Migraine

Diseases

Diagnosis:

The diagnosis is clinical: after history & physical exam. On occasion imaging and other tests should be obtained to exclude competing differential diagnoses.
Adapted from International Headache Society IHS Criteria, used mainly in research:

Migraine without aura a.k.a. Common Migraine:

A.     At least 5 attacks fulfilling criteria B through D
B.     Headache lasting from 4-72 hours
C.     Headache has at least 2 of the following characteristics:

  1. unilateral
  2. pulsating
  3. moderate-severe
  4. aggravated by walking stairs or similar activity

D.     During headache, at least 1 of the following occurs:

  1. Nausea and/or vomiting
  2. Photophobia and/or phonophobia

E.     No organic disease

Migraine with aura are a.k.a. Classic Migraine:

A.     At least 2 attacks fulfilling the following characteristics:
B.     At least 3 of the following 4 features present:

  1. Fully reversible aura symptoms indicating focal brain dysfunction
  2. At least 1 aura symptom that develops gradually over more than 4 minutes, or 2 or more symptoms that occur in succession
  3. No single aura symptom lasting more than 60 minutes
  4. Headache usually follows the aura within an hour

C.     No organic disease

Chronic migraine:

Migraine = or >15 days per month for >3 months, without medications overuse.

Status migrainosus:

Migraine attack lasting >72 hours.

Other types:

Typical aura without headache

Some patients will get the typical migraine aura without the headache

Basilar type migraine formerly basilar artery migraine, basilar migraine:
  • Fully reversible
  • Aura with brainstem features without motor weakness
  • E.g. tinnitus, vertigo, diplopia, dysarthria, dysphagia, ataxia, hyperacusis, bilateral paraesthesia, bilateral visual field defects, decreased level of consciousness.
Sporadic hemiplegic migraine:
  • Migraine with aura +motor weakness but no 1st or 2nd degree relative with this condition. Dysphagia & sensory symptoms can occur.
Other features that may occur:
  • Central sensitization: development of allodynia in the head or pain on moving the head after an attack.

Clinical pearls:

  • If woman with miscarriage, check for antiphospholipid syndrome antibodies
  • If with family history of dementia & stroke: tests for CADASIL

 

Pathophysiology of migraine:

Intracranial vasoconstriction leads to the aura. Extracrainal vasodilation leads to the headache:

  • Support for the theory:
    • Vasoconstrictors abort the headache. Amyl nitrite, a vasodilator, gets rid of the aura.
    • In the aura cerebral blood flow decreases in the occipital area & spreads. Later cerebral blood flow increases in parts of the cortex & contralateral brainstem.
  • Against the theory:
    • The decrease in cerebral blood flow doesn’t follow the distribution of the vessels. It’s in cytoarchitectural pattern
    • The effects of valproate & amitriptyline

The current understanding:

  • The phases:
    • The prodrome a.k.a. premonitory: Hypothalamic dysfunction (craving, irritability etc.)
    • Aura: Electrical depolarisation (a.k.a. cortical spreading depression CSD), followed by reduced cerebral blood flow
    • Headache:
      • Trigeminovascular system:
        • CSD activates releases neuropeptides (substance P CGRP, neurokinin A) leading to sterile inflammation of the dura.
        • Trigeminal nerve afferents are activated. 1st order, then 2nd order & 3rd
      • Areas in the brainstem are stimulated e.g. dorsal raphe nuclei
    • Postdrome: feeling wiped out, tired or hung over
  • Support for the theory:
    • Brainstem stimulation in the dorsal raphe nucleus & periaqueductal gray matter leads to migraine headaches
    • CGRP (calcitonin gene-related peptide), a vasodilator, is increased in migraine headache & cluster headache. Serotonin receptor agonist decrease CGRP release (probably via action on presynaptic 5HT1D receptor)
  • 5HT1D on trigeminal nerves causes reduction of proinflammatory neuropeptides & 5HT1B found on meningeal blood vessels

Treatment options:

There are many treatment options for migraine. Generally this includes avoiding triggers, abortive medications for acute attacks. In patients with frequent or disabling attacks prophylactic medications are useful. Lastly, frequent use of abortive medications, >2 days per week, is discouraged as it can lead to medication over-use headache.
Please see pharmacology notes to learn about some of the medications.

