Migraine Headache

• Neurogenic inflammation hypothesis: Activation of trigeminal sensory neurons innervating intracranial meninges and blood vessels initiates migraine. Substance P, calcitonin gene-related peptide (CGRP), and other neuropeptides are released from trigeminal terminals, causing neurogenic inflammation characterized by vasodilation, plasma protein extravasation, and meningeal mast cell degranulation. CGRP plays a particularly central role—it is elevated during migraine attacks and contributes to both vascular and neuronal changes. Monoclonal antibodies targeting CGRP and its receptor have validated this pathway therapeutically.

• Cortical spreading depression (CSD): In migraine with aura, CSD represents a wave of neuronal and glial depolarization that propagates across the cerebral cortex at 3-5 mm/min, producing the characteristic visual, sensory, or motor symptoms of aura. CSD triggers trigeminal nociceptor activation and subsequent headache mechanisms. This explains why aura symptoms correlate with cortical topography and why migraine with aura carries specific vascular risk implications (see Complications).

• Brainstem-monoaminergic dysfunction: The dorsal raphe nucleus, locus coeruleus, and other brainstem regions show altered serotonergic and noradrenergic neurotransmission in migraineurs. Serotonin (5-HT) dysregulation appears bidirectional—migraineurs exhibit both central serotonin deficiency and abnormal receptor sensitivity. The trigeminovascular system connects brainstem pain-modulating regions to the trigeminal nucleus and meningeal afferents, integrating motor control, emotional processing, and nociception. Catecholamine sensitivity may explain migraine precipitation by stress and withdrawal (rebound) phenomena.

• Genetic and ion channel mechanisms: Twin studies demonstrate 50% heritability for migraine without aura and 60% for migraine with aura. Familial hemiplegic migraine (FHM), a rare autosomal-dominant subtype with motor weakness during aura, has revealed mutations in CACNA1A (Cav2.1 calcium channel), SCN1A (Nav1.1 sodium channel), and ATP1A2 (Na+/K+ ATPase) genes. These mutations impair neuronal excitability regulation, producing a "hyperexcitable brain" phenotype that facilitates both CSD and trigeminal activation. Common migraine variants identified via genome-wide association studies (GWAS) implicate genes affecting vascular function, ion transport, and glutamate signaling.

• Central sensitization: Repeated migraine attacks induce long-term potentiation-like changes in trigeminal nucleus and thalamic relay neurons, lowering pain thresholds and increasing headache frequency and severity (frequency escalation). This mechanism underlies chronic migraine progression and explains the rationale for preventive therapy to interrupt attack cycles.

Non-modifiable risk factors

• Female sex: Women are 2-3× more likely to suffer migraines than men; hormonal fluctuations (menstrual cycle, oral contraceptives, hormone replacement therapy) modulate migraine risk. Perimenstrual migraine occurs in 60% of women with migraine, typically 2 days before to 3 days after menses.
• Age: Migraine onset typically occurs between ages 10-40; prevalence peaks in the 40s-50s, with decline thereafter.
• Family history: Positive family history increases migraine risk ~3-fold; earlier onset and higher frequency associate with strong familial clustering.
• Genetic polymorphisms: MTHFR, ESR1, and other polymorphisms correlate with migraine susceptibility in population studies.

Modifiable triggers (attack precipitants)

• Hormonal: Estrogen fluctuation, oral contraceptives, hormone replacement therapy, menstruation.
• Environmental: Bright lights, loud sounds, strong odors, weather changes (barometric pressure), high altitude.
• Behavioral: Sleep deprivation or excess, skipped meals, dehydration, intense physical exertion, sexual activity.
• Dietary: Tyramine (aged cheeses, cured meats), monosodium glutamate (MSG), aspartame, nitrates (processed meats), caffeine withdrawal, alcohol (particularly red wine and beer).
• Psychological: Emotional stress, anxiety, depression; notably, migraines often occur during the "letdown" phase after stress resolution (weekend migraine).
• Medication-related: Vasodilators (nitrates, calcium channel blockers), hormone therapy, overuse of acute medications (medication overuse headache).
• Systemic factors: Infection, fever, menstruation, pregnancy, postpartum period.

