Migraine

Migraine is a primary headache characterized by recurrent episodes of unilateral, localized pain that are frequently accompanied by nausea, vomiting, and sensitivity to light and sound. In approximately 25% of cases, patients experience an aura preceding the headache, which involves reversible focal neurological abnormalities, e.g., visual field defects (scotomas) or paresis lasting less than an hour. Migraine is a clinical diagnosis and imaging is generally not indicated. Treatment of attacks consists of general measures (e.g., minimizing light and sound) together with administration of nonsteroidal antiinflammatory drugs (e.g., aspirin) and antiemetics (e.g., prochlorperazine) if nausea is present. In severe cases, triptans may be added. Prophylactic treatment (e.g., beta blockers) may be indicated if migraines are especially frequent or long-lasting, or if abortive therapy fails or is contraindicated.

• Prevalence: ∼ 17% of females and ∼ 6% of males ^[1]
• Peak incidence: 30–39 years ^[2][3]
• Migraine is the second most common type of headache.

Among patients presenting to the emergency department with a headache, migraine is the most common cause. ^[4]

Epidemiological data refers to the US, unless otherwise specified.

• The exact pathophysiology is unclear. ^[5]
• Genetic predisposition
• Potential triggers
  • Certain food and beverages: alcohol, nicotine, citrus fruits, dairy products, food containing tyramine (e.g., chocolate, red wine)
  • Fasting, dehydration
  • Poor sleeping habits
  • Emotional stress
  • Weather changes
  • Hormonal changes in women: menstruation; , hormone intake (oral contraceptive pills)

• The pathophysiology of migraine is not fully understood.
• Various factors are thought to contribute to the development and severity of migraines.
  • Activation of meningeal nociceptors
    • Dilatation of intracranial blood vessels → activation of meningeal nociceptors
    • Activation of the trigeminovascular pathway: activation of trigeminal neurons → release of vasoactive neuropeptides such as substance P or calcitonin gene-related peptide (CGRP) → vasodilatation and release of proinflammatory molecules (histamine, bradykinin, serotonin, prostaglandins) → neurogenic inflammation → activation of meningeal nociceptors ^[6]
    • Cortical spreading depression: excitation and inhibition of the cerebral cortex → changes in cortical enzymatic activity (proinflammatory molecules) → neurogenic inflammation → activation of meningeal nociceptors ^[7]
  • Dysregulation of pain sensitization in the trigeminal system (CN V): cortical spreading depression → dysregulation of trigeminovascular neurons → neurogenic inflammation → hypersensitization → nausea, loss of appetite, yawning, fatigue, anxiety, depression ^[8]
  • Genetic predisposition: in individuals with migraine, the brain does not have the ability to habituate itself to external stimuli (e.g., stress, hormonal changes) → hyperexcitable brain ^[7]
  • Activation of the autonomic nervous system; : external physiological and emotional stimulation (e.g., hormonal changes, stress) → hypothalamic response to the change in homeostasis → hypothalamic neurons influence the autonomic nervous system → shift toward a parasympathetic tone → constriction and dilatation of intracranial, especially the meningeal, blood vessels ^[7]

Vasodilatation is now considered an epiphenomenon rather than the primary cause of migraine headache. ^[6]

Migraine is characterized by recurrent attacks and may occur with aura (∼ 25% of cases) or without aura (∼ 75% of cases). A typical migraine attack passes through four stages, and the aura (if present) typically occurs before the headache. However, migraine patterns may differ and not follow the characteristic stages.

1. Prodrome (facultative)

• 24–48 hours before the headache starts
• Excessive yawning
• Difficulties with writing or reading
• Sudden hunger or lack of appetite
• Mood changes

2. Aura

Paroxysmal, focal, neurological symptoms that precede (or, in some cases, occur during) the headache.

