminal nucleus caudalis (group of nuclei that filter sensory information); altered inhibition that occurs during migraine allows more sensory information to reach processing centers of brain; cervical nerve roots—sensory nerve roots C2 and C3 (in area of brainstem) provide sensory information from musculature of head and neck; during migraine, information from C2, C3, and trigeminal nerve branches integrated in nucleus caudalis; central sensitization—progression from peripherally driven condition to centrally maintained pain syndrome; migraine becomes increasingly difficult to treat; pain becomes throbbing; sensitization can occur quickly; patients may develop allodynia (normally benign stimuli [eg, light, noise] registered as pain)

Limbic influences: migraine pain not limited to somatosensory pain; emotional pain (eg, from death of spouse or parent) may contribute; limbic (emotional) pathways involved in clinical presentation and symptoms of migraine; limbic cortex—group of nuclei that innervate frontal areas; involved in pain memory and fight or flight response; integrated with somatosensory process; limbic system sets “level of vigilance” of nervous system; descending pathways into midbrain may amplify or diminish pain; symptoms (eg, anxiety, fear) can become part of migraine

Types of migraine: with aura—15% to 20% of migraines; without aura—75% to 80% of migraines; episodic or chronic; not uncommon for patients to have both types (with and without aura)

International Headache Society (IHS) criteria: migraine without aura—recurrence (≥5 attacks); headache lasts 4 to 72 hr; headache associated with ≥2 of 4 qualities (unilaterality; moderate to severe pain; aggravation by or avoidance of physical activity; throbbing sensation); nausea and/or vomiting or photophobia and phonophobia occur during headache; common symptoms not listed in IHS criteria include muscle pain and tenderness and autonomic activation (eg, nasal congestion, rhinorrhea); symptoms not attributable to underlying disease

Chronic migraine: migraine occurring ≥15 days/mo for 3 to 4 consecutive months; chronicity develops as complication of episodic migraine; new criteria—headache present ≥15 days/mo; migraine features present ≥8 of 15 days, or headache responds to migraine-specific medications; tension headache or probable migraine may occur during remaining 7 days; definition involves patient features and pattern of headache rather than specific presentations; medication overuse—use of acute medications for 10 to 15 days can be etiologic factor in transforming migraine; improvement with medication withdrawal no longer required criterion; use of opioids, combination analgesics, triptans, or ergotamines for ≥10 days/mo or simple analgesics for ≥15 days/mo increases risk

Migraine with aura: auras—most visual (eg, dissimilating lights) with positive and negative features; somatosensory auras (eg, paresthesias, numbness) occur in 15%; tend to march (ie, visual auras start in center and progress to periphery; somatosensory auras start in fingers and move up arm); as aura subsides, areas that were first involved are first to improve; worrisome auras—warrant complete neurologic work-up; motor symptoms during aura; brainstem symptoms (eg, tinnitus, dizziness) as significant features of aura, as in, eg, basilar migraine; prolonged (>60 min) duration; atypical aura (eg, hallucinations, seizures)

Migraine diagnosis: stable pattern of disabling headache that disrupts function should be considered migraine until proven otherwise; migraine not necessarily diagnosis of exclusion; pattern of migraine stable for ≥6 mo; 80% of cases of disabling headaches with nausea meet IHS criteria (95% of cases with 2-3 associated symptoms meet criteria); 1990 study showed that 50% of people with migraine did not have physician diagnosis (results did not change after 10 yr); diagnosis difficult due to spectrum of migraine (eg, tension headaches; migraine associated with sinus symptoms, menstruation, stress, or allergy)

Tension headache: bilateral; nonpressing; mild to moderate severity; does not produce severe disability; patients not likely to seek medical advice unless headache becomes chronic; common diagnosis; variable frequency; chronic—associated symptoms (eg, nausea, photophobia, phonophobia) similar to those of migraine; pain more intense; probable migraine—“basically migraine, missing one symptom”; response similar to that of migraine; migraineurs with tension headache respond to triptans

Migraine patients: 1) patients with recurrent self-limited attack of headache, nausea, sensory sensitivity lasting 24 to 48 hr; patients return to normal function; 2) patients do not return to normal function (eg, have persistent low- grade headaches between migraine attacks); patients with chronic migraine—may develop depression, anxiety, sleep disruption, aches and pains, or other medical conditions; often use multiple medications; physiologic disruption— sleep disturbances; gastrointestinal (GI) complaints; muscle complains; fibromyalgia; depression; patterns— infrequent episodic migraine; frequent episodic migraine (never becomes chronic); transforming (changes between frequent and infrequent); chronic persistent migraine (severely disabling); important to understand where patients exist in spectrum

Assessing comorbidity: treat migraine and comorbidities separately; with first episode of comorbidity, use pre- ventive approach for 3 to 6 mo (third episode suggests chronic condition); multiple diseases may be involved and have important management implications

Treatment: consider pattern and comorbidity; determine whether treatment should treat attacks or prevent attacks; analyze episode and stage of migraine; stage 1—focus on treatment of acute attack; intervene early; consider lifestyle modifications; stage 2—encourage patient participation (eg, keeping headache diary); control acute attacks; stage 3—symptoms often suggest comorbidities (identify and treat); chronicity increases; stage 4—manage chronic migraine (education cornerstone of successful management); general issues—form partnership with patient; understand role of preventive medicines, lifestyle, and adherence; importance of early intervention—treating attacks before pain has progressed improves efficacy of drugs; efficacies of triptans, aspirin, metoclopramide, ergotamine, and caffeine best with early use; once migraine becomes centrally propagated, patients become resistant to oral triptans; study found 15 min of face-to-face patient education on early intervention increased efficacy of medical therapy from 61% to 72%; management goals—crucial to set goals with patients; identify and reverse episode of migraine; minimize functional impairment associated with acute attack

Preventive therapy: protects nervous system from vulnerability to migraine; can be used daily or during well-defined time of vulnerability (eg, menstruation); options include tricyclic antidepressants, β-blockers, and neuronal stabilizers; short-term use—nonsteroidal anti-inflammatory drugs (NSAIDs; eg, naproxen); triptans (eg, sumatriptan, naratriptan, frovatriptan); some studies on ergotamines; managing comorbidities—do not assume treatment with one drug or one dose sufficient to manage migraine and comorbid conditions; behavioral therapy—essential adjunct to pharmacotherapy; education empowers patient