Risk factors for migraine chronification

• Frequent episodic migraine (≥4 attacks/month)
• Female sex
• Obesity
• Sleep disorders
• Medication overuse
• Comorbid mood disorders
• Low socioeconomic status

Migraine without aura (classic presentation)

• Headache characteristics: Unilateral (60% of cases; 40% bilateral), pulsatile/throbbing quality, moderate-to-severe intensity (often described as 6-8/10 pain severity), duration 4-72 hours if untreated. Pain is aggravated by routine physical activity (walking upstairs, bending forward) and improves with darkness and quiet.
• Associated symptoms: Nausea (80% of attacks), vomiting (40%), photophobia, phonophobia; patient often reports seeking a dark, quiet room.
• Prodromal symptoms (hours to 1-2 days prior): Yawning, mood changes (depression or euphoria), fatigue, food cravings, difficulty concentrating, neck stiffness.
• Postdromal phase: After headache resolution, patients experience fatigue, difficulty concentrating, or mood changes lasting hours to days.

Migraine with aura (20% of migraine cases)

• Aura characteristics: Transient, fully reversible neurological symptoms that precede or accompany headache onset, duration 5-60 minutes (typically 20-30 min). Auras progress gradually over minutes (not sudden onset, distinguishing from stroke).
• Visual aura (most common, 90% of auras): Positive phenomena include scintillating scotomas (flickering lights, often forming homonymous hemianopic field defects), fortification spectra (zigzag, jagged lines resembling castle fortifications), photopsia; negative phenomena include scotomas (blind spots), blurred vision, tunnel vision. Visual symptoms respect the vertical meridian (true homonymous hemianopia) consistent with retinal/occipital cortex origin.
• Sensory aura (second most common): Paresthesias beginning in fingers/perioral region, spreading proximally in "march-like" fashion over 5-20 minutes; typically contralateral and may be unilateral.
• Speech/language aura: Dysarthria, anomia, difficulty finding words.
• Motor aura (rare; defines hemiplegic migraine): Transient weakness of limbs, face, or tongue; causes diagnostic confusion with TIA/stroke but key distinguishing features include slow progression, gradual spread (not maximal at onset), and complete resolution within 24 hours.
• Brainstem aura (vestibular-basilar migraine): Vertigo, ataxia, diplopia, tinnitus, decreased hearing, dysarthria, bilateral paresthesias or visual symptoms.
• Headache follows aura: Typically within 60 minutes; aura may occur during headache or rarely absent (aura without headache, ~5% of migraine with aura patients).

Physical examination

• Interictally: Neurological examination is completely normal; migraine is a functional disorder with no structural abnormalities.
• During acute attack: Patient appears in distress, photophobic (avoids light), phonophobic; may exhibit nausea and vomiting. Cranial nerves are intact; motor, sensory, and cerebellar examinations are normal. Absence of neurological deficits between attacks is cardinal—any persistent neurological finding warrants neuroimaging to exclude secondary headache.
• Vital signs: Normal blood pressure and heart rate; fever should raise suspicion for infection (meningitis) or other secondary causes.
• Fundoscopy: Normal; retinal migraine (retinal artery vasospasm) is rare and manifests as monocular vision loss with migraine aura.

• Often results from progression of episodic migraine
• Characterized by daily or near-daily headaches with migraine features
• Frequently associated with medication overuse headache
• Requires preventive therapy given impact on function and quality of life

Diagnostic criteria for Migraine without Aura (≥5 attacks required)

• Headaches lasting 4-72 hours (untreated or unsuccessfully treated)
• At least 2 of 4 pain characteristics: 1) Unilateral location, 2) Pulsatile quality, 3) Moderate or severe intensity, 4) Aggravation by routine physical activity (walking, climbing stairs)
• At least 1 of 2 associated symptoms: 1) Nausea and/or vomiting, 2) Photophobia and phonophobia
• No better explanation for headaches

Diagnostic criteria for Migraine with Aura

• ≥2 attacks meeting criteria
• Aura: Fully reversible visual, sensory, speech, motor, brainstem, or retinal symptoms with ≥2 of the following characteristics: 1) Spread gradually over ≥5 minutes, 2) Individual symptoms last 5-60 minutes, 3) ≥1 symptom is unilateral, 4) ≥1 positive symptom (scintillations, photopsia), 5) Accompanied or followed within 60 minutes by headache
• No better explanation

