Migraine Headache

Migraine headache is a primary headache disorder and is among the most prevalent disorders in the world. Migraine is characterized by episodic, moderate to severe headaches that may be associated with increased sensitivity to light and sound, as well as nausea and/or vomiting. A migraine attack might be preceded by a so-called aura—neurologic phenomena of visual, auditory, sensual, or motor quality. There is a strong hereditary component in the etiology of migraines. Migraine headache is a clinical diagnosis with several variants. Management strategies include abortive therapy such as NSAIDs and triptans to manage acute episodes as well as preventive strategies to minimize morbidity and pain-related disability.

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Overview

Definition

Migraine headaches are primary headaches commonly associated with nausea, photophobia, phonophobia, and exacerbation by physical activity.

Distinguishing features:

  • Unilateral, rarely bilateral
  • Pulsatile quality
  • Moderate to severe intensity
  • Headache duration: 4–72 hours
  • Worsens with physical activity 
  • Associated with:
    • Nausea and/or vomiting
    • Photophobia and/or phonophobia

Migraine-related terminology:

  • Prodrome: symptoms that appear 24–48 hours prior to migraine onset
    • Yawning
    • Euphoria
    • Depression
    • Irritability
    • Cravings
    • Diarrhea/constipation
    • Neck discomfort
  • Aura:
    • Reported by approximately 25% of individuals with migraine
    • Reversible neurologic phenomena that often precede or coincide with headache onset
    • Gradual in onset and progression
    • Positive aura symptoms (“gain of function” in CNS neurons): 
      • Visual (e.g., bright lines, shapes, objects)
      • Auditory (e.g., tinnitus, noises, music)
      • Sensory (e.g., numbness, pain, paresthesia, allodynia)
      • Motor (e.g., tremor, jerking, repetitive movements) 
    • Negative aura symptoms (“loss of function” in CNS neurons):
      • Visual loss
      • Hearing loss
      • Sensory loss (e.g., anesthesia, numbness)
      • Language loss (e.g., word-finding difficulty, aphasia)
  • Postdrome: 
    • Reported by approximately 75% of individuals with migraine.
    • Pain in the location of the headache after the headache abates triggered by head movement
    • Feeling of exhaustion (more common) or euphoria encountered after the headache abates

Epidemiology

  • Lifetime prevalence: approximately 12% in the United States
  • Women > men: 2–4:1 depending on age
  • Equal sex prevalence in childhood 
  • 75% of those with migraine have symptom onset by age 35. 
  • Only about half of U.S. adults with migraine receive an accurate diagnosis. 
  • Migraine is a significant cause of work-related disability.

Classification

Migraine headache is classified among the primary headache disorders as well as having subtypes of its own. 

Primary headache disorders:

  • Migraine headache
  • Cluster headache
  • Tension headache

Subtypes of migraine headache:

  • Low-frequency episodic: < 10 headache days per month
  • High-frequency episodic: 10–14 headache days per month
  • Chronic: ≥ 15 headache days per month
  • Migraine with and without aura
  • Migraine with brain stem aura
  • Hemiplegic migraine
  • Retinal migraine

Pathophysiology

Current consensus holds that a primary neuronal dysfunction is responsible for a sequence of intracranial and extracranial changes that trigger prodromic and postdromic symptoms, aura, and the headache itself.

Cortical spreading depression

  • Self-propagating depolarization of neurons and glial cells that spreads across the cerebral cortex. 
  • Assumed to: 
    • Trigger the aura of migraine
    • Activate afferent fibers of the trigeminal nerve 
    • Increase permeability of the blood–brain barrier to matrix metalloproteinases

Trigeminal activation

  • Induces inflammatory changes in meningeal nociceptors responsible for the headache
  • Projections innervate large cerebral vessels, large venous sinuses, and the dura mater, which explains the typical location of migraine pain.

Vasoactive neuropeptides

  • Released on stimulation of the trigeminal ganglion 
  • Lead to: 
    • Neurogenic inflammation
    • Vasodilation of the trigeminovascular system
    • Extravasation of plasma proteins into the CSF
  • Vasoactive peptides include:
    • Substance P
    • Calcitonin gene–related peptide (CGRP)
    • Neurokinin A
    • Serotonin
  • Calcitonin gene–related peptide and serotonin are pharmacologic targets of migraine therapy → CGRP antagonists and serotonin agonists (= triptans)

Prolonged and repetitive inflammation of the trigeminal system

  • Leads to sensitization
  • Afferent activation occurs at a lower threshold and produces an exaggerated pain response.

Genetics

  • 75% of individuals with migraine have 1st-degree relative with migraines.
  • Twin studies: monozygotic twin concordance > dizygotic twin concordance 
  • Inheritance pattern is multifactorial.
  • No single mendelian model of inheritance has been identified.

