Migraine with and without Aura

• Cortical spreading depression (CSD) in aura: The aura phase in MwA is thought to result from CSD, a wave of neuronal and glial depolarization that propagates across the cortex at 3-5 mm/minute, preceded by hyperpolarization. This phenomena causes the characteristic visual scotoma or other focal deficits and is accompanied by sequential changes in regional cerebral blood flow—initial hyperperfusion followed by prolonged oligemia. CSD activates the trigeminovascular system and likely triggers the subsequent headache phase; neuroimaging during aura shows this propagating wave of reduced cortical blood flow and altered metabolic activity. CSD may be triggered by genetic channelopathies (particularly in familial hemiplegic migraine with CACNA1A mutations affecting calcium channels) or by metabolic stress, allowing cortical irritability in migraine-prone individuals.

• Trigeminovascular system activation and neurogenic inflammation: The headache phase involves activation of the trigeminal nerve system, with release of neuropeptides including calcitonin gene-related peptide (CGRP), substance P, and neurokinin A from trigeminal nociceptive terminals around intracranial blood vessels. CGRP is a potent vasodilator that increases vascular permeability and promotes plasma extravasation, creating neurogenic inflammation. Activation of trigeminal C-fibers leads to antidromic conduction, releasing vasoactive peptides that further enhance vasodilation and inflammation. This trigeminovascular activation explains the efficacy of triptans (5-HT1B/1D agonists) and CGRP monoclonal antibodies in migraine treatment, as they inhibit CGRP release and receptor signaling.

• Brainstem nuclei dysfunction and serotonergic dysregulation: Functional neuroimaging during migraine demonstrates hyperactivity in the brainstem, particularly the periaqueductal gray matter (PAG) and rostral ventromedial medulla. The PAG serves as a key integration center for pain modulation and contains high concentrations of serotonergic neurons. Altered serotonin (5-HT) neurotransmission is central to migraine pathophysiology—reduced baseline serotonin levels, increased 5-HT reuptake, and abnormal receptor sensitivity contribute to migraine susceptibility. During migraine attacks, there is dysregulation of dorsal raphe serotonergic neurons that normally provide descending pain inhibition, resulting in loss of endogenous analgesic control. This serotonergic dysfunction explains the mechanism of preventive medications such as tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs).

• Genetic predisposition and ion channel dysfunction: Migraine demonstrates a strong genetic component (heritability 40-50%), with family history present in 60-70% of migraineurs. Rare familial hemiplegic migraine (FHM) subtypes are caused by single-gene mutations affecting ion channels (CACNA1A encoding Cav2.1 calcium channel, ATP1A2 encoding Na+/K+-ATPase, SCN1A encoding sodium channel), which reduce the threshold for CSD and trigeminovascular activation. Common genetic variants identified through genome-wide association studies (GWAS) implicate genes involved in vascular function, ion transport, and neurotransmitter metabolism, suggesting polygenic inheritance for typical migraine. These genetic factors predispose to increased cortical excitability and impaired neurovascular regulation.

• Hormonal influences and estrogen sensitivity: The female predominance of migraine, particularly MwA, and the relationship between migraine and menstrual cycle strongly suggest hormonal modulation. Migraine often worsens perimenstrually due to fluctuating estrogen levels, with some women experiencing menstrual migraine (attacks within 2 days before or 3 days after menses onset). Estrogen withdrawal rather than absolute estrogen levels appears critical—migraineurs may have heightened sensitivity to estrogen fluctuations. Oral contraceptives and hormone replacement therapy can exacerbate migraine, particularly in those with MwA, potentially through thrombotic and vasomotor effects.

• Metabolic and vascular dysregulation: Migraineurs demonstrate altered metabolic activity with impaired cerebral energy metabolism and increased lactate accumulation, particularly in models involving repeated CSD. Endothelial dysfunction and abnormal vasomotor reactivity are present between attacks and may predispose to both vascular headache generation and stroke risk in MwA. Altered autoregulation of cerebral blood flow and impaired response to metabolic demands further contribute to the migraine cascade.

