Migraine

01Pathophysiology

Migraine is not simply a vascular headache. It is a primary neurological disorder rooted in cortical hyperexcitability and abnormal activation of the trigeminovascular system. Understanding this mechanism is essential because vignettes often test whether students can connect the symptom pattern to the underlying biology.

The process begins centrally. In genetically predisposed individuals, the cerebral cortex has a lower threshold for depolarization. Various triggers (stress, hormonal shifts, sleep changes, dietary factors) can initiate abnormal neuronal activity in the brainstem and hypothalamus. This explains the prodromal phase, which occurs hours to days before the headache and manifests as fatigue, mood changes, food cravings, yawning, and neck stiffness. When these symptoms appear in a vignette before the headache begins, the test-writer is pointing you toward migraine.

In patients who experience aura, a phenomenon called cortical spreading depression (CSD) occurs. CSD is a slowly propagating wave of neuronal and glial depolarization that travels across the cortex at approximately 2 to 5 mm per minute, followed by a period of sustained suppression of neural activity. When CSD passes through the visual cortex (the most common location), it produces the classic visual aura: scintillating scotoma (a shimmering, zigzag crescent of light), fortification spectra, or a region of visual loss that expands gradually over 5 to 60 minutes. If it spreads to the somatosensory cortex, the patient reports unilateral paresthesias. If it involves language areas, the patient develops transient dysphasia. The key testing point is that aura symptoms develop gradually over 5 or more minutes and resolve fully within 60 minutes, which distinguishes them sharply from stroke (sudden onset, persistent deficits).

CSD triggers the next critical step: activation of the trigeminovascular system. The wave of depolarization causes release of inflammatory mediators (potassium, hydrogen ions, nitric oxide, arachidonic acid) from neurons and glia into the perivascular space. These substances activate the meningeal nociceptors of the trigeminal nerve (cranial nerve V), particularly the ophthalmic division (V1). Once these nociceptors fire, signals travel along the trigeminal nerve to the trigeminal nucleus caudalis in the brainstem, and then relay through the thalamus to cortical pain-processing regions.

Activation of the trigeminal nerve also causes antidromic release of CGRP, substance P, and neurokinin A from perivascular nerve terminals. CGRP is the most important of these peptides for exam purposes. CGRP causes meningeal vasodilation, plasma protein extravasation, mast cell degranulation, and neurogenic inflammation around the dural blood vessels. This creates a positive feedback loop that sustains and intensifies the headache. The recognition that CGRP is the central mediator of the pain cascade explains why anti-CGRP therapies (monoclonal antibodies and gepants) are effective.

The throbbing quality of the pain directly results from sensitization of perivascular nociceptors to arterial pulsation. As the attack progresses, central sensitization develops in the trigeminal nucleus caudalis and thalamus. This is why patients develop cutaneous allodynia (pain from normally non-painful stimuli such as touching the scalp, wearing eyeglasses, or combing hair). Once central sensitization is established, triptans become less effective, which is clinically important and frequently tested.

Photophobia and phonophobia arise from convergence of trigeminal and visual/auditory pathways in the brainstem and thalamus. Nausea and vomiting result from activation of the nucleus tractus solitarius and area postrema in the brainstem, which are closely connected to the trigeminal nucleus caudalis.

02Classification and Clinical Manifestation

Migraine Classification (ICHD-3)

Phases of a Migraine Attack

03Diagnostic Workup

Migraine is a clinical diagnosis. There is no lab test, imaging study, or biomarker that confirms it. The diagnosis rests entirely on pattern recognition from the history, and this is exactly what the exam tests. A vignette will describe a young woman with recurrent episodes of unilateral, pulsating headache lasting several hours, worsened by walking upstairs, associated with nausea and sensitivity to light and sound, with a normal neurological exam. The correct answer is migraine, and the correct next step is no further workup needed.

The moment the exam tests diagnostic workup, it is testing your ability to recognize red flag features (sometimes called "SNOOP" criteria) that should prompt neuroimaging:

• Systemic symptoms (fever, weight loss, immunosuppression, cancer history)

• Neurological signs (focal deficits, papilledema, altered consciousness)

• Onset that is sudden or "thunderclap" (peak intensity within seconds)

• Older age at onset (new headache after age 50)

• Progressive pattern (increasing frequency/severity, change in character)

If the vignette includes any of these red flags, the answer shifts to CT head without contrast as the best initial test, followed by MRI brain for more detailed evaluation if CT is normal but clinical suspicion remains. If the presentation suggests subarachnoid hemorrhage (sudden "worst headache of my life"), a negative CT should be followed by lumbar puncture looking for xanthochromia.

For a new headache in a patient over age 50, always consider giant cell arteritis. The best initial test in that scenario is ESR (markedly elevated, often > 50 mm/hr), and the most accurate test is temporal artery biopsy.

04Management and Treatment

Acute Treatment

Prophylactic Treatment

Acute treatment should be initiated as early as possible once the headache begins. The concept of "treat early" is high-yield because early intervention (within 1 hour of onset) produces significantly better outcomes. For mild to moderate attacks, an NSAID such as ibuprofen 400 mg or naproxen sodium 500 mg is first-line. Adding metoclopramide 10 mg PO improves gastric motility (which is slowed during a migraine attack) and provides antiemetic benefit.