• Typical aura ^[9][10]
  • Visual disturbances, sensory and/or speech symptoms (positive ; and/or negative ;)
    • Scintillating scotoma: an arch-shaped scotoma that starts centrally and shifts peripherally (appears for ∼ 15–30 minutes)
    • Central scotoma
    • Flashing lights
    • Distorted color perception
    • Fortification spectra: star-like, zigzag figures
    • Sensory deficits, paresthesia
    • Aphasia
  • No motor symptoms
  • Develops gradually
  • Completely reversible
  • Symptoms last ≤ 60 minutes each
• Atypical aura
  • Paresis
  • Dizziness
  • Persistent or long-lasting symptoms

3. Headache

• Localization
  • Typically unilateral, but bilateral headache is possible
  • Especially frontal, frontotemporal, retro-orbital
• Duration: usually 4–24 hours (rarely over 72 hours)
• Course: progression of pulsating, throbbing, or pounding pain
• Exacerbated by physical activity
• Accompanying symptoms: photophobia, phonophobia, and nausea/vomiting

4. Postdrome (facultative)

• Feeling of exhaustion or euphoria
• Muscle weakness
• Anorexia or food cravings

The typical migraine headache is “POUND”: Pulsatile, One-day duration, Unilateral, Nausea, Disabling intensity.

All variants of acute migraine should raise suspicion for other diagnoses (e.g., transient ischemic attack), especially if the first aura occurs after 40 years of age, auras last an atypical amount of time, or symptoms are predominantly negative.

Migraine with brainstem aura ^[9]

• Previously known as basilar migraine
• Patients have episodes of migraine preceded at least some of the time by brainstem aura (but can also be preceded by typical aura).
• Criteria for brainstem aura
  • ≥ 2 fully reversible brainstem symptoms (e.g., dysarthria, vertigo, tinnitus, diplopia, ataxia, hearing loss, impaired consciousness)
  • No motor or retinal symptoms

Vestibular migraine ^[9][11]

• Most common cause of spontaneous episodic vertigo
• Diagnosed migraine plus ≥ 5 episodes of vestibular symptoms (e.g., vertigo) lasting ≤ 72 hours
• Treatment may be complemented with antivertigo agents (e.g., dimenhydrinate ).

Hemiplegic migraine ^[9]

• May be familial or sporadic
• Main differential diagnosis: epilepsy
• Fully reversible aura (lasts ∼ 72 hours) consisting of both motor weakness and visual, sensory, or speech impairment

Retinal migraine ^[9]

• Aura consists of monocular visual phenomena (e.g., scintillation, scotoma, blindness).
• All symptoms are fully reversible.
• Aura fulfills ≥ 2 of the following criteria:
  • Spread: gradually over ≥ 5 minutes
  • Duration: 5–60 minutes
  • Onset of headache: within 60 minutes

Typical aura without headache (silent migraine) ^[9]

• Aura symptoms are present.
• Aura lasts for ≥ 60 minutes before the onset of the headache, which might not develop at all.
• Episodes may coexist with typical migraine symptoms.

Chronic migraine ^[9]

• Patients with migraine diagnosis (with or without aura) presenting with a ≥ 3-month history of the following:
  • Headaches (variable in intensity and type ) ≥ 15 days/month
  • ≥ 8 days/month headache has migraine characteristics or is relieved by migraine-specific medication (triptans, ergotamine).
• A headache diary is recommended for patients to help optimize treatment.
• Main differential diagnosis: medication overuse headache

Migraine is a clinical diagnosis based on history and physical examination. The most important step is to exclude red flags for headache that suggest a secondary headache (e.g., infection, hemorrhage, intracranial mass) and require more exhaustive investigation (e.g., imaging). Suspect a primary headache when no red flags are identified, and confirm the diagnosis using the diagnostic criteria for migraine. ^[9][12]

Migraine is a clinical diagnosis that is based on patient history and physical examination.

Diagnostic criteria

Avoid anchoring bias in patients with known migraines and pursue a diagnostic workup for headache in patients with red flags for headache.

Laboratory studies

• Not routinely indicated
• Consider a urine pregnancy test to guide pharmacotherapy choices in women of childbearing age.

Imaging ^[12][13][14]

Neurological imaging is not routinely indicated for uncomplicated migraine.

• Indications
  • Clinical features suggest a secondary headache (see “Red flags for headache” and “High-risk headache”).
  • Migraine with the following characteristics: ^[14]
    • Unusual, prolonged, or persisting aura
    • First episode of brainstem aura, hemiplegic migraine, retinal migraine, aura without headache
    • Change in baseline migraine clinical features (frequency, severity, aura)
    • Consider in first migraine
• Procedure
  • MRI is preferred over CT (except in emergency settings if there is suspicion of a vascular hemorrhagic event).
  • See “Imaging for headaches.”
• Findings ^[14]
  • Typically normal
  • Nonspecific white-matter changes may be seen ^[14]

Avoid imaging in patients presenting with a recurrent known migraine unless new concerning features are present, e.g., seizures, focal neurological deficits, or recent change in headache pattern.

