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Episodic Migraine With and Without Aura: Key Differences and Implications for Pathophysiology, Management, and Assessing Risks

  • Angeliki Vgontzas
  • Rebecca Burch
Episodic Migraine (S Nahas, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Episodic Migraine

Abstract

Purpose of Review

To review the pathophysiologic, epidemiologic, and clinical evidence for similarities and differences between migraine with and without aura.

Recent Findings

The ICHD-3 has recently refined the diagnostic criteria for aura to include positive symptomatology, which better differentiates aura from TIA. Although substantial evidence supports cortical spreading depression as the cause of visual aura, the role (if any) of CSD in headache pain is not well understood. Recent imaging evidence suggests a possible hypothalamic origin for a headache attack, but further research is needed. Migraine with aura is associated with a modest increase in the risk of ischemic stroke. The etiology for this association remains unclear. There is a paucity of evidence regarding treatments specifically aimed at the migraine with aura subtype, or whether migraine with vs without aura responds to treatment differently. Migraine with typical aura is therefore often treated similarly to migraine without aura. Lamotrigine, daily aspirin, and flunarizine have evidence for efficacy in prevention of migraine with aura, and magnesium, ketamine, furosemide, and single-pulse transcranial magnetic stimulation have evidence for use as acute treatments. Although triptans have traditionally been contraindicated in hemiplegic migraine and migraine with brainstem aura, this prohibition is being reconsidered in the face of evidence suggesting that use may be safe.

Summary

The debate as to whether migraine with and without aura are different entities is ongoing. In an era of sophisticated imaging, genetic advancement, and ongoing clinical trials, efforts to answer this question are likely to yield important and clinically meaningful results.

Keywords

Migraine Migraine with aura Migraine pathophysiology Hemiplegic migraine Brainstem aura Aura treatment Cardiovascular risk 