For moderate to severe attacks or when NSAIDs fail, triptans are the standard of care. Sumatriptan is the most commonly tested. Oral sumatriptan 50 to 100 mg may be given; subcutaneous sumatriptan 6 mg has the fastest onset and highest efficacy. Triptans work by agonizing 5-HT1B receptors on meningeal blood vessels (causing vasoconstriction) and 5-HT1D receptors on trigeminal nerve terminals (inhibiting CGRP release). Because of their vasoconstrictive properties, triptans are contraindicated in patients with coronary artery disease, prior stroke or TIA, uncontrolled hypertension, Prinzmetal angina, and peripheral vascular disease. They are also traditionally avoided in hemiplegic migraine and migraine with brainstem aura. Another critical contraindication is concurrent use of ergotamine (risk of prolonged vasospasm) and use within 2 weeks of an MAO inhibitor.

If a patient has cardiovascular contraindications to triptans, the exam often tests gepants as the alternative. Ubrogepant and rimegepant are oral CGRP receptor antagonists that provide acute relief without vasoconstriction, making them safe in patients with vascular risk factors. Lasmiditan, a 5-HT1F agonist (a "ditan"), is another non-vasoconstrictive option, but it causes dizziness and sedation, so patients should not drive within 8 hours of taking it.

Prophylactic therapy is indicated when the patient has 4 or more migraine days per month, significant disability despite acute treatment, contraindication to or overuse of acute medications, or presence of uncommon migraine subtypes (hemiplegic, brainstem aura, migrainous infarction). The traditional first-line oral agents are propranolol, topiramate, valproate, and amitriptyline. All require 2 to 3 months of adequate-dose treatment before efficacy can be assessed. The CGRP monoclonal antibodies (erenumab, fremanezumab, galcanezumab, eptinezumab) are now recommended as first-line or early-line preventive therapy by the AHS (2024 consensus), particularly in patients who have failed or cannot tolerate oral preventives. They are given as monthly or quarterly injections and have a favorable side-effect profile compared to traditional oral medications.

For chronic migraine that has not responded to at least 2 preventive medications, onabotulinumtoxinA (Botox) is an established treatment, given every 12 weeks. It works by inhibiting the release of CGRP and other nociceptive neurotransmitters from trigeminal nerve endings.

A crucial management pearl: always assess for and address medication overuse headache (MOH). If a patient with chronic daily headache is using simple analgesics 15 or more days per month, or triptans/opioids/combination analgesics 10 or more days per month, the most important next step is withdrawal of the offending medication combined with a preventive agent and a bridging strategy (short course of naproxen or prednisone).

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The most common trap on this topic is confusing the aura of migraine with a transient ischemic attack or stroke. The exam will present a young patient with transient visual or sensory symptoms followed by a headache. Students panic and choose stroke workup. The critical discriminator is tempo: migraine aura develops gradually over 5 or more minutes (the "march"), whereas TIA and stroke symptoms appear suddenly, within seconds. Additionally, migraine aura characteristically produces positive phenomena first (flashing lights, scintillating scotoma, tingling) followed by negative phenomena (visual loss, numbness), while ischemic events produce purely negative symptoms from the start.

Another frequent trap involves the management sequence. The vignette describes a patient who has been using sumatriptan 10 or more days per month for chronic daily headache. Students choose to increase the triptan dose or add another acute agent. The correct answer is to recognize medication overuse headache and withdraw the offending medication while initiating prophylaxis. The test-writer is checking whether you understand that overuse of acute migraine medications paradoxically perpetuates the headache cycle.

A third high-yield trap involves triptan contraindications. When the vignette describes a migraine patient with a history of coronary artery disease, prior myocardial infarction, or uncontrolled hypertension, the answer is never sumatriptan. The correct choice is an NSAID, a gepant (ubrogepant, rimegepant), or lasmiditan.

Students also miss the prophylaxis indication question. When a patient has frequent migraines (4+ days per month) causing disability, the next best step is to start a preventive medication, not to continue treating each individual attack. The exam is testing whether you can shift from acute management to prevention.

Finally, remember the pregnancy trap. A woman of childbearing potential with migraine should not receive valproate (neural tube defects) or topiramate (cleft lip/palate). The preferred prophylactic agent in pregnancy is a beta-blocker (propranolol) or, in more recent guidelines, a CGRP monoclonal antibody may be considered, though data in pregnancy remain limited. For acute treatment during pregnancy, acetaminophen is first-line, while triptans (particularly sumatriptan, which has the most safety data) may be used when the benefit outweighs the risk.

The core competency being tested across all migraine questions is threefold: (1) pattern recognition of the classic clinical presentation (unilateral, pulsating, 4 to 72 hours, nausea, photo/phonophobia, worsened by activity), (2) knowing when imaging is and is not indicated (red flags versus classic presentation), and (3) correct sequencing of acute versus prophylactic therapy with awareness of contraindications.