Abstract
Purpose of Review
Neuromyelitis optica (NMO) classically features a clinical presentation that includes longitudinally extensive transverse myelitis and optic neuritis. However, many other pathognomonic phenomena have more recently been described in patients diagnosed with NMO, including intractable hiccups, vomiting, and painful tonic spasms, but less has been reported regarding the relationship between NMO and headache. Though headache is well established as both a symptom and comorbidity of multiple sclerosis (MS), it has been much less described thus far in the NMO literature and warrants more careful evaluation. Many questions remain unanswered about the relationship between NMO and headache, including headache prevalence in certain groups, distribution of primary and symptomatic headache disorders that are seen most frequently and the specific neuroimaging findings that are associated with an increased risk of headache.
Recent Findings
Various types of headache, such as cervicogenic headache and trigeminal autonomic cephalalgia-like headache, have been reported as the initial clinical presentation of NMO. Other publications have emphasized the association of NMO and other etiologies of headache, such as trigeminal neuralgia, PRES, and preeclampsia. Certain MR imaging findings such as medullary lesions in patients with NMO have also been associated with headache.
Summary
The link between headache and NMO is evident not only in limited case reports and clinical studies but also with both MR imaging and even with some potential common underlying biomarkers such as pentraxin-3 and interleukin-6. Developing a further understanding in the association between these two diseases may lead to better management of headache in patients with NMO and potentially lead to earlier diagnosis of NMO in whom headache may serve as an initial presenting symptom and may even herald a disease exacerbation.
This is a preview of subscription content, access via your institution.

References
Papers of particular interest, published recently, have been highlighted as: •• Of major importance
Lennon VA et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 2004;364(9451):2106–12.
Flanagan EP et al. Epidemiology of aquaporin-4 autoimmunity and neuromyelitis optica spectrum. Ann Neurol. 2016;70(5):775–83.
Wingerchuk et al. The spectrum of neuromyelitis optica. Lancet Neurol. 2007;6:805–15.
Popescu BF, Lennon VA, Parisi JE, Howe CL, Weigand SD, Cabrera-Gómez JA, et al. Neuromyelitis optica unique area postrema lesions: nausea, vomiting, and pathogenic implications. Neurology. 2011;76:1229–37.
Apiwattanakul M, Popescu BF, Matiello M, Weinshenker BG, Lucchinetti CF, Lennon VA, et al. Intractable vomiting as the initial presentation of neuromyelitis optica. Ann Neurol. 2010;68:757–61.
Kremer L et al. Brainstem manifestations in neuromyelitis optica: a multicenter study of 258 patients. Mult Scler. 2014;20(7):843–7.
Pittock et al. Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expression. Arch Neurol. 2006;63:964–8.
Hsu C-L et al. Persistent hyperthermia in a patient with aquaporin-4 antibody positive neuromyelitis optica spectrum disorder. J Clin Neurol. 2016;12(4):515–6.
Watanabe M et al. Galactorrhea in a patient with aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder: a case report and review of the literature. Neurologist. 2015;20(6):101–3.
Baba T, Nakashima I, Kanbayashi T, Konno M, Takahashi T, Fujihara K, et al. Narcolepsy as an initial manifestation of neuromyelitis optica with anti-aquaporin-4 antibody. J Neurol. 2009;256:287–8.
Elsone et al. Neuropathic pruritis (itch) in neuromyelitis optica. Mult Scler. 2013;19(4):475–9.
Hyun J-W et al. Evaluation of the 2015 diagnostic criteria for neuromyelitis optica spectrum disorder. Neurology. 2015;86(19):1772–9.
•• Wingerchuk et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85(2):177–89. This publication reevaluated the diagnostic criteria for NMOSD and highlighted the different clinical and radiological findings that are necessary for diagnosis of NMOSD depending on AQP4 antibody status.
Yang X et al. The role of AQP4 in neuromyelitis optica: more answers, more questions. J Neuroimmunol. 2016;298:63–70.