Notes

Compliance with Ethical Standards

Conflict of Interest

Angeliki Vgontzas and Rebecca Burch declare no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Buse DC, Loder EW, Gorman JA, Stewart WF, Reed ML, Fanning KM, et al. Sex differences in the prevalence, symptoms, and associated features of migraine, probable migraine and other severe headache: results of the American Migraine Prevalence and Prevention (AMPP) Study. Headache. 2013;53(8):1278–99.CrossRefGoogle Scholar
  2. 2.
    Tfelt-Hansen PC. History of migraine with aura and cortical spreading depression from 1941 and onwards. Cephalalgia. 2010;30(7):780–92.CrossRefGoogle Scholar
  3. 3.
    Olesen J. International classification of headache disorders. Lancet Neurol. 2018;17:396–7.CrossRefGoogle Scholar
  4. 4.
    Blau JN. Migraine prodromes separated from the aura: complete migraine. Br Med J. 1980;281(6241):658–60.CrossRefGoogle Scholar
  5. 5.
    Giffin NJ, Lipton RB, Silberstein SD, Olesen J, Goadsby PJ. The migraine postdrome: an electronic diary study. Neurology. 2016;87(3):309–13.CrossRefGoogle Scholar
  6. 6.
    • Lebedeva ER, Gurary NM, Gilev DV, Olesen J. Prospective testing of ICHD-3 beta diagnostic criteria for migraine with aura and migraine with typical aura in patients with transient ischemic attacks. Cephalalgia. 2018;38(3):561–7 A study showing that the revised migraine with aura criteria better differentiate migraine aura from TIA. CrossRefGoogle Scholar
  7. 7.
    Russell MB, Rasmussen BK, Fenger K, Olesen J. Migraine without aura and migraine with aura are distinct clinical entities: a study of four hundred and eighty-four male and female migraineurs from the general population. Cephalalgia. 1996;16(4):239–45.CrossRefGoogle Scholar
  8. 8.
    Eriksen MK, Thomsen LL, Olesen J. The Visual Aura Rating Scale (VARS) for migraine aura diagnosis. Cephalalgia. 2005;25(10):801–10.CrossRefGoogle Scholar
  9. 9.
    Bickerstaff ER. Impairment of consciousness in migraine. Lancet. 1961;2(7211):1057–9.CrossRefGoogle Scholar
  10. 10.
    Kirchmann M, Thomsen LL, Olesen J. Basilar-type migraine: clinical, epidemiologic, and genetic features. Neurology. 2006;66(6):880–6.CrossRefGoogle Scholar
  11. 11.
    Li D, Christensen AF, Olesen J. Field-testing of the ICHD-3 beta/proposed ICD-11 diagnostic criteria for migraine with aura. Cephalalgia. 2015;35(9):748–56.CrossRefGoogle Scholar
  12. 12.
    Leao AA. Spreading depression of activity in the cerebral cortex. J Neurophysiol. 1944;7(6).Google Scholar
  13. 13.
    Sugaya E, Takato M, Noda Y. Neuronal and glial activity during spreading depression in cerebral cortex of cat. J Neurophysiol. 1975;38(4):822–41.CrossRefGoogle Scholar
  14. 14.
    Shinohara M, Dollinger B, Brown G, Rapoport S, Sokoloff L. Cerebral glucose utilization: local changes during and after recovery from spreading cortical depression. Science. 1979;203(4376):188–90.CrossRefGoogle Scholar
  15. 15.
    Busija DW, Bari F, Domoki F, Horiguchi T, Shimizu K. Mechanisms involved in the cerebrovascular dilator effects of cortical spreading depression. Prog Neurobiol. 2008;86(4):379–95.CrossRefGoogle Scholar
  16. 16.
    Cutrer FM, Sorensen AG, Weisskoff RM, Ostergaard L, Sanchez del Rio M, Lee EJ, et al. Perfusion-weighted imaging defects during spontaneous migrainous aura. Ann Neurol. 1998;43(1):25–31.CrossRefGoogle Scholar
  17. 17.
    •• Hadjikhani N, Sanchez Del Rio M, Wu O, Schwartz D, Bakker D, Fischl B, et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci U S A. 2001;98(8):4687–92 Imaging study showing that migraine aura is caused by cortical spreading depression. CrossRefGoogle Scholar
  18. 18.
    Richter F, Lehmenkuhler A. Cortical spreading depression (CSD): a neurophysiological correlate of migraine aura. Schmerz. 2008;22(5):544–6 8-50.CrossRefGoogle Scholar
  19. 19.
    Moskowitz MA. Neurogenic inflammation in the pathophysiology and treatment of migraine. Neurology. 1993;43(6 Suppl 3):S16–20.PubMedGoogle Scholar
  20. 20.
    Zhang X, Levy D, Kainz V, Noseda R, Jakubowski M, Burstein R. Activation of central trigeminovascular neurons by cortical spreading depression. Ann Neurol. 2011;69(5):855–65.CrossRefGoogle Scholar
  21. 21.
    Hougaard A, Amin FM, Christensen CE, Younis S, Wolfram F, Cramer SP, et al. Increased brainstem perfusion, but no blood-brain barrier disruption, during attacks of migraine with aura. Brain. 2017;140(6):1633–42.CrossRefGoogle Scholar
  22. 22.
    May A, Goadsby PJ. Substance P receptor antagonists in the therapy of migraine. Expert Opin Investig Drugs. 2001;10(4):673–8.CrossRefGoogle Scholar
  23. 23.
    Goldstein DJ, Offen WW, Klein EG, Phebus LA, Hipskind P, Johnson KW, et al. Lanepitant, an NK-1 antagonist, in migraine prevention. Cephalalgia. 2001;21(2):102–6.CrossRefGoogle Scholar
  24. 24.