Diagnostic investigations

• Neuroimaging (MRI or CT) is NOT required for diagnosis if history and examination are typical for migraine without red flags. However, obtain imaging if:
• First or worst headache of life (subarachnoid hemorrhage, ICH)
• New-onset migraine in patients >50 years (tumor, stroke, vasculitis)
• Change in migraine pattern, frequency, severity, or character
• Atypical aura features (e.g., gradual onset, symptoms lasting >60 min, motor symptoms, brainstem symptoms)
• Focal neurological deficits on examination
• Signs of secondary headache (systemic illness, meningeal signs, papilledema)
• Immunocompromised state

• MRI brain (preferred): Gold standard if imaging needed. In uncomplicated migraine, MRI findings are normal. White matter hyperintensities on FLAIR sequences occur in 15-20% of migraineurs, particularly those with migraine with aura, but significance remains unclear and do not change management in asymptomatic patients.

• CT brain: Acceptable alternative if MRI contraindicated; less sensitive for subtle lesions but sufficient to exclude mass, hemorrhage, hydrocephalus.

• Lumbar puncture: Indicated only if suspicion for meningitis, encephalitis, or subarachnoid hemorrhage; CSF is normal in migraine. Opening pressure is normal.

• Laboratory studies: No specific laboratory test confirms migraine. Obtain:
• Complete metabolic panel: Excludes electrolyte abnormalities, renal disease, metabolic disorders
• Magnesium level: Migraineurs show low intracellular Mg2+; level may guide supplementation trials
• Thyroid function: If thyroid disease suspected clinically
• ESR/CRP: Consider if vasculitis or giant cell arteritis suspected based on age and clinical features
• Blood pressure: Exclude hypertensive emergency; migraine itself does not cause elevated BP during attacks

• Electroencephalography (EEG): NOT indicated for migraine diagnosis; obtain only if seizure suspected (though migraine aura may mimic seizure, EEG is not diagnostic of migraine).

• Migraine-specific diagnostic markers (research use): CGRP and CGRP receptor antibodies in serum; transient elevation during attacks; not routinely measured clinically.

Diagnostic accuracy and pitfalls

• Migraine with aura can mimic TIA/stroke: Distinguish by slow symptom progression (5-20 min for migraine vs. sudden for stroke), complete symptom resolution within 1 hour (migraine vs. TIA/stroke), and head pain following neurological symptoms in migraine. Migraine with aura increases stroke risk 3-fold (see Complications).
• Tension-type headache vs. migraine: Tension headaches are bilateral, pressing, non-pulsatile, not associated with nausea/vomiting, unaffected by activity. Mixed presentations occur.
• Medication overuse headache: Develops in patients overusing acute migraine medications ≥10-15 days/month for ≥3 months; requires medication withdrawal and preventive therapy initiation.

ACUTE MIGRAINE TREATMENT

First-line pharmacotherapy

• Triptans (5-HT1B/1D receptor agonists): Gold standard for moderate-to-severe migraine. Mechanism: Cause cranial vasoconstriction and inhibit trigeminal nociceptor activity via presynaptic serotonin receptor activation. Most effective when dosed early in attack (pain phase, before nausea onset). Classes include:
• Sumatriptan: Rapidly effective; available as SQ injection (gold standard, 20 mg; fastest onset 10-15 min), intranasal spray (20 mg), or oral tablet (50, 100 mg; onset 30-60 min). Dosing: Oral 50-100 mg, repeat after 2 hours if needed (max 200 mg/day); SQ 6 mg, repeat after 1 hour if needed (max 12 mg/day).
• Zolmitriptan, rizatriptan, naratriptan, almotriptan, frovatriptan, eletriptan: Oral agents with varying potency and half-lives; eletriptan (40-80 mg) most potent; frovatriptan (2.5 mg) longest half-life favoring use in long-lasting migraines.
• Adverse effects: Coronary vasospasm (contraindicated in CAD, uncontrolled hypertension, Prinzmetal angina), chest/throat tightness, paresthesias, triptan-induced medication overuse headache (MOH). Relative contraindications: cerebrovascular disease, uncontrolled hypertension.
• Efficacy: 65-75% pain freedom at 2 hours; recurrence (return of headache) in 15-40% requiring redosing.