D’Amico D et al. Prevalence of primary headaches in people with multiple sclerosis. Cephalalgia. 2004;24(11):980–4.
Ergun U et al. Headaches in the different phases of relapsing-remitting multiple sclerosis: a tendency for stabbing headaches during relapses. Neurologist. 2009;15(4):212–6.
Villani V et al. Primary headache and multiple sclerosis: preliminary results of a prospective study. Neurol Sci. 2008;29(1):146–8.
Tortorella P et al. Assessment of MRI abnormalities of the brainstem from patients with migraine and multiple sclerosis. J Neurol Sci. 2006;244(1-2):137–41.
Gee JR et al. The association of brainstem lesions with migraine-like headache: an imaging study of multiple sclerosis. Headache. 2005;45(6):670–7.
Lin GY et al. Multiple sclerosis presenting initially with a worsening of migraine symptoms. J Headache Pain. 2013;14:70.
Fragoso YD, Brooks JBB. Two cases of lesions in brainstem in multiple sclerosis and refractory migraine. Headache. 2007;14:852–4.
Gonzalez-Quintanilla V et al. Cluster-tic syndrome as the initial manifestation of multiple sclerosis. J Headache Pain. 2012;14:425–9.
Kister I et al. Tension-type headache and migraine in multiple sclerosis. Curr Pain Headache Rep. 2010;14(6):441–8.
Qian P et al. Association of neuromyelitis optica with severe and intractable pain. Arch Neurol. 2012;69(11):1482–7.
Kanamori Y et al. Pain in neuromyelitis optica and its effect on quality of life: a cross-sectional study. Neurology. 2011;77(7):652–8.
Carnero Contentti et al. Neuromyelitis optica: association with paroxysmal painful tonic spasms. Neurologia. 2016;31:8.
Morrow M, Wingerchuk D. Neuromyelitis optica. J Neuroophthalmol. 2012;32(2):154–66.
Kim SM, et al. Gender effect on neuromyelitis optica spectrum disorder with aquaporin4-immunoglobulin G. Mult Scler. 2016. epub.
Cruccu G et al. Trigeminal neuralgia: new classification and diagnostic grading for practice and research. Neurology. 2016;87(2):220–8.
Truini A et al. A dual concurrent mechanism explains trigeminal neuralgia in patients with multiple sclerosis. Neurology. 2016;86(22):2094–9.
Sugiyama A et al. Trigeminal root entry zone involvement in neuromyelitis optica and multiple sclerosis. J Neurol Sci. 2015;355(1-2):147–9.
Cruccu G et al. Trigeminal neuralgia and pain related to multiple sclerosis. Pain. 2009;143(3):186–91.
Hinchey J et al. A reversible posterior leukoencephalopathy syndrome. N Eng J Med. 1996;334(8):494.
Magana SM et al. Posterior reversible encephalopathy syndrome in neuromyelitis optica spectrum disorders. Neurology. 2009;72(8):712–7.
Papadopoulous M, Verkman AS. Aquaporin 4 and neuromyelitis optica. Lancet Neurol. 2012;11(6):535–44.
Cheng C et al. Clinical, radiographic characteristics and immunomodulating changes in neuromyelitis optica with extensive brain lesions. BMC Neurol. 2013;13:72.
Berger JR et al. Posterior reversible encephalopathy syndrome masquerading as progressive multifocal leukoencephalopathy in rituximab treated neuromyelitis optica. Mult Scler Relat Disord. 2014;3(6):728–31.
Saadoun S et al. Neuromyelitis optica IgG causes placental inflammation and fetal death. J Immunol. 2013;191(6):2999–3005.
Reuss R et al. A woman with acute myelopathy in pregnancy: case outcome. BMJ. 2009;339:b4026.
Davoudi V et al. Immunology of neuromyelitis optica during pregnancy. Neurol Neuroimmunol Neuroinflamm. 2016;3(6):e288.
