Relapsing Painful Ophthalmoplegic Neuropathy: No longer a “Migraine,” but Still a Headache

  • Stacy V. Smith
  • Nathaniel M. Schuster
Uncommon and/or Unusual Headaches and Syndromes (J Ailani, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Uncommon and/or Unusual Headaches and Syndromes


Purpose of Review

Recurrent painful ophthalmoplegic neuropathy (RPON), formerly known as ophthalmoplegic migraine, is an uncommon disorder with repeated episodes of ocular cranial nerve neuropathy associated with ipsilateral headache. This review discusses the clinical presentation, current understanding of the pathophysiology, key differential diagnoses, and evaluation and treatment of RPON.

Recent Findings

The literature is limited due to the rarity of the disorder. Recent case reports and series continue to suggest the age of first attack is most often during childhood or adolescence as well as a female predominance. Multiple recent case reports and series demonstrate focal enhancement of the affected cranial nerve, as the nerve root exits the brainstem. This finding contributed to the current classification of the disorder as a neuropathy, with the present understanding that it is due to a relapsing-remitting inflammatory or demyelinating process. The link to migraine remains a cause of disagreement in the literature.


RPON is a complex disorder with features of inflammatory neuropathy and an unclear association with migraine. Regardless, the overall prognosis is good for individual episodes, but permanent nerve damage may accumulate with repeated attacks. A better understanding of the pathogenesis is needed to clarify whether it truly represents a single disorder and to guide its treatment. Until that time, a combined approach with acute and preventive therapies can mitigate acute symptoms as well as attempt to limit recurrence of this disabling syndrome.


Ophthalmoplegic migraine Cranial neuropathy External ophthalmoplegia Relapsing neuropathy Demyelinating neuropathy 


Compliance with Ethical Standards

Conflict of Interest

The authors declare that there is 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.