General approach:
  • Try to avoid triggers
  • OCP is contraindicated if the migraine condition is severe
Acute treatment, consider:
  • Avoid overuse, use <3 days per week as overuse can contribute to medication overuse headache.
  • Acute treatment s most effective when taken as early as possible
  • A stratified approach: where for mild pain the patient uses simple analgesics. If the patient has severe or refractory pain tryptans or ergot preparations are used. Not that tryptans are less effective once central sensitisation occur.
  • Combined approach: for example sumatriptan/naproxen might be more effective. [RCT]

Simple analgesics:

  • Naproxen sodium, ibuprofen
  • Aspirin +paracetamol +caffeine combinations are often used. There is evidence against Paracetamol alone
  • Ketorolac or diclofenac

Triptans, 5HT1D & 5HT1B receptor agonist:

  • Sumatriptan, Rizatriptan, zolmitriptan, naratriptan, almotriptan (strong evidence base for all of tryptans)
  • Sumatriptan 25, 50, 100 mg orally, 25 mg suppository, 10, 20 mg nasal spray, 6mg subcutaneous (strong evidence base for all formulation)
  • Zolmitriptan 2.5, 5 mg oral including disintegrating form 2.5, 5mg nasal spray (strong evidence base),
  • Naratriptan 2.5 mg oral. Less efficacy but longer efficacy than sumatriptan (strong evidence base)
  • Rizatriptan 10mg oral (strong evidence base)
  • Almotriptan 12.5 mg oral A Probably less side effects than sumatriptan. (strong evidence base)
  • Eletriptan 20, 40 mg oral (strong evidence base)
  • Frovatriptan 2.5 mg oral, Less efficacy but longer efficacy than sumatriptan (strong evidence base)

Ergot preparation:

  • Dihydroergotamine +metoclopramide
  • Inconsistant evidence: for Ergotamine/caffeine

Dexamethasone IV 10-20mg X1 dose as an adjunct in emergency room acute attacks may reduce recurrence. [Metanalysis].
Other agents that have been tried:

  • Magnesium I.V.
  • Haloperidol I.V.
Prophylactic treatment:

Is indicated If:

  • Headache frequency >2 per week or >8 per month
  • Complicated (basilar or Hemiplegic migraine), migraine-induced stroke or prolonged aura >1 hour
  • Disability from headache

prophylactic treatment trial:

  • A trial of 2 months is needed to determine efficacy. i.e. >50% reduction in frequency
  • End of treatment trial: consider discontinuing therapy after 6-12 months of good effect. Discontinue by tapering

Medications that have been used for prophylaxis:

  • In female patients of childbearing potential, make note of pregnancy category and counsel the patient.
  • Betablockers:
    • Metoprolol 50–200 mg (strong evidence base)
    • Propranolol 40–240 mg (strong evidence base)
    • Bisoprolol 5–10 mg (moderate evidence base)
  • Calcium channel blockers
    • Flunarizine 5–10 mg (strong evidence base)
    • Verapamil
  • Antiepileptic drugs
    • Valproic acid 500–1800 mg but avoid in women of childbearing potential (strong evidence base)
    • Topiramate 25–100 mg (strong evidence base)
  • Antidepressants:
    • Amitriptyline 50–150 mg (moderate evidence base)
    • Venlafaxine 75–150 mg (moderate evidence base)
  • CGRP inhibitors:
    • Erenumab subscutaneously 70mg or 140mg monthely [RCT]
    • Fremanezumab subcutaneously monthly [RCT]
  • Botulinum toxin A BTX lasts 3 months, is effective for certain subtypes
  • Naproxen 2 · 250–500 mg (moderate evidence base)
  • Petasites extracts (Butterbur) 2 · 75 mg (moderate evidence base)
  • Riboflavin (B2) 400 mg P.O. [RCT],  Magnesium 400-600 mg P.O. [RCT]

Non-pharmacological measures that have been tried:

  • Acupuncture for prophyaxis, correct needle placement does not seem to be critical [good evidence, by multiple RCTs, and 2009 Cochrane systematic review]
  • Cognitive behaviour therapy CBT
  • Biofeedback
  • Relaxation techniques

Ineffective:

  • Acebutolol, pindolol, Carbamazepine CBZ, nicardipine, nifedipine, indomethacin
  • Homeopathy, TENS, Manipulative treatment,

Related articles:

References:

  1. Silberstein, S.D., et al., Multimechanistic (sumatriptan-naproxen) early intervention for the acute treatment of migraine. Neurology, 2008. 71(2): p. 114-21.
  2. Dahlof, C. and R. Bjorkman, Diclofenac-K (50 and 100 mg) and placebo in the acute treatment of migraine. Cephalalgia, 1993. 13(2): p. 117-23.
  3. Karachalios, G.N., et al., Treatment of acute migraine attack with diclofenac sodium: a double-blind study. Headache, 1992. 32(2): p. 98-100.
  4. Del Bene, E., et al., Intramuscular treatment of migraine attacks using diclofenac sodium: a crossover clinical trial. J Int Med Res, 1987. 15(1): p. 44-8.
  5. A study to compare oral sumatriptan with oral aspirin plus oral metoclopramide in the acute treatment of migraine. The Oral Sumatriptan and Aspirin plus Metoclopramide Comparative Study Group. Eur Neurol, 1992. 32(3): p. 177-84.
  6. Cabarrocas, X., Efficacy and tolerability of subcutaneous almotriptan for the treatment of acute migraine: a randomized, double-blind, parallel-group, dose-finding study. Clin Ther, 2001. 23(11): p. 1867-75.
  7. Honkaniemi, J., et al., Haloperidol in the acute treatment of migraine: a randomized, double-blind, placebo-controlled study. Headache, 2006. 46(5): p. 781-7.
  8. Singh, A., H.J. Alter, and B. Zaia, Does the addition of dexamethasone to standard therapy for acute migraine headache decrease the incidence of recurrent headache for patients treated in the emergency department? A meta-analysis and systematic review of the literature. Acad Emerg Med, 2008. 15(12): p. 1223-33.
  9. Colman, I., et al., Parenteral dexamethasone for acute severe migraine headache: meta-analysis of randomised controlled trials for preventing recurrence. Bmj, 2008. 336(7657): p. 1359-61.
  10. Jensen, R., T. Brinck, and J. Olesen, Sodium valproate has a prophylactic effect in migraine without aura: a triple-blind, placebo-controlled crossover study. Neurology, 1994. 44(4): p. 647-51.
  11. Schoenen, J., J. Jacquy, and M. Lenaerts, Effectiveness of high-dose riboflavin in migraine prophylaxis. A randomized controlled trial. Neurology, 1998. 50(2): p. 466-70.
  12. Peikert, A., C. Wilimzig, and R. Kohne-Volland, Prophylaxis of migraine with oral magnesium: results from a prospective, multi-center, placebo-controlled and double-blind randomized study. Cephalalgia, 1996. 16(4): p. 257-63.
  13. Linde K, Allais G, Brinkhaus B, Manheimer E, Vickers A, White AR. Acupuncture for migraine prophylaxis. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD001218. DOI: 10.1002/14651858.CD001218.pub2.
  14. Silberstein SD, Dodick DW, Bigal ME, Yeung PP, Goadsby PJ, Blankenbiller T, Grozinski-Wolff M, Yang R, Ma Y, Aycardi E. Fremanezumab for the Preventive Treatment of Chronic Migraine. N Engl J Med. 2017 Nov 30;377(22):2113-2122. doi: 10.1056/NEJMoa1709038. PMID: 29171818.
  15. Goadsby PJ, Reuter U, Hallström Y, Broessner G, Bonner JH, Zhang F, Sapra S, Picard H, Mikol DD, Lenz RA. A Controlled Trial of Erenumab for Episodic Migraine. N Engl J Med. 2017 Nov 30;377(22):2123-2132. doi: 10.1056/NEJMoa1705848. PMID: 29171821.