• Genetic predisposition: Family history is the strongest modifiable risk factor, with 60-70% of migraineurs having an affected first-degree relative. This genetic loading likely involves complex gene-environment interactions rather than single-gene inheritance in common migraine. Individuals with two affected parents have approximately 75% lifetime migraine risk. Specific genetic variants affecting PRDM16, TRPM8, MTHFR, and other genes have been identified in GWAS studies.

• Female sex and reproductive hormonal factors: Women are 2-3 times more likely to develop migraine than men, with the female predominance emerging after menarche and peaking during reproductive years. Migraine often improves with age in women after menopause, though hormonal therapy can modulate this pattern. Specific triggers include ovulation, contraceptive use (particularly estrogen-containing formulations, which increase stroke risk in MwA), and perimenstrual timing. Pregnancy may improve, worsen, or have variable effects on migraine; postpartum relapse is common.

• Age-related factors: Migraine typically begins in adolescence or early adulthood, peaks in prevalence during the third to fourth decade, and generally decreases in frequency and severity with advancing age. Onset after age 50 is unusual and should prompt investigation for secondary causes. Childhood migraine presents differently (often bilateral, shorter duration) and has different natural history than adult-onset migraine.

• Modifiable triggers and environmental factors: Recognized triggers include inadequate sleep or sleep disruption, skipped meals or fasting, stress and emotional triggers (stress paradoxically, or post-stress let-down), menstruation, dietary factors (caffeine withdrawal, monosodium glutamate, aged cheeses with tyramine, alcohol particularly red wine), weather changes (barometric pressure drops), sensory stimuli (bright lights, loud sounds, strong odors), and excessive physical exertion. Individual trigger profiles vary substantially, and triggers are often cumulative. Caffeine overuse (>200 mg daily) can lead to medication overuse headache (MOH).

• Cardiovascular risk factors and comorbidities: Hypertension, diabetes, hyperlipidemia, and obesity are associated with increased migraine frequency and severity. Notably, migraine with aura is associated with increased cardiovascular and cerebrovascular event risk (ischemic stroke, myocardial infarction), particularly in women with additional risk factors (smoking, oral contraceptive use, age >35). This association justifies stroke prevention strategies in high-risk MwA patients.

• Psychiatric and neurological comorbidities: Depression, anxiety disorders, and bipolar disorder are significantly overrepresented in migraineurs (2-3 fold increased prevalence), with bidirectional associations suggesting shared neurobiological pathways. Attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorders also show increased migraine prevalence. Epilepsy is comorbid in 5-7% of migraineurs, with shared genetic predisposition for neuronal hyperexcitability.

• Medication-related factors: Migraine can be triggered or exacerbated by vasodilators (nitrates, calcium channel blockers), estrogen-containing therapies, and excessive analgesic use. Medication overuse headache (MOH) develops with frequent use (≥10-15 days/month depending on medication type) of acute migraine medications over ≥3 months.

• Other established risk factors: High caffeine consumption (though acute caffeine can relieve headache), smoking, high stress levels, and poor sleep quality increase migraine frequency. Sleep disorders such as sleep apnea are overrepresented in migraineurs.

• Headache quality and location: The headache is characteristically unilateral (though can be bilateral), described as pulsatile or throbbing in nature, with moderate-to-severe intensity (pain rating 5/10 or higher, often 7-8/10, sufficiently severe to impair function). Location commonly involves the frontotemporal or occipital regions. Some patients experience hemicranial distribution that remains on the same side with each attack (side-locked migraine), while others may alternate sides between attacks. The headache is typically deep rather than superficial.