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

  1. 1.
    Notta A. Mémoire sur les lésions functionneles qui sont sous la dépendence des néuralgies. Arch gen med 5 me sér. 1854;4:1–29. 290–316Google Scholar
  2. 2.
    Gubler A. Paralysie de la troisieme paire droite, recidivant pour la troisieme fois. Gazette des Hospitaux Civil et Militaires. 1860;33:65–6.Google Scholar
  3. 3.
    Charcot JM. Sur un cas de migraine ophtalmoplégique (paralysie oculo-motrice periodique). Prog Med (Paris). 1890;31:83–6. 32:99–102Google Scholar
  4. 4.
    Headache Society Classification Committee of the International Headache Society. Classification and criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia. 1988;8(suppl 7):1–96.Google Scholar
  5. 5.
    Headache Classification Subcommittee of the International Headache Society. The international classification of headache disorders: 2nd edition. Cephalalgia. 2004;24(Suppl 1):9.Google Scholar
  6. 6.
    Headache Classification Committee of the International Headache Society. The international classification of headache disorders, 3rd edition (beta version). Cephalalgia. 2013;33:629–808.CrossRefGoogle Scholar
  7. 7.
    •• Headache Classification Committee of the International Headache Society. The international classification of headache disorders: 3rd edition. Cephalalgia. 2018;38:1–211. The International Headache Society finalized the most recent version of the recurrent painful ophthalmoplegic neuropathy criteria.CrossRefGoogle Scholar
  8. 8.
    Pacheva IH, Ivanov IS. Migraine variants—occurrence in pediatric neurology practice. Clin Neurol Neurosurg. 2013;115:1775–83. Scholar
  9. 9.
    Wang Y, Wang XH, Tian MM, Xie CJ, Liu Y, Pan QQ, et al. Ophthalmoplegia starting with a headache circumscribed in a line-shaped area: a subtype of ophthalmoplegic migraine? J Headache Pain. 2014;15:19.
  10. 10.
    Huang C, Amasanti M, Lovell B, Young T. Recurrent painful ophthalmoplegic neuropathy. Pract Neurol. 2017;17:318–20. Scholar
  11. 11.
    • Friedman DI. The ophthalmoplegic migraines: a proposed classification. Cephalalgia. 2010;30:646–7. Friedman discusses a set of alternative diagnostic criteria that reflects the heterogeneity of patient presentation. CrossRefPubMedGoogle Scholar
  12. 12.
    Hansen SL, Borelli-Møller L, Strange P, Nielsen BM, Olesen J. Ophthalmoplegic migraine: diagnostic criteria, incidence of hospitalization and possible etiology. Acta Neurol Scand. 1990;81:54–60.CrossRefPubMedGoogle Scholar
  13. 13.
    •• Gelfand AA, Gelfand JM, Prabakhar P, Goadsby PJ. Ophthalmoplegic “migraine” or recurrent ophthalmoplegic cranial neuropathy: new cases and a systematic review. J Child Neurol. 2012;27:759–66. The authors performed a systematic review of cases with magnetic resonance imaging. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Friedman DI. Silberstein SD. Medlink: Recurrent painful ophthalmoplegic neuropathy; 2017. Accessed February 7, 2018 at
  15. 15.
    Evers S. Facial pain: overlapping syndromes. Cephalalgia. 2017;37:705–13. Scholar
  16. 16.
    Tocco P, Fenzi F, Cerini R, Monaco S. Adult-onset migraine-related ophthalmoplegia and omolateral fetal-type posterior cerebral artery. BMJ Case Rep. 2011:pii:bcr1020114930;
  17. 17.
    Lyerly MJ, Peterson BW, Lara AK, McGrath TM. Ophthalmoplegic migraine. Headache. 2011;51:1167–8. Scholar
  18. 18.
    Roy M, Ghosh J, Deb S, Pandit N. Childhood steroid-responsive ophthalmoplegic migraine. J Pediatr Neurosci. 2011;6:69–71. Scholar
  19. 19.
    Patro S, Banerjee T. A case of ophthalmoplegic migraine: some observations. Neuroradiol J. 2011;24:862–6.CrossRefPubMedGoogle Scholar
  20. 20.
