Migraine: A Complete Clinical Guide

1. Definition & Overview

• Bradley and Daroff's Neurology in Clinical Practice, p. 2486
• Adams and Victor's Principles of Neurology, 12th Ed., p. 192

2. Classification (ICHD-3)

Episodic Migraine

• Migraine without aura (common migraine) - the most frequent type (ratio ~5:1 vs. migraine with aura)
• Migraine with aura (classic migraine) - preceded by focal neurological symptoms

Chronic Migraine

Special Subtypes

3. Phases of a Migraine Attack

Prodrome (Premonitory Phase)

• Occurs 24-72 hours before headache onset
• Hypothalamic activation on imaging
• Symptoms: mood changes, fatigue, food cravings, polyuria, yawning, photophobia, hyperacusis, neck stiffness

Aura (in ~20% of migraineurs)

• Develops over 5-20 minutes, lasts 5-60 minutes
• Visual aura (most common): fortification spectra (zigzag lines), scotomas, photopsia - starts in one occipital lobe
• Sensory aura: unilateral paresthesias with "marching" characteristic (hand → face → tongue)
• Motor aura: contralateral weakness (hemiplegic variants)
• Speech aura: mild dysphasia

Headache Phase

• Lasts 4-72 hours
• Unilateral (60-75%), pulsating/throbbing quality
• Moderate-to-severe intensity
• Aggravated by routine physical activity
• Associated with nausea ± vomiting, photophobia, phonophobia, osmophobia, cutaneous allodynia

Postdrome

• Follows headache resolution (hours to 1-2 days)
• Fatigue, cognitive "fog," mood changes, scalp tenderness

4. Pathophysiology

Cortical Spreading Depression (CSD)

• The electrophysiological basis of the migraine aura
• A slow self-propagating wave of neuronal and glial depolarization followed by hyperpolarization, moving at ~2-3 mm/min across the cortex (starting in occipital lobe, moving forward)
• First described by Leão in animals; corroborated by fMRI/PET imaging in humans
• Associated with reduction in regional cerebral blood flow ("spreading oligemia")
• CSD may activate the trigeminocervical system, triggering the headache phase

The Trigeminovascular System

• The dominant hypothesis for the pain phase
• Nociceptive fibers of the trigeminal nerve (primarily ophthalmic division, V1) innervate intracranial dural vessels
• Activation leads to release of vasoactive neuropeptides: substance P, CGRP (calcitonin gene-related peptide), and neurokinin A
• These cause sterile neurogenic inflammation of dural vessels ("trigeminovascular complex")
• Pain signals ascend via the trigeminal nucleus caudalis to the thalamus and cortex

The Role of CGRP

• CGRP is massively released during migraine attacks
• CGRP levels correlate with headache severity
• Intravenous CGRP can trigger migraine in susceptible individuals
• This is the basis for the most important recent drug class: anti-CGRP monoclonal antibodies

Serotonin (5-HT)

• Plasma/platelet 5-HT levels fluctuate during attacks
• Urinary 5-HT metabolites are elevated during attacks
• Drugs that release 5-HT (reserpine, fenfluramine) can trigger migraine
• 5-HT1B/1D receptor agonists (triptans) are the cornerstone of acute therapy

Central Sensitization

• During an attack, ~75% of patients develop central sensitization (reduced pain thresholds in trigeminal and extra-trigeminal territories)
• ~66% develop cutaneous allodynia (pain from normally non-painful stimuli to the skin)
• A hyperexcitable migraine brain: exuberant cortical responses to sensory stimuli, hypoactivation of pain-inhibitory brainstem regions, lack of habituation to repetitive stimuli

Genetics

• ~40 genome-wide susceptibility loci identified; many linked to vascular smooth muscle genes
• First-degree relatives of migraine-without-aura probands: ~2x risk; relatives of migraine-with-aura: ~4x risk
• Familial hemiplegic migraine: monogenic (channelopathy - CACNA1A, ATP1A2, SCN1A)
• Adams and Victor's Principles of Neurology, pp. 193-195
• Bradley and Daroff's Neurology, p. 300-311

5. Triggers

Note: The classic advice to strictly "avoid all triggers" has been challenged. Habituation strategies (controlled exposure) to some triggers (e.g., bright light) may actually reduce headache days vs. avoidance, which can increase sensitivity over time.

6. Diagnostic Criteria (ICHD-3)

Migraine Without Aura

1. Headache lasting 4-72 hours
2. ≥2 of the following:
   • Unilateral location
   • Pulsating quality
   • Moderate or severe intensity
   • Aggravated by routine physical activity
3. During headache, ≥1 of:
   • Nausea and/or vomiting
   • Photophobia AND phonophobia

Migraine With Aura

• Visual (most common - zigzag lines, scotomas)
• Sensory (paresthesias with "marching" character)
• Speech/language (dysphasia)
• Motor (hemiplegic variants only)
• Brainstem (basilar-type)
• Retinal

Red Flags Warranting Investigation (SNNOOP10)

• Systemic symptoms (fever, weight loss)
• Neurological signs/symptoms
• New onset or sudden onset ("thunderclap")
• Older age (>50 years, new headache)
• Onset with Valsalva/exertion
• Postural component
• Papilledema
• Progressive worsening pattern
• Pregnancy/postpartum
• Prior headache history changes dramatically

7. Treatment

7A. Acute (Abortive) Treatment

Mild-to-Moderate Attacks

• NSAIDs - ibuprofen, naproxen sodium, aspirin, diclofenac (first-line for mild attacks)
• Paracetamol (acetaminophen) - less effective for moderate/severe; IV form NOT recommended in ED
• Combination analgesics - aspirin + paracetamol + caffeine (Excedrin)