    May A, Gijsman HJ, Wallnofer A, Jones R, Diener HC, Ferrari MD. Endothelin antagonist bosentan blocks neurogenic inflammation, but is not effective in aborting migraine attacks. Pain. 1996;67(2–3):375–8.CrossRefGoogle Scholar
  25. 25.
    Borgdorff P. Arguments against the role of cortical spreading depression in migraine. Neurol Res. 2018;40(3):173–81.CrossRefGoogle Scholar
  26. 26.
    Brennan KC, Pietrobon D. A systems neuroscience approach to migraine. Neuron. 2018;97(5):1004–21.CrossRefGoogle Scholar
  27. 27.
    Charles AC, Baca SM. Cortical spreading depression and migraine. Nat Rev Neurol. 2013;9(11):637–44.CrossRefGoogle Scholar
  28. 28.
    Pietrobon D, Moskowitz MA. Pathophysiology of migraine. Annu Rev Physiol. 2013;75:365–91.CrossRefGoogle Scholar
  29. 29.
    Hauge AW, Asghar MS, Schytz HW, Christensen K, Olesen J. Effects of tonabersat on migraine with aura: a randomised, double-blind, placebo-controlled crossover study. Lancet Neurol. 2009;8(8):718–23.CrossRefGoogle Scholar
  30. 30.
    Tozzi A, de Iure A, Di Filippo M, Costa C, Caproni S, Pisani A, et al. Critical role of calcitonin gene-related peptide receptors in cortical spreading depression. Proc Natl Acad Sci U S A. 2012;109(46):18985–90.CrossRefGoogle Scholar
  31. 31.
    Piper RD, Edvinsson L, Ekman R, Lambert GA. Cortical spreading depression does not result in the release of calcitonin gene-related peptide into the external jugular vein of the cat: relevance to human migraine. Cephalalgia. 1993;13(3):180–3 discussion 49.CrossRefGoogle Scholar
  32. 32.
    Ebersberger A, Schaible HG, Averbeck B, Richter F. Is there a correlation between spreading depression, neurogenic inflammation, and nociception that might cause migraine headache? Ann Neurol. 2001;49(1):7–13.CrossRefGoogle Scholar
  33. 33.
    •• Schulte LH, May A. The migraine generator revisited: continuous scanning of the migraine cycle over 30 days and three spontaneous attacks. Brain. 2016;139(Pt 7):1987–93 Study showing that the hypothalamus is involved in generation of a migraine attack. CrossRefGoogle Scholar
  34. 34.
    Mahmoud AN, Mentias A, Elgendy AY, Qazi A, Barakat AF, Saad M, et al. Migraine and the risk of cardiovascular and cerebrovascular events: a meta-analysis of 16 cohort studies including 1 152 407 subjects. BMJ Open. 2018;8(3):e020498.CrossRefGoogle Scholar
  35. 35.
    Lantz M, Sieurin J, Sjolander A, Waldenlind E, Sjostrand C, Wirdefeldt K. Migraine and risk of stroke: a national population-based twin study. Brain. 2017;140(10):2653–62.CrossRefGoogle Scholar
  36. 36.
    Kurth T, Winter AC, Eliassen AH, Dushkes R, Mukamal KJ, Rimm EB, et al. Migraine and risk of cardiovascular disease in women: prospective cohort study. BMJ. 2016;353:i2610.CrossRefGoogle Scholar
  37. 37.
    • Adelborg K, Szepligeti SK, Holland-Bill L, Ehrenstein V, Horvath-Puho E, Henderson VW, et al. Migraine and risk of cardiovascular diseases: Danish population based matched cohort study. BMJ. 2018;360:k96 Observational study showing increased risk of cardiovascular disease in migraine with aura.CrossRefGoogle Scholar
  38. 38.
    Tietjen GE, Collins SA. Hypercoagulability and migraine. Headache. 2018;58(1):173–83.CrossRefGoogle Scholar
  39. 39.
    Bashir A, Lipton RB, Ashina S, Ashina M. Migraine and structural changes in the brain: a systematic review and meta-analysis. Neurology. 2013;81(14):1260–8.CrossRefGoogle Scholar
  40. 40.
    Hauge AW, Hougaard A, Olesen J. On the methodology of drug trials in migraine with aura. Cephalalgia. 2010;30(9):1041–8.CrossRefGoogle Scholar
  41. 41.
    Ayata C, Jin H, Kudo C, Dalkara T, Moskowitz MA. Suppression of cortical spreading depression in migraine prophylaxis. Ann Neurol. 2006;59(4):652–61.CrossRefGoogle Scholar
  42. 42.
    Lampl C, Katsarava Z, Diener HC, Limmroth V. Lamotrigine reduces migraine aura and migraine attacks in patients with migraine with aura. J Neurol Neurosurg Psychiatry. 2005;76(12):1730–2.CrossRefGoogle Scholar
  43. 43.
    Pascual J, Caminero AB, Mateos V, Roig C, Leira R, Garcia-Monco C, et al. Preventing disturbing migraine aura with lamotrigine: an open study. Headache. 2004;44(10):1024–8.CrossRefGoogle Scholar
  44. 44.
    Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the quality standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1337–45.CrossRefGoogle Scholar
  45. 45.
    Bogdanov VB, Multon S, Chauvel V, Bogdanova OV, Prodanov D, Makarchuk MY, et al. Migraine preventive drugs differentially affect cortical spreading depression in rat. Neurobiol Dis. 2011;41(2):430–5.CrossRefGoogle Scholar
  46. 46.
    Reuter U, Del Rio MS, Diener HC, Allais G, Davies B, Gendolla A, et al. Migraines with and without aura and their response to preventive therapy with topiramate. Cephalalgia. 2010;30(5):543–51.CrossRefGoogle Scholar