Clinical Presentation

History

  • Classic pain descriptors for migraine headache:
    • Throbbing
    • Pounding
    • Pulsatile
  • Onset most commonly in teens or early 20s
  • A minimum of 5 individual headache episodes typical of migraine is required to establish a diagnosis of migraine.
  • Features:
    • Most often unilateral, but can be bilateral
    • Moderate to severe intensity
    • Duration: 4–72 hours per attack
    • Location:
      • Entire side of head, including the face
      • May be most intense behind the eye or cheek
      • May include the upper cervical region ipsilateral to the headache
    • Physical activity:
      • Individuals often seek a place to lie down.
      • Headache is often relieved by sleep.
    • Light and noise:
      • Symptoms worsen with bright lights and loud noises.
      • Individuals often seek a dark, quiet place.
    • Cutaneous allodynia:
      • Innocuous stimulation of normal skin in the affected area produces pain.
      • May be present during or even between attacks.
    • Nausea and/or vomiting
    • Prodrome and postdrome
    • Aura:
      • Most commonly visual
      • The same person may experience migraine attacks with and without an aura. 
      • Aura may be present without being followed by headache.
    • Triggers (precipitating or aggravating stimuli):
      • Stress 
      • Hormonal fluctuation
      • Weather changes
      • Sleep disturbances 
      • Medications
      • Smells
      • Neck pain 
      • Cervical manipulation
      • Lights
      • Sounds
      • Alcohol 
      • Cigarette/cigar smoke 
      • Heat 
      • Food (e.g., cheese, chocolate)
      • Exercise 
      • Sexual activity

Physical exam

Physical examination may be entirely normal unless the individual is currently experiencing an attack.

Aura symptoms:

  • Visual
  • Sensory
  • Speech and/or language
  • To be diagnosed with migraine with aura, 3 of 6 features must be present:
    • ≥ 1 aura symptom(s) onset/progression over ≥ 5 minutes
    • ≥ 2 aura symptoms occur together
    • Duration: about 5–60 minutes each
    • ≥ 1 aura symptom is unilateral.
    • ≥ 1 aura symptom is a positive visual symptom.
    • Aura accompanies or precedes headache by ≤ 1 hour.

During an attack:

  • Cutaneous allodynia
  • Focal neurologic deficits
  • Decreased hearing acuity
  • Visual-field deficits
  • Dysarthria
  • Aphasia
  • Ataxia
  • Altered level of consciousness
  • Fever
  • Seizure activity

Specific subtypes

  • Hemiplegic migraine:
    • Aura includes motor weakness plus ≥ 1 of the following:
      • Scotoma
      • Visual-field deficit
      • Sensory symptoms (e.g., numbness, paresthesia)
      • Aphasia
      • Fever
      • Altered level of consciousness (e.g., lethargy, coma) 
      • Seizures
    • Associated with or preceding headache
  • Migraine with brain stem aura:
    • Formerly termed “basilar” migraine
    • Aura symptoms arise from the brain stem:
      • Vertigo/dizziness
      • Tinnitus
      • Decreased hearing acuity
      • Diplopia
      • Dysarthria
      • Ataxia
      • Altered level of consciousness
    • Associated with or preceding headache
  • Retinal migraine:
    • Formerly termed “ocular” migraine
    • Aura involves episodes of unilateral scintillation, scotoma, visual-field deficits, or blindness lasting ≤ 1 hour.
    • Before, during,?”,m or after headache
    • Occasionally leads to permanent visual deficits

Diagnosis

Diagnostic criteria

General:

To diagnose migraine, there should have been ≥ 5 attacks meeting ≥ 2 of the following criteria:

  • Unilateral 
  • Pulsatile quality
  • Moderate to severe intensity
  • Headache duration: 4–72 hours
  • Worsens with physical activity 
  • Associated with:
    • Nausea and/or vomiting
    • Photophobia and/or phonophobia

Migraine with aura:

To diagnose migraine with aura, 3 of the 6 following features must be present:

  • ≥ 1 aura symptom(s) builds in intensity over ≥ 5 minutes.
  • ≥ 2 aura symptoms occur together.
  • Aura symptoms last 5–60 minutes each.
  • ≥ 1 aura symptom is unilateral.
  • ≥ 1 aura symptom is a positive visual symptom.
  • Aura accompanies or precedes headache by ≤ 1 hour.