Moderate-to-Severe Attacks - Triptans (First-Line)

Ergot Alkaloids

• Ergotamine tartrate + caffeine (Cafergot): vasoconstrictive; oral/rectal; take at onset; nausea limits dosing
• Dihydroergotamine (DHE): IV, IM, intranasal; potent; minimal peripheral arterial constriction; useful in status migrainosus
• Contraindications: angina, MI, peripheral vascular disease

Newer Acute Agents

• Lasmiditan (ditan): 5-HT1F receptor agonist - no vasoconstriction, safe in cardiovascular disease; CNS side effects (dizziness, sedation)
• Gepants (CGRP receptor antagonists): Ubrogepant, rimegepant - effective without vasoconstriction; can also be used for prevention (rimegepant)

Emergency Department Treatment (2025 AHS Guidelines)

• Must offer (Level A): IV prochlorperazine, greater occipital nerve block (GONB)
• Should offer (Level B): IV dexketoprofen, ketorolac, IV metoclopramide, IV magnesium, IV valproate (for status)
• Must NOT offer: IV opioids (hydromorphone), IV acetaminophen for pain relief
• Additional: IV fluids, IV methylprednisolone, IV metoclopramide

7B. Preventive (Prophylactic) Treatment

• ≥3-4 disabling migraines/month
• Frequent or prolonged aura
• Poor response or contraindications to acute therapies
• Medication overuse headache risk
• Chronic migraine (≥15 headache days/month)

Traditional Preventive Agents

CGRP-Targeting Therapies (2024 AHS: Now First-Line)

• Rimegepant (Vydura) 75 mg every other day - also treats acute attacks
• Atogepant - oral daily preventive

Botulinum Toxin

• OnabotulinumtoxinA (Botox): 155-195 units injected across 31 sites on scalp/neck every 12 weeks
• Approved for chronic migraine (≥15 headache days/month)
• PREEMPT protocol

Non-Pharmacological Prevention

• Biofeedback and relaxation therapy (strong evidence)
• Cognitive-behavioral therapy
• Regular sleep schedule
• Regular exercise
• Acupuncture (moderate evidence)
• Dietary: omega-3 ↑ / omega-6 ↓ fatty acids; magnesium (400-600 mg/day); riboflavin (vitamin B2, 400 mg/day); butterbur (Petasites, though hepatotoxicity concerns)
• Avoiding prolonged fasts, alcohol, excessive caffeine

8. Special Situations

Migraine in Pregnancy

• Migraine often improves in 2nd and 3rd trimesters (75-80% of women)
• Medication restrictions: avoid ergots, triptans (limited safety data), NSAIDs (3rd trimester), valproate, topiramate
• Safer options: paracetamol, beta-blockers, tricyclic antidepressants (in selected cases)
• Magnesium supplementation is safe and beneficial

Menstrual (Catamenial) Migraine

• Attacks driven by estrogen withdrawal pre-menstrually
• Often more severe, longer, treatment-refractory, rarely with aura
• Perimenstrual prevention (days -3 to +3):
  • Naproxen sodium 550 mg bid
  • Frovatriptan 2.5 mg bid (triptan mini-prophylaxis)
  • Zolmitriptan 2.5 mg bid
  • Ergotamine + caffeine
  • Transdermal estradiol (to blunt withdrawal)

Status Migrainosus (>72 hours)

• Often precipitated by analgesic overuse (rebound), stress, head injury, viral illness
• Discontinue offending medications
• IV DHE infusion protocol, IV prochlorperazine, IV ketorolac, IV magnesium, IV glucocorticoids, IV hydration

Medication Overuse Headache (MOH)

• Results from using acute headache medications >10-15 days/month
• Triptans, ergots, opioids, combination analgesics most implicated
• Leads to transformation: episodic → chronic daily headache with low-grade background pain
• Treatment: withdrawal of overused medication (often requires bridging with NSAIDs or corticosteroids), followed by appropriate preventive therapy

Migraine with Prolonged Aura / Migrainous Infarction

• Rare but important: stroke can occur in the distribution of the aura
• Risk factors: smoking + OCP use in young women with aura (strongly synergistic)
• Avoid combined oral contraceptives in migraine with aura

Pediatric Migraine

• Attacks shorter (2-72 hours), more often bilateral
• Abdominal pain, vomiting, pallor prominent
• "Periodic syndromes" (abdominal migraine, cyclic vomiting) recognized as migraine precursors
• Alternating hemiplegia of childhood may be related
• Ibuprofen, sumatriptan (nasal), and preventive agents (amitriptyline, topiramate, propranolol) used

9. Migraine vs. Other Headaches: Differential

10. Comorbidities

• Depression and anxiety (2-4x higher prevalence)
• Epilepsy (2-4x higher risk)
• Ischemic stroke (especially migraine with aura, especially in young women on estrogen-containing OCP + smokers)
• Cardiovascular disease (modest association)
• Sleep disorders (insomnia, restless legs)
• Patent foramen ovale (PFO) - higher prevalence in migraine with aura
• Fibromyalgia and chronic pain syndromes
• Raynaud's phenomenon

Key 2024-2025 Updates

• 2024 AHS guidelines: CGRP-targeting therapies (anti-CGRP monoclonal antibodies, gepants) are now first-line for both episodic and chronic migraine prevention - no longer reserved after traditional agents fail (PMID: 40423758 - narrative review of anti-CGRP consequences)
• 2025 AHS ED guidelines: IV prochlorperazine and greater occipital nerve blocks must be offered (Level A); IV opioids must NOT be offered (Level A) (PMID: 41321235)
• CGRP mAb blood pressure effects are under active review (PMID: 39877974 - systematic review in Cephalalgia, Jan 2025)