  47. 47.
    Alemdar M, Akman O, Selekler H, Komsuoglu S, Ates N. Does metoprolol inhibit the cortical spreading depression? Acute effects of systematic metropol on CSD in rats. Cephalalgia. 2007;27(9):1010–3.CrossRefGoogle Scholar
  48. 48.
    Bates D, Ashford E, Dawson R, Ensink FB, Gilhus NE, Olesen J, et al. Subcutaneous sumatriptan during the migraine aura. Sumatriptan Aura Study Group. Neurology. 1994;44(9):1587–92.CrossRefGoogle Scholar
  49. 49.
    Banerjee M, Findley LJ. Sumatriptan in the treatment of acute migraine with aura. Cephalalgia. 1992;12(1):39–44.CrossRefGoogle Scholar
  50. 50.
    Aurora SK, Barrodale PM, McDonald SA, Jakubowski M, Burstein R. Revisiting the efficacy of sumatriptan therapy during the aura phase of migraine. Headache. 2009;49(7):1001–4.CrossRefGoogle Scholar
  51. 51.
    Bu F, Du R, Li Y, Quinn JP, Wang M. NR2A contributes to genesis and propagation of cortical spreading depression in rats. Sci Rep. 2016;6:23576.CrossRefGoogle Scholar
  52. 52.
    Kaube H, Herzog J, Kaufer T, Dichgans M, Diener HC. Aura in some patients with familial hemiplegic migraine can be stopped by intranasal ketamine. Neurology. 2000;55(1):139–41.CrossRefGoogle Scholar
  53. 53.
    Afridi SK, Giffin NJ, Kaube H, Goadsby PJ. A randomized controlled trial of intranasal ketamine in migraine with prolonged aura. Neurology. 2013;80(7):642–7.CrossRefGoogle Scholar
  54. 54.
    Marmura MJ, Silberstein SD, Schwedt TJ. The acute treatment of migraine in adults: the american headache society evidence assessment of migraine pharmacotherapies. Headache. 2015;55(1):3–20.CrossRefGoogle Scholar
  55. 55.
    Lipton RB, Dodick DW, Silberstein SD, Saper JR, Aurora SK, Pearlman SH, et al. Single-pulse transcranial magnetic stimulation for acute treatment of migraine with aura: a randomised, double-blind, parallel-group, sham-controlled trial. Lancet Neurol. 2010;9(4):373–80.CrossRefGoogle Scholar
  56. 56.
    Rozen TD. Treatment of a prolonged migrainous aura with intravenous furosemide. Neurology. 2000;55(5):732–3.CrossRefGoogle Scholar
  57. 57.
    de Almeida RF, Leao IA, Gomes JB, da Silva AA Jr, Teixeira AL. Migraine with persistent visual aura: response to furosemide. Clinics (Sao Paulo). 2009;64(4):375–6.CrossRefGoogle Scholar
  58. 58.
    Lim J, Jo KD, Lee MK, Jang W. Persistent negative visual aura in migraine without headache: a case report. J Med Case Rep. 2014;8:61.CrossRefGoogle Scholar
  59. 59.
    Amin FM, Asghar MS, Ravneberg JW, de Koning PJ, Larsson HB, Olesen J, et al. The effect of sumatriptan on cephalic arteries: a 3T MR-angiography study in healthy volunteers. Cephalalgia. 2013;33(12):1009–16.CrossRefGoogle Scholar
  60. 60.
    Artto V, Nissila M, Wessman M, Palotie A, Farkkila M, Kallela M. Treatment of hemiplegic migraine with triptans. Eur J Neurol. 2007;14(9):1053–6.CrossRefGoogle Scholar
  61. 61.
    Klapper J, Mathew N, Nett R. Triptans in the treatment of basilar migraine and migraine with prolonged aura. Headache. 2001;41(10):981–4.CrossRefGoogle Scholar
  62. 62.
    Mathew PG, Krel R, Buddhdev B, Ansari H, Joshi SG, Spinner WD, et al. A retrospective analysis of triptan and the use for basilar and hemiplegic migraine. Headache. 2016;56:841–8.CrossRefGoogle Scholar
  63. 63.
    • Pelzer N, Stam AH, Haan J, Ferrari MD, Terwindt GM. Familial and sporadic hemiplegic migraine: diagnosis and treatment. Curr Treat Options Neurol. 2013;15(1):13–27 Comprehensive review of management of hemiplegic migraine.CrossRefGoogle Scholar
  64. 64.
    Kurth T, Diener HC, Buring JE. Migraine and cardiovascular disease in women and the role of aspirin: subgroup analyses in the Women’s Health Study. Cephalalgia. 2011;31(10):1106–15.CrossRefGoogle Scholar
  65. 65.
    Turk WE, Uiterwijk A, Pasmans R, Meys V, Ayata C, Koehler PJ. Aspirin prophylaxis for migraine with aura: an observational case series. Eur Neurol. 2017;78(5–6):287–9.CrossRefGoogle Scholar
  66. 66.
    Anoaica MB, Anoaica PG, Popescu F. Acetylsalicylic acid in migraine with aura prevention - a retrospective study. Curr Health Sci J. 2014;40(2):126–8.PubMedPubMedCentralGoogle Scholar
  67. 67.
    CDC. US Medical Eligibility Criteria (US MEC) for contraceptive use. In: Services HaH, editor. 2017.Google Scholar
  68. 68.
    Calhoun AH, Gill N. Presenting a new, non-hormonally mediated cyclic headache in women: end-menstrual migraine. Headache. 2017;57(1):17–20.CrossRefGoogle Scholar
  69. 69.
    Sheikh HU, Pavlovic J, Loder E, Burch R. Risk of stroke associated with use of estrogen containing contraceptives in women with migraine: a systematic review. Headache. 2018;58(1):5–21.CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Graham Headache Center, Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA

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