• Associated symptoms during headache phase: Photophobia (light sensitivity) and phonophobia (sound sensitivity) are core features due to trigeminovascular system activation and altered sensory processing; patients typically seek dark, quiet environments. Nausea occurs in 80% of migraineurs and vomiting in 30-40%, related to brainstem involvement and vestibular system activation. Symptoms are often worse with physical activity, and patients prefer to remain still. Osmophobia (smell sensitivity) may accompany the sensory hypersensitivity. Approximately 30-40% of migraineurs experience cognitive difficulty (migraine-related cognitive impairment or "brain fog") during attacks.

• Aura symptoms in migraine with aura: Aura occurs in 20-25% of migraineurs and is a transient, focal neurological symptom complex that precedes the headache by 5-60 minutes (typically 20-30 minutes). Visual aura is the most common (60-90% of aura cases) and typically presents as a scintillating scotoma—a bright, shimmering, geometric pattern or fortification spectrum (resembling castle battlements) that gradually expands across the visual field over 5-30 minutes, often with an associated area of visual loss (scotoma). Other visual manifestations include photopsia (seeing flashes), blurred vision, or tunnel vision. Motor aura (15-30% of aura cases) involves transient unilateral motor weakness, parasthesias, or heaviness affecting the contralateral limbs or face (numbering paresthesias progressing from the hand to mouth over minutes). Sensory aura involves tingling or numbness, often following a characteristic progression from hand to face. Aphasic aura (speech disturbance or difficulty finding words) occurs in 10-20% of those with aura. Crucially, aura symptoms are typically negative phenomena (visual loss, weakness) rather than positive phenomena (convulsions, involuntary movements), develop over minutes (not instantaneously), and completely resolve before or as the headache begins, distinguishing them from seizure or stroke.

• Prodromal and postdromal phases: Many patients (30-40%) report a prodrome occurring hours to 1-2 days before the headache phase, characterized by mood changes (depression, euphoria, irritability), fatigue, concentration difficulty, or appetite changes. The postdrome or "migraine hangover" follows the headache resolution and involves persistent fatigue, mood changes, cognitive blunting, and residual malaise for 24-48 hours, even after pain resolution.

• Attack duration and temporal pattern: Migraine without aura typically lasts 4-72 hours if untreated; migraine with aura may be shorter (1-24 hours) due to early headache relief or treatment. Frequency ranges from episodic (4 or fewer attacks monthly) to chronic migraine (≥15 headache days per month for ≥3 months). Status migrainosus is defined as migraine attack lasting ≥72 hours despite acute treatment and represents a severe, disabling migraine state.

• Physical examination findings: The general neurologic examination is typically normal between attacks. During an acute migraine attack, patients often appear in distress, may prefer darkness, and may demonstrate photophobia (eye closure, grimacing with light). Neck stiffness should NOT be present (if present, consider meningitis); meningismus is not a feature of migraine. Fundoscopy is normal. Cranial nerve and motor/sensory examination findings should be normal; persistent focal neurological signs suggest secondary headache. Blood pressure may be elevated during acute pain. A focused assessment for secondary causes should be performed, particularly with first or worst headache, atypical features, or change in headache pattern.

• Important clinical variants: Hemiplegic migraine is a rare subtype with transient hemiparesis (motor aura), which can closely resemble stroke; it may be familial (FHM) or sporadic. Basilar migraine (now termed basilar-type migraine) features aura symptoms suggesting basilar artery origin (vertigo, ataxia, diplopia, dysarthria, bilateral visual symptoms, bilateral paresthesias, decreased consciousness) preceding a severe, often occipital headache. Retinal migraine features monocular visual symptoms distinct from typical migraine aura. Chronic migraine is defined as ≥15 headache days per month, with at least 8 days having migraine features, present for ≥3 months; it often develops from episodic migraine through progressive attack frequency increase. Menstrual migraine occurs predictably in relation to menstrual cycle (perimenstrually), with or without aura. Migraine-associated vertigo features vestibular symptoms as part of the migraine syndrome.