    Rocha AJ, Breinis P, Monteiro ML. Magnetic resonance appearance of recurrent ophthalmoplegic migraine. Arq Neuropsiquiatr. 2012;70:77.CrossRefPubMedGoogle Scholar
  21. 21.
    • Chakravarty A, Mukherjee A. Ophthalmoplegic migraine: a critical analysis and a new proposal. Ann Indian Acad Neurol. 2012;15(Suppl 1):S2–6. The authors compiled a large case series of adult patients, although most cases did not meet the current diagnostic criteria. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Maggioni F, Briani C, Margoni M, Zanchin G. Ophthalmoplegic migraine: could electroencephalogram still be a useful tool to better understand the pathogenetic mechanism? Cephalalgia. 2012;32:1227–9. Scholar
  23. 23.
    Sobreira I, Sousa C, Raposo A, Fagundes F, Dias AI. Ophthalmoplegic migraine with persistent dilated pupil. J Child Neurol. 2013;28:275–6. Scholar
  24. 24.
    Sharma B, Sannegowda RB, Kumar S, Dubey P. Ophthalmoplegic migraine with trigeminal nerve involvement. BMJ Case Rep. 2013:pii:bcr2013009630;
  25. 25.
    Shetty A, Khardenavis S, Deshpande A. Ophthalmoplegic migraine with isolated third cranial nerve palsy in a known case of juvenile myoclonic epilepsy. BMJ Case Rep. 2013:pii:bcr2013201718;
  26. 26.
    Ghosh PS. Recurrent right-sided ptosis in a child. Recurrent painful ophthalmoplegic neuropathy. JAMA Pediatr. 2015;169:693–4. Scholar
  27. 27.
    Chan JW, Albretson J. Causes of isolated recurrent ipsilateral sixth nerve palsies in older adults: a case series and review of the literature. Clin Ophthalmol. 2015;9:373–7. Scholar
  28. 28.
    Takizawa T, Shibata M, Fujiwara H, Shimizu T, Momoshima S, Suzuki N. Adult-onset recurrent painful ophthalmoplegic neuropathy displaying atypical oculomotor nerve gadolinium-enhancement pattern in the orbit and cavernous sinus. Cephalalgia. 2016;36:199–200. Scholar
  29. 29.
    Tripathi R, Tselis A, Bernitsas E. Bilateral cisternal abducens nerve involvement with ophthalmoplegic migraine. Cephalalgia. 2017;37:1211–2. Scholar
  30. 30.
    Kobayashi Y, Kondo Y, Uchibori K, Tsuyuzaki J. Recurrent painful ophthalmoplegic neuropathy with residual mydriasis in an adult: should it be classified as ophthalmoplegic migraine? Intern Med. 2017;56:2769–72. Scholar
  31. 31.
    Okura Y, Wakayama A, Yoshizawa C, Kobayashi I, Takahashi Y. Recurrent painful ophthalmoplegic neuropathy in a 12-year-old boy. Pediatr Int. 2017;59:1208–10. Scholar
  32. 32.
    Hung CH, Chang KH, Chu CC, Liao MF, Chang HS, Lyu RK, et al. Painful ophthalmoplegia with normal cranial imaging. BMC Neurol. 2014;14:7.
  33. 33.
    McMillan HJ, Keene DL, Jacob P, Humphreys P. Ophthalmoplegic migraine: inflammatory neuropathy with secondary migraine? Can J Neurol Sci. 2007;34:349–55.CrossRefPubMedGoogle Scholar
  34. 34.
    Peck R. Ophthalmoplegic migraine presenting in infancy: a self-reported case. Cephalalgia. 2006;26:1242–4.CrossRefPubMedGoogle Scholar
  35. 35.
    Romano LM, Besocke AG. Teaching video neuroimages: recurrent oculomotor neuropathy with isolated ptosis vs ophthalmoplegic migraine. Neurology. 2009;72:e44. Scholar
  36. 36.
    Gulkilik G, Cagatay HH, Oba EM, Uslu C. Ophthalmoplegic migraine associated with recurrent isolated ptosis. Ann Ophthalmol (Skokie). 2009;41:206–7.Google Scholar
  37. 37.
    Stidham DB, Butler IJ. Recurrent isolated ptosis in presumed ophthalmoplegic migraine of childhood. Ophthalmology. 2000;107:1476–8.CrossRefPubMedGoogle Scholar
  38. 38.
    Barriga FJ, López de Silanes C, Gili P, Pareja JA. Ciliary ganglioplegic migraine: migraine-related prolonged mydriasis. Cephalalgia. 2011;31:291–5. Scholar
  39. 39.
    Bek S, Genc G, Demirkaya S, Eroglu E, Odabasi Z. Ophthalmoplegic migraine. Neurologist. 2009;15:147–9. Scholar
  40. 40.