• See “Differential diagnoses of headache.”
• Paroxysmal hemicrania
• Medication overuse headache

The differential diagnoses listed here are not exhaustive.

See “Migraine management in pregnancy” for abortive and preventative agents that are safe for pregnant individuals. The following recommendations are consistent with American Headache Society (AHS) guidelines. ^{[15][16][17][18]}

Abortive therapy for migraines ^[18][19]

All patients

• Limit stimuli (i.e., light, loud noises) and activity.
• Start abortive treatment as soon as possible. ^[19]
• Treat nausea and vomiting, if present.
  • IV fluids
  • Parenteral antiemetics: e.g., metoclopramide, prochlorperazine ^[15]

Avoid opioids as first-line treatment for acute migraines, given their unclear efficacy and potential harm (e.g., worse nausea and vomiting). ^[15][20]

Mild to moderate headache ^[9][15]

• First-line treatment: consists of NSAIDs, acetaminophen, acetylsalicylic acid, or combinations including caffeine.
  • If tolerating PO, consider one of the following:
    • Ibuprofen
    • Aspirin
    • Acetaminophen
    • Acetaminophen/aspirin/caffeine
  • If nausea/vomiting are present, consider one of the following:
    • Ketorolac
    • Diclofenac
• Second-line: Treat as “Moderate to severe headache.”
• Children: ibuprofen and family counseling

Moderate to severe headache ^[9][15][20]

Trial a parenteral antidopaminergic agent OR start a migraine-specific agent.

• Parenteral antidopaminergics
  • Metoclopramide ^[15][20]
  • Prochlorperazine PLUS diphenhydramine ^[15][20]
  • Monitor for extrapyramidal symptoms, e.g., akathisia or acute dystonia, and treat them if they develop.
• Migraine-specific agents: triptans (e.g., sumatriptan) OR ergotamine; do not combine these agents! ^[21]
  • First-line: oral or parenteral triptans
    • If tolerating PO, consider one of the following:
      • Sumatriptan-naproxen
      • Zolmitriptan
    • If nausea/vomiting are present or there is a higher analgesic requirement, consider one of the following:
      • Sumatriptan
      • Zolmitriptan
  • Second-line: consider a parenteral ergotamine (e.g., dihydroergotamine )
• Short-term recurrence prevention: Consider IV dexamethasone. ^[22]
• Refractory headache: See “Status migrainosus.”

Parenteral antidopaminergics (i.e., IV metoclopramide or IV prochlorperazine) are effective first-line agents for migraine regardless of GI symptoms or ability to tolerate oral medication.

In the emergency department, consider IV dexamethasone to reduce the risk of recurrent migraine after discharge. ^[15]

Overview of migraine-specific agents

Remember to check for drug interactions (e.g., with SSRIs or macrolides) before starting triptans or ergotamines to avoid adverse events. Coronary spasm and/or serotonin syndrome can occur if triptans and ergotamines are combined.

Ergotamines are contraindicated in pregnancy. ^[24]

A SUMo wrestler TRIPs ANd falls on his head: SUMaTRIPtANs are used for headaches (cluster and migraine).

Prophylactic therapy of migraine

Nonpharmacological ^[25]

• Lifestyle modifications
  • Exercise in moderation
  • Maintain a healthy diet
  • Identify and try to avoid potential triggers
  • Follow a regular sleeping schedule
• Other: There is some evidence that the following nonpharmacological interventions have some benefits for patients with migraine
  • Acupuncture ^[26]
  • Noninvasive neuromodulation
  • Behavioral therapy
  • Relaxation techniques
  • Biofeedback

Pharmacological ^[27]