• International Headache Society Diagnostic Criteria: The International Classification of Headache Disorders, 3rd edition (ICHD-3) provides standardized diagnostic criteria. Migraine without aura requires: (A) at least 5 attacks fulfilling criteria B-D; (B) headache attacks lasting 4-72 hours (untreated or unsuccessfully treated); (C) headache having at least 2 of 4 characteristics: unilateral location, pulsating quality, moderate or severe pain intensity, or aggravation by or causing avoidance of routine physical activity; and (D) during headache at least one of: nausea/vomiting OR photophobia AND phonophobia. Migraine with aura requires: (A) at least 2 attacks fulfilling B-D; (B) aura consisting of fully reversible visual, sensory, speech, motor, brainstem, or retinal symptoms; (C) aura developing gradually over minutes or occurring sequentially, with at least 2 symptoms; (D) each aura symptom lasting 5-60 minutes (multiple symptoms duration extended up to 24 hours); (E) aura occurring with headache onset or before, with headache following within 60 minutes; and (F) not better explained by other diagnosis. Note that aura can occasionally occur without headache (aura without migraine). These criteria emphasize the reproducible, stereotyped nature of migraine attacks.

• Detailed clinical history and headache diary: Diagnosis relies on comprehensive history documenting headache frequency, duration, quality, location, associated symptoms, provoking and relieving factors, and impact on function. A structured headache diary over 4-8 weeks documenting headache type, features, and potential triggers provides objective documentation and helps identify patterns. The POUND mnemonic

• Dopamine (D2) antagonist antiemetics: metoclopramide or prochlorperazine IV — antiemetic and independently analgesic, and they reverse the gastroparesis that blocks oral absorption. Diphenhydramine is commonly co-administered or given as rescue for akathisia/dystonia, although prophylactic benefit is inconsistent in trials.
• Parenteral NSAID: ketorolac IV/IM, blocking prostaglandin-mediated neurogenic inflammation.
• IV fluids for vomiting-related volume loss; dexamethasone before discharge reduces early headache recurrence.
• Dihydroergotamine (DHE) is an option for refractory/prolonged attacks when vascular contraindications are absent.

• NSAIDs/simple analgesics: ibuprofen, naproxen, or aspirin-acetaminophen-caffeine for mild-moderate attacks.
• Triptans (5-HT1B/1D agonists): sumatriptan — constrict dilated meningeal vessels and inhibit CGRP release from trigeminal terminals. Take at headache onset; use subcutaneous or nasal routes if vomiting. Two triptan failures justify switching agents.

Escalation/second line

• Gepants (CGRP receptor antagonists): ubrogepant, rimegepant — no vasoconstriction, so usable in coronary or cerebrovascular disease.
• Lasmiditan (5-HT1F agonist): non-vasoconstrictive; causes driving-impairing sedation.

Contraindicated

• Triptans and ergots: ischemic heart disease, prior stroke, uncontrolled hypertension, Prinzmetal angina, pregnancy (ergots). Product labeling and the AHS 2021 consensus also list hemiplegic migraine and migraine with brainstem aura as contraindications, although some experts consider the vascular rationale weak; for boards, treat them as contraindications and use a gepant or lasmiditan instead.
• Triptan–ergot stacking: never give one within 24 hours of the other; ergots/DHE are also contraindicated with strong CYP3A4 inhibitors (macrolides, azoles, protease inhibitors).
• Combined estrogen contraceptives in migraine with aura: CDC US Medical Eligibility Criteria category 4 (stroke risk).
• Valproate and topiramate in pregnancy (neural tube defects, oral clefts); ACOG favors acetaminophen ± metoclopramide.
• Opioids and butalbital: discouraged by AHS — poor efficacy, high medication-overuse risk.