    Choi JY, Jang SH, Park MH, Kim BJ, Lee DH. Ophthalmoplegic migraine with alternating unilateral and bilateral internal ophthalmoplegia. Headache. 2007;47:726–8.CrossRefPubMedGoogle Scholar
  41. 41.
    Arasho BD. Ophthalmoplegic migraine in a 15-year-old Ethiopian: case report and literature review. J Headache Pain. 2009;10:45–9. Scholar
  42. 42.
    Iannetti P, Spalice A, Iannetti L, Verrotti A, Parisi P. Residual and persistent Adie’s pupil after pediatric ophthalmoplegic migraine. Pediatr Neurol. 2009;41:204–6. Scholar
  43. 43.
    Lal V, Sahota P, Singh P, Gupta A, Prabhakar S. Ophthalmoplegia with migraine in adults: is it ophthalmoplegic migraine? Headache. 2009;49:838–50. Scholar
  44. 44.
    Bharucha DX, Campbell TB, Valencia I, Hardison HH, Kothare SV. MRI findings in pediatric ophthalmoplegic migraine: a case report and literature review. Pediatr Neurol. 2007;37:59–63.CrossRefPubMedGoogle Scholar
  45. 45.
    Lavin PJ, Aulino JM, Uskavitch D. “Ophthalmoplegic migraine” with reversible MRI enhancement of the cisternal sixth cranial nerve. J Neuroophthalmol. 2009;29:151–3. Scholar
  46. 46.
    Lee TG, Choi WS, Chung KC. Ophthalmoplegic migraine with reversible enhancement of intraparenchymal abducens nerve on MRI. Headache. 2002;42:140–1.CrossRefPubMedGoogle Scholar
  47. 47.
    van der Dussen DH, Bloem BR, Liauw L, Ferrari MD. Ophthalmoplegic migraine: migrainous or inflammatory? Cephalalgia. 2004;24:312–5.CrossRefPubMedGoogle Scholar
  48. 48.
    Walsh JP, O'Doherty DS. A possible explanation of the mechanism of ophthalmoplegic migraine. Neurology. 1960;10:1079–84.CrossRefPubMedGoogle Scholar
  49. 49.
    Lane R, Davies P. Ophthalmoplegic migraine: the case for reclassification. Cephalalgia. 2010;30:655–61. Scholar
  50. 50.
    Lance JW, Zagami AS. Ophthalmoplegic migraine: a recurrent demyelinating neuropathy? Cephalalgia. 2001;21:84–9.CrossRefPubMedGoogle Scholar
  51. 51.
    Carlow TJ. Oculomotor ophthalmoplegic migraine: is it really migraine? J Neuroophthalmol. 2002;22:215–21.CrossRefPubMedGoogle Scholar
  52. 52.
    Miglio L, Feraco P, Tani G, Ambrosetto P. Computed tomography and magnetic resonance imaging findings in ophthalmoplegic migraine. Pediatr Neurol. 2010;42:434–6. Scholar
  53. 53.
    Shin DJ, Kim JH, Kang SS. Ophthalmoplegic migraine with reversible thalamic ischemia shown by brain SPECT. Headache. 2002;42:132–5.CrossRefPubMedGoogle Scholar
  54. 54.
    Margari L, Legrottaglie AR, Craig F, Petruzzelli MG, Procoli U, Dicuonzo F. Ophthalmoplegic migraine: migraine or oculomotor neuropathy? Cephalalgia. 2012;32:1208–15. Scholar
  55. 55.
    Linn J, Schwarz F, Reinisch V, Straube A. Ophthalmoplegic migraine with paresis of the sixth nerve: a neurovascular compression syndrome? Cephalalgia. 2008;28:667–70. Scholar
  56. 56.
    Vieira JP, Castro J, Gomes LB, Jacinto S, Dias A. Ophthalmoplegic migraine and infundibular dilatation of a cerebral artery. Headache. 2008;48:1372–4. Scholar
  57. 57.
    Gladstone JP. An approach to the patient with painful ophthalmoplegia, with a focus on Tolosa-Hunt syndrome. Curr Pain Headache Rep. 2007;11:317–25.CrossRefPubMedGoogle Scholar
  58. 58.
    Kim R, Kim JH, Kim E, Yang HK, Hwang JM, Kim JS. Oculomotor nerve tumors masquerading as recurrent painful ophthalmoplegic neuropathy: report of two cases and review of the literature. Cephalalgia. 2015;35:825–30. Scholar
  59. 59.
    • Shin RK, Mejico LJ, Kawasaki A, Purvin VA, Moster ML, Younge BR, et al. Transient ocular motor nerve palsies associated with presumed cranial nerve schwannomas. J Neuroophthalmol. 2015;35:139–43. Schwannoma is an important differential diagnosis in RPON, as it can mimic not only the clinical symptoms but also the imaging abnormality.
  60. 60.