• Indications ^[28][29]
  • ≥ 2 attacks/month that produce disability that lasts ≥ 3 days
  • Severe disability regardless of frequency (e.g., hemiplegic migraine)
  • ≥ 2 attacks/week regardless of severity
  • Failure/contraindications/major side effects from acute medications
• General considerations ^[27]
  • Consider comorbidities when selecting a drug.
  • Encourage headache diary to assess response to treatment.
  • Start with a low dose and increase until reaching the therapeutic goal.
  • Goals of prophylaxis
    • Reduce frequency, severity, and duration of attacks.
    • Improve response to acute treatment.
• General prophylaxis
  • First-line ; ^[27]
    • Anticonvulsants (e.g., topiramate; , valproate; ) ^[27]
    • Beta blockers (e.g., propranolol; , metoprolol , timolol ) ^[27]
  • Second-line ; ^[27]
    • Tricyclic antidepressant: amitriptyline ^[27]
    • NSAIDs: fenoprofen ^[27]
  • Other: calcium channel blockers (e.g., flunarizine)
• Menstrual-related migraine ^[27]
  • First-line: frovatriptan ^[27]
  • Second-line
    • Naratriptan ^[27]
    • Zolmitriptan ^[27]
• Chronic migraine
  • Botulinum toxin (e.g., OnabotulinumtoxinA ) ^[10][30]
  • Monoclonal antibodies: anti-CGRP or anti-CGRP receptor (e.g., erenumab, galcanezumab, fremanezumab) ^[10]

Status migrainosus ^[9]

• Description: Debilitating migraine attack in a patient with a known migraine diagnosis (with or without aura)
  • Exceptional in duration (≥ 72 hours) and severity
  • Often related to medication overuse
• Treatment: stepwise therapy with reassessment between drug administration ^[31]
  • IV fluids
  • Antiemetic (e.g., metoclopramide )
  • NSAID (e.g., ketorolac )
  • Dihydroergotamine ^[31]
  • Dexamethasone ^[22]
  • Valproate ^[32]
  • Consider IV magnesium sulfate as adjunctive therapy under specialist guidance. ^[17][33]
  • Consider inpatient management by a specialist if there is no improvement.

We list the most important complications. The selection is not exhaustive.

• Migraine of any severity
  • Consider CT/MRI of the brain with or without contrast if the presentation is atypical or red flags for headache are present. ^[34][35]
  • Reduce light/noise in the patient's environment.
  • Fluid hydration
  • Begin pharmacologic treatment within 1 hour of symptom onset, if possible.
  • Treat nausea/vomiting, if present.
• Mild to moderate headache
  • Start a nonspecific agent (e.g., NSAID, acetaminophen, or combinations including caffeine).
• Moderate to severe headache, or if the above treatments fail
  • Consider trialing a parenteral antiemetic (i.e., metoclopramide or prochlorperazine).
  • Start a migraine-specific agent.
    • First-line: oral or parenteral triptans
    • Second-line: parenteral ergotamines
  • Consider early recurrence prevention with dexamethasone.
• Status migrainosus refractory to the above ^[31]
  • Escalating therapy with antiemetic, NSAID, dihydroergotamine, dexamethasone, and valproic acid
  • Consider inpatient treatment.
  • Neurology consultation
  • Consider alternative diagnoses.

• Most patients with migraines can be managed as outpatients.
• Consider hospitalization in the following cases:
  • Status migrainosus refractory to initial therapy
  • Inability to tolerate oral nutrition or hydration
  • Chronic migraine complicated by medication overuse headache requiring inpatient supervised withdrawal (see also “Disposition and referrals” in “Medication overuse headache”)
• Consider referral to neurology or a specialized headache clinic.
• If discharging from the emergency department, provide patient counseling and consider appropriate prescription of abortive and prophylactic medications.
• See also “Disposition” in “Headache.”

Management of migraine in pregnancy ^[24][37]

Abortive therapies

• Pain control
  • First-line: acetaminophen (either alone or in combination with caffeine)
  • Second-line: NSAIDs (safe to use until the end of the 2^nd trimester of pregnancy)
  • Third-line
    • Triptans: can potentially cause constriction of uterine vessels and uterine contractions ^[24]
    • Opioids: can cause neonatal withdrawal syndrome and exacerbate nausea/vomiting
  • Ergot derivatives are contraindicated because they induce uterine contractions.
• Control of nausea/vomiting: the following medications are safe to use in pregnancy
  • Diphenhydramine
  • Promethazine
  • Metoclopramide
  • Chlorpromazine
  • Ondansetron

Prophylactic therapy

• First-line
  • Beta-blockers
  • Cyproheptadine
  • Calcium channel blockers
• Second-line
  • SSRIs and SNRIs (except paroxetine)
  • Gabapentin

• One-Minute Telegram 29-2021-3/3: Eptinezumab shows promise in the treatment of migraine attacks

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