Laboratory evaluation

  • Laboratory evaluation is indicated only if the following conditions are suspected:
    • Organ dysfunction
    • Volume depletion/overload
    • Electrolyte disturbance
    • Infectious process
  • Laboratory testing should be specific to suspected underlying cause(s):
    • Organ dysfunction:
      • Cardiac biomarkers
      • BUN, creatinine (renal function)
      • AST/ALT (hepatic function)
    • Volume depletion/overload:
      • BUN/creatinine (renal function)
      • AST/ALT (hepatic function)
      • BNP (indicates heart failure)
      • Thyroid studies
    • Electrolyte disturbance: chemistry panel or electrolyte panel
    • Infectious process:
      • CBC
      • CSF studies

Imaging

  • Indication at the initial evaluation of migraine:
    • Headache is associated with neurologic symptoms.
    • Headache presents with focal neurologic findings or seizure.
    • Rule out secondary causes of headache.
  • Repeat imaging only in the following cases:
    • Red flag headache symptoms
    • Focal neurologic findings 
    • Headache characteristics have changed or can no longer be classified as any of the primary headache disorders.
  • Imaging methods:
    • MRI: test of choice
    • CT: faster for triage of suspected acute intracranial hemorrhage

Management

Abortive therapy

Regardless of the abortive strategy used, allowing the migraine sufferer to lie down in a dark, quiet room is favorable.

  • 1st-line therapies:
    • Simple analgesics (single-ingredient, nonopioid, nonbarbiturate):
      • Aspirin
      • Acetaminophen
      • NSAIDs (ibuprofen, naproxen) 
      • More effective if given early in the course of the headache (i.e., onset of prodrome, aura, or pain)
      • May be more effective if used in combination with triptans
      • May need to administer with an antiemetic if nausea and vomiting are present
    • Triptans (oral):
      • More effective if given early in the course of the headache (i.e., onset of prodrome, aura, or pain)
      • May be more effective if used in combination with simple analgesics
      • May need to administer with an antiemetic if nausea and vomiting are present
    • Triptans (subcutaneous, intranasal):
      • May be administered at home (self-injection) or in doctor’s office
      • Rapid onset of action
      • Useful if nausea and vomiting are present
  • 2nd-line therapies:
    • CGRP antagonists 
      • Rimegepant
      • Ubrogepant
    • Lasmiditan (selective serotonin 1F receptor agonist)
    • Dihydroergotamine
  • Severe, refractory migraines or status migrainosus:
    • IV fluids
    • Ketorolac (NSAID) +/– dopamine antagonist (antiemetics that may also abort headaches)
    • Dexamethasone (IM, IV, SC) to prevent headache rebound
  • Antiemetics if nausea and vomiting are present:
    • Prochlorperazine
    • Metoclopramide
    • Chlorpromazine
  • Nonpharmacologic therapy:
    • Interventional pain therapies:
      • Occipital nerve blocks (local anesthetic +/– corticosteroid)
      • Sphenopalatine ganglion blocks (local anesthetic +/– corticosteroid)
    • Neuromodulation:
      • Supraorbital nerve, vagus nerve
      • Transcutaneous electrical and/or magnetic stimulation

Preventive therapy

Goals:

  • Reduce headache burden (frequency, severity, duration).
  • Improve function.
  • Reduce disability.
  • Prevent progression of migraine chronicity.
  • Improve response to abortive therapies. 
  • Avoid toxicity to abortive medications.
  • Prevent medication-overuse headache.

Indications:

  • Episodic and chronic migraine headache 
  • Prevention/treatment of abortive medication-overuse headache and toxicity
  • Frequent or long-lasting migraine headaches
  • Significant migraine-associated disability or diminished quality of life
  • Poor response, intolerance, or contraindication to abortive therapies
  • Menstrual migraine

Preventive treatment options:

  • Beta blockers:
    • Metoprolol, propranolol, timolol 
    • May be useful in those also diagnosed with:
      • Hypertension
      • Tachyarrhythmia
      • Ischemic heart disease
      • Stable heart failure
  • Calcium channel blockers:
    • 1st-line agents
    • Verapamil most widely studied
    • May be useful in those also diagnosed with:
      • Hypertension
      • Tachyarrhythmia
      • Ischemic heart disease
  • ACEis/ARBs:
    • Lisinopril, candesartan 
    • May be useful in those also diagnosed with:
      • Hypertension
      • Stable heart disease
      • Stable CKD
  • Antidepressants:
    • Amitriptyline, venlafaxine 
    • May be useful in those also diagnosed with:
      • Depression
      • Anxiety
      • Chronic pain disorders (especially neuropathic pain)
  • Anticonvulsants:
    • Valproate, topiramate, gabapentin 
    • May be useful in those also diagnosed with:
      • Seizure disorder
      • Chronic pain disorders (especially neuropathic pain)
  • CGRP antagonists:
    • 2nd-line agents
    • Oral agents (-gepant) or injectable (-mab) available:
      • Rimegepant
      • Atogepant
      • Erenumab
      • Fremanezumab
      • Galcanezumab
      • Eptinezumab
  • Botulinum toxin: 
    • 2nd-line agent
    • Injected into cranial/cervical musculature
  • Neuromodulation: 
    • Vagus nerve stimulation
    • Deep brain stimulation
  • Behavioral approaches:
    • Migraine education
    • Trigger desensitization
    • Lifestyle modifications:
      • Avoidance of triggers (e.g., alcohol, strong smells)
      • Regular sleep
      • Exercise
    • CBT
    • Relaxation techniques
    • Biofeedback