Complications of the disease

• Status migrainosus: debilitating attack >72 hours from sustained trigeminovascular activation and central sensitization; signalled by unremitting pain with dehydration and intractable vomiting. Requires parenteral rescue therapy.
• Migrainous infarction — emergency: aura symptoms persisting beyond 60 minutes in a known migraineur with aura, with infarction in a matching territory on MRI (typically posterior circulation). Mechanism is prolonged oligemia after cortical spreading depression superimposed on endothelial dysfunction/hypercoagulability. Any aura that fails to resolve is a stroke until proven otherwise — image urgently.
• Persistent aura without infarction: aura ≥1 week with normal imaging; distinguishes benign persistent aura from infarction.
• Migraine aura-triggered seizure: shared cortical hyperexcitability; a seizure occurring during or within an hour of aura.
• Chronification to chronic migraine: progressive central sensitization (cutaneous allodynia is the clinical marker) converting episodic to ≥15 headache days/month.
• Cardiovascular risk: migraine with aura independently raises ischemic stroke risk, amplified by smoking and estrogen-containing contraceptives.

Complications of treatment

• Medication overuse headache: from triptans/combination analgesics ≥10 days/month or simple analgesics ≥15 days/month; signalled by daily morning headache that worsens when the drug is withheld. Treat by withdrawal plus bridging preventive therapy.
• Triptan-induced coronary vasospasm: 5-HT1B receptors on coronary smooth muscle; chest tightness with ECG ischemia is an emergency.
• Ergotism: ergot plus a CYP3A4 inhibitor (macrolide, azole, protease inhibitor) causes severe peripheral vasospasm with cold, pulseless limbs.
• Akathisia/acute dystonia from metoclopramide or prochlorperazine: D2 blockade; treat with diphenhydramine or benztropine.
• Topiramate: nephrolithiasis and metabolic acidosis (carbonic anhydrase inhibition), oligohidrosis, cognitive slowing, and acute angle-closure glaucoma — painful red eye with blurred vision is an ophthalmologic emergency.
• Valproate: hepatotoxicity, pancreatitis, teratogenicity. Propranolol: bronchospasm, bradycardia, masked hypoglycemia.

• Aura marches, TIA does not: migraine aura spreads gradually over 5–60 minutes (cortical spreading depression at 3–5 mm/min) and is dominated by positive visual phenomena — the scintillating scotoma and fortification spectra. Abrupt, maximal-at-onset deficit = ischemia; seizure aura is seconds-long and stereotyped with automatisms.
• Migraine with aura + combined estrogen contraceptive + smoking is the association examiners test most: CDC US Medical Eligibility Criteria classify combined hormonal contraception as category 4 (unacceptable risk) in any woman with migraine with aura. Best next step: switch to a progestin-only or non-hormonal method.
• Single best next step in a vomiting patient with a severe attack: parenteral therapy — IV metoclopramide or prochlorperazine plus ketorolac and fluids, not another oral triptan. Add dexamethasone before discharge to reduce recurrence.
• Triptans are contraindicated in coronary artery disease, prior stroke, and uncontrolled hypertension because 5-HT1B receptors sit on coronary smooth muscle. In that patient, use a gepant (ubrogepant) or lasmiditan, which do not vasoconstrict.
• Normal neurologic exam + criteria-fulfilling history = no neuroimaging. The common distractor is ordering MRI for classic migraine. Image only for red flags: thunderclap onset, first or worst, fever/meningismus, papilledema, immunosuppression, new focal deficit, or new headache after age 50 (check ESR/CRP for giant cell arteritis).
• Aura that does not resolve is a stroke until proven otherwise — urgent MRI for migrainous infarction.
• Prophylaxis pearls by comorbidity: propranolol if hypertensive but avoid in asthma; topiramate if obese (weight loss) but counsel on kidney stones, glaucoma, and teratogenicity; amitriptyline if insomnia or comorbid tension-type headache; valproate is off-limits in women of childbearing potential.
• Daily headache in a frequent triptan or butalbital user = medication overuse headache; the answer is withdrawal plus a preventive, never dose escalation. Opioids and butalbital are discouraged by the American Headache Society.