Gold SM et al. Pregnancy and multiple sclerosis: from molecular mechanisms to clinical applications. Semin Immunopathol. 2016;38(6):709–18.
Bourre B et al. Neuromyelitis optica and pregnancy. Neurology. 2012;78(12):875–9.
Skliut M, Jamieson DG. Imaging of headache in pregnancy. Curr Pain Headache Rep. 2016;20:56.
Rubio-Ochoa J et al. Physical examination tests for screening and diagnosis of cervicogenic headache: a systematic review. Man Ther. 2016;21:35–40.
Choi S et al. A case of neuromyelitis optica misdiagnosed as cervicogenic headache. Korean J Pain. 2014;27:77–80.
Zhao S et al. Neuropathic pain in neuromyelitis optica affects activities of daily living and quality of life. Mult Scler J. 2014;20(12):1658–61.
Horbinski C et al. A 10-year old girl with neck pain. Brain Pathol. 2010;20(2):519–22.
Wang JY et al. Meningoencephalitis as an initial manifestation of neuromyelitis optica spectrum disorder. Mult Scler. 2013;19(5):639–43.
Fujikura. A case of neuromyelitis optica presenting marked pleocytosis and hypogylcorrhachia. Rinsho Shinkeigaku. 2016;56(8):569–72.
Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition beta. Cephalalgia. 2013;33(9):629–808.
Mathew T et al. Trigeminal autonomic cephalalgia as a presenting feature of neuromyelitis optica: “a rare combination of two uncommon disorders”. Mult Scler Relat Disord. 2016;6:73–4.
Zhao S et al. An unusual case of ‘itchy paralysis’: neuromyelitis optica presenting with severe neuropathic itch. Pract Neurol. 2015;15:149–51.
Xiao L et al. Intractable pruritis in neuromyelitis optica. Neurol Sci. 2016;37(6):949–54.
Netravathi, Manjunath, et al. Is pruritis an indicator of aquaporin-positive neuromyelitis optica? Mult Scler. 2016; 1–8. doi:10.1177/1352458516665497.
Doi H et al. Frequency of chronic headaches in Japanese patients with multiple sclerosis: with special reference to opticospinal and common forms of multiple sclerosis. Headache. 2009;49(10):1513–20.
Wang Y et al. Comparative clinical characteristics of neuromyelitis optica spectrum disorders with and without medulla oblongata lesions. J Neurol. 2014;261(5):954–62.
Pittock S et al. Neuromyelitis optica and non-organ specific autoimmunity. Arch Neurol. 2008;65(1):78–83.
Alexopoulos H et al. Anti-aquaporin-4 autoantibodies in systemic lupus erythematosus persist for years and induce astrocytic cytotoxicity but not CNS disease. J Neuroimmunol. 2015;289:8–11.
Tjensvoll AB et al. Migraine is frequent in patients with systemic lupus erythematosus: a case-control study. Cephalalgia. 2011;31(4):401–8.
Zhong, Y.H., et al. Comparisons of presentations and outcomes of neuromyelitis optica patients with and without Sjogren’s syndrome. Neurol Sci. 2017;38(2):271–7.
Carvalho D et al. Sjogren syndrome and neuromyelitis optica spectrum disorder co-exist in a common autoimmune milieu. Arg Neurossiquiatr. 2014;72(8):619–24.
Morreale M et al. Neurological involvement in primary Sjogren syndrome: a focus on central nervous system. PLoS One. 2014;9(1):e84605.
Moreira I et al. Frequent involvement of central nervous system in primary Sjogren syndrome. Rheumatol Int. 2015;35(2):289–94.
Katsumata Y et al. Semiquantitative measurement of aquaporin-4 antibodies as a possible surrogate marker of neuromyelitis optica spectrum disorders with systemic autoimmune diseases. Mod Rheumatol. 2012;22(5):676–84.
Makhani N, Bigi S, Banwell