Complications

  • Status migrainosus: severe migraine headache lasting > 72 hours (rare; < 1% of migraine cases)
  • Persistent aura without infarction: aura symptoms (+/– headache) persisting ≥ 1 week without clinical evidence of cerebral infarction
  • Migrainous infarction: migraine headache with aura symptoms persisting ≥ 1 hour with clinical evidence of cerebral infarction
  • Migraine aura-triggered seizure: seizure activity associated with a migraine with aura

Differential Diagnosis

  • Vestibular migraine: episodic vertigo in individuals with migraines or with symptoms suggestive of migraine (e.g., photophobia, phonophobia, aura). The association of headache with vertigo is variable, even within the same individual. The diagnosis is clinical after exclusion of Ménière disease, cerebellar disorders, brain stem disorders, and vascular insufficiency. Treatment is aimed at managing the underlying headache and vertigo.
  • Menstrual migraine: migraine headache that occurs in specific phases of the menstrual cycle, most commonly right before or during the period. Estrogen levels are assumed to play a role in pathogenesis. The diagnosis is clinical. Typical migraine therapies should be used for treatment, but a more aggressive approach may be needed. 
  • Tension headache: mild to moderate common primary headache, often bilateral in presentation and without neurologic symptoms. Tension headaches are often self-diagnosed. Management includes rest and simple analgesics.
  • Cluster headache: primary headache that is severe and unilateral, often around the eye, with a duration of minutes up to 3 hours. More common in men. Individuals typically present with accompanying autonomic symptoms, such as nasal congestion and swelling or watering of the eyes. Diagnosis is clinical based on the typical symptoms. Management includes administration of oxygen and triptans and avoiding triggers, such as smoking and alcohol.
  • Medication-overuse headache: also called rebound headache. Medication-overuse headache is a type of secondary headache in individuals who have frequent or daily headaches despite, or because of, the regular use of headache medications. Medication-overuse headache is usually preceded by an episodic primary headache disorder that has been treated with excessive amounts of abortive medications, especially combination drugs with caffeine and codeine. Treatment consists of establishing an effective preventive regimen so that the offending abortive agent(s) may be weaned or discontinued. 
  • Sinus headache: headache that occurs in the setting of acute or chronic sinusitis. The pain is typically described as constant and deep around the cheeks, forehead, or bridge of the nose. Sinus headache is associated with symptoms including a runny nose, swelling or tearing of the eyes, and fever. Management includes decongestants, antihistamines in the case of allergy, and antibiotics in the presence of a bacterial infection.  
  • Cervicogenic headache: headache caused by referred pain from the upper cervical joints. Cervicogenic headache is typically unilateral, of moderate to severe intensity, and increased by movement of the head, with radiation from occipital to frontal regions. Diagnosis is clinical based on typical symptoms. Management includes simple analgesics, physical therapy, nerve blocks, or spinal manipulation.
  • Transient ischemic attack (TIA) or cerebrovascular accident: neurologic signs, symptoms, or deficits attributable to interrupted blood supply to the brain parenchyma. Transient ischemic attack may be the result of arterial occlusion or hemorrhage from disrupted vascular integrity. Diagnosis is made via a thorough history and neurologic examination and confirmed with neuroimaging. Treatment is aimed at restoration of blood flow, prevention of further ischemic events, and treatment of underlying vascular risk factors. 
  • Seizure: spectrum of neurologic disorders affecting intracranial structures. Seizure can manifest as an abnormal neuronal discharge causing neurologic changes, tonic-clonic activity, altered mental status, and/or loss of consciousness. Diagnosis is made with a detailed history and neurologic exam and confirmed with EEG or neuroimaging. Treatment includes antiepileptics and addressing any underlying structural brain disease.

References

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  4. Vogelgsang J, Wolff-Menzler C, Kis B, Abdel-Hamid M, Wiltfang J, Hessmann P. (2018). Cardiovascular and metabolic comorbidities in patients with Alzheimer’s disease and vascular dementia compared to a psychiatric control cohort. Psychogeriatrics 18:393–401. 
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