    Wang QJ, Guo Y, Zhang Y, Hu YY, Li WP, Lu W, et al. 3D MRI of oculomotor nerve schwannoma in the prepontine cistern: a case report. Clin Imaging. 2013;37:947–9.
  61. 61.
    Bisdorff AR, Wildanger G. Oculomotor nerve schwannoma mimicking ophthalmoplegic migraine. Cephalalgia. 2006;26:1157–9.CrossRefPubMedGoogle Scholar
  62. 62.
    Murakami T, Funatsuka M, Komine M, Hirayama Y, Suzuki H, Shishikura K, et al. Oculomotor nerve schwannoma mimicking ophthalmoplegic migraine. Neuropediatrics. 2005;36:395–8.Google Scholar
  63. 63.
    Shin RK, Mejico LJ, Boghen D. Re: oculomotor nerve tumors masquerading as recurrent painful ophthalmoplegic neuropathy. Cephalalgia. 2016;36:814. Scholar
  64. 64.
    Akimoto J, Fukami S, Hashimoto R, Haraoka J. Neuromuscular hamartoma is a possible primary pathology of oculomotor ophthalmoplegic migraine. Cephalalgia. 2012;32:171–4. Scholar
  65. 65.
    Jacobson DM, Vierkant RA. Comparison of cholinergic supersensitivity in third nerve palsy and Adie’s syndrome. J Neuroophthalmol. 1998;18:171–5.PubMedGoogle Scholar
  66. 66.
    Jacobson DM. Benign episodic unilateral mydriasis. Clinical characteristics. Ophthalmology. 1995;102:1623–7.CrossRefPubMedGoogle Scholar
  67. 67.
    Langer-Gould AM, Anderson WE, Armstrong MJ, Cohen AB, Eccher MA, Iverson DJ, et al. The American Academy of Neurology’s top five choosing wisely recommendations. Neurology. 2013;81:1004–11.
  68. 68.
    Ogose T, Manabe T, Abe T, Nakaya K. Ophthalmoplegic migraine with a rise in cytomegalovirus-specific IgG antibody. Pediatr Int. 2009;51:143–5. Scholar
  69. 69.
    Vasconcelos LP, Stancioli FG, Leal JC, da Silva A, Gómez RS, Teixeira AL. Ophthalmoplegic migraine: a case with recurrent palsy of the abducens nerve. Headache. 2008;48:961–4. Scholar
  70. 70.
    Crevits L, Verschelde H, Casselman J. Ophthalmoplegic migraine: an unresolved problem. Cephalalgia. 2006;26:1255–9.CrossRefPubMedGoogle Scholar
  71. 71.
    Verhagen WI, Prick MJ, van Dijk Azn R. Onset of ophthalmoplegic migraine with abducens palsy at middle age? Headache. 2003;43:798–800.CrossRefPubMedGoogle Scholar
  72. 72.
    Pareja JA, Churruca J, de la Casa FB, de Silanes CL, Sánchez C, Barriga FJ. Ophthalmoplegic migraine. Two patients with an absolute response to indomethacin. Cephalalgia. 2010;30:757–60. Scholar
  73. 73.
    De Silva DA, Siow HC. A case report of ophthalmoplegic migraine: a differential diagnosis of third nerve palsy. Cephalalgia. 2005;25:827–30.CrossRefPubMedGoogle Scholar
  74. 74.
    Manzouri B, Sainani A, Plant G, Lee J, Sloper J. The aetiology and management of long-lasting sixth nerve palsy in ophthalmoplegic migraine. Cephalalgia. 2007;27:275–8.CrossRefPubMedGoogle Scholar
  75. 75.
    Mucchiut M, Valentinis L, Provenzano A, Cutuli D, Bergonzi P. Adult-onset ophthalmoplegic migraine with recurrent sixth nerve palsy: a case report. Headache. 2006;46:1589–90.CrossRefPubMedGoogle Scholar
  76. 76.
    O'Hara MA, Anderson RT, Brown D. Magnetic resonance imaging in ophthalmoplegic migraine of children. J AAPOS. 2001;5:307–10.CrossRefPubMedGoogle Scholar
  77. 77.
    Orr SL, Friedman BW, Christie S, Minen MT, Bamford C, Kelley NE, et al. Management of adults with acute migraine in the emergency department: the American Headache Society Evidence Assessment of Parenteral Pharmacotherapies. Headache. 2016;56:911–40.Google Scholar

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Authors and Affiliations

  1. 1.Department of Neurology, Houston Methodist Neurological InstituteHouston Methodist The Woodlands HospitalThe WoodlandsUSA
  2. 2.Center for Pain Medicine, Department of AnesthesiologyUniversity of California, San DiegoLa JollaUSA

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