• Non-steroidal anti-inflammatory drugs (NSAIDs): First-line for mild-to-moderate migraine; comparable efficacy to triptans in early treatment. Agents include:
• Ibuprofen: 400-800 mg oral
• **Naprox

Complications of the disease

• Status migrainosus: A debilitating attack lasting >72 hours (ICHD-3). Reflects entrenched central sensitization plus dehydration from vomiting. Managed urgently in the ED with parenteral hydration, dopamine antagonists (metoclopramide or prochlorperazine), ketorolac, and often a corticosteroid such as dexamethasone to reduce early recurrence.
• Migrainous infarction: Emergency. Aura symptoms persisting beyond 60 minutes with imaging-confirmed infarction in the corresponding territory (typically posterior circulation). Mechanism is presumed prolonged cortical spreading depression with oligemia and vasospasm. Any aura that fails to resolve or that is maximal at onset must be worked up as acute stroke, not as migraine.
• Persistent aura without infarction / migraine aura-triggered seizure: Aura lasting ≥1 week with normal imaging, or a seizure occurring during or within an hour of aura (migralepsy) — both reflect a hyperexcitable cortex and both mandate imaging and EEG on first presentation.
• Ischemic stroke and vascular risk: Migraine with aura roughly doubles ischemic stroke risk, and risk multiplies with cigarette smoking and estrogen-containing contraception. The CDC US Medical Eligibility Criteria classify combined hormonal contraceptives as category 4 (unacceptable risk) in any woman with migraine with aura.
• Chronic migraine and medication overuse headache: Central sensitization plus overuse of acute agents (especially butalbital combinations, opioids, and triptans) converts episodic into near-daily headache; the signal is escalating acute-drug days with declining response.

Complications of treatment

• Triptans: 5-HT1B-mediated vasoconstriction can precipitate coronary vasospasm — chest tightness in a patient with CAD is an emergency until ischemia is excluded.
• Ergotamine/dihydroergotamine: Peripheral ischemia (ergotism); never combine with a triptan within 24 hours.
• Topiramate: Acute angle-closure glaucoma from ciliary body swelling (emergency — painful red eye, blurred vision), plus nephrolithiasis, oligohidrosis, cognitive slowing, and orofacial clefts in pregnancy.
• Valproate: Neural tube defects, hepatotoxicity, pancreatitis — contraindicated in pregnancy and in people who may become pregnant.
• Dopamine antagonists: Akathisia and acute dystonia; treat with diphenhydramine or benztropine.
• CGRP monoclonal antibodies: Constipation (notably erenumab) and blood pressure elevation.

• The aura buzzwords: Scintillating scotoma and fortification spectra that expand over 5–20 minutes and resolve completely. Gradual march is the discriminator from TIA/stroke, where deficits are maximal at onset. A march of paresthesias from fingers to face is migraine sensory aura, not a partial seizure (seizure spread is faster, seconds to a minute).
• Best next step in a typical case is treatment, not imaging: In a patient meeting ICHD-3 criteria with a normal neurologic exam and no red flags, neuroimaging is low-value care (an American Headache Society Choosing Wisely recommendation). Image for the first/worst headache, new headache after age 50, change in pattern, focal deficit, papilledema, or immunocompromise.
• The association examiners test: Migraine with aura plus estrogen-containing contraception plus smoking multiplies ischemic stroke risk — combined hormonal contraceptives are CDC US MEC category 4 in migraine with aura. Switch to a progestin-only or nonhormonal method.
• Acute therapy tiering: NSAID for mild attacks; a triptan (or triptan–NSAID combination) for moderate-to-severe attacks, taken early. Antiemetic dopamine antagonists are adjuncts. Avoid opioids and butalbital — the American Headache Society explicitly discourages them because they drive medication overuse headache.
• When a triptan is off the table: Known CAD, uncontrolled hypertension, or prior stroke. Board-favored alternatives are the gepants (small-molecule CGRP receptor antagonists, e.g., ubrogepant) and lasmiditan (5-HT1F agonist), neither of which vasoconstricts.
• Preventive therapy is indicated when attacks are frequent or disabling (commonly ≥4 headache days/month by AAN/AHS guidance): beta blockers (propranolol), topiramate, valproate, amitriptyline, or CGRP-pathway monoclonal antibodies; onabotulinumtoxinA is approved for chronic migraine only.
• Pregnancy: Acetaminophen first, metoclopramide for nausea; valproate and topiramate are teratogenic and off-limits.
• Common distractor: Near-daily headache in a patient using acute medication ≥10–15 days/month is medication overuse headache — the answer is withdrawal plus a preventive, not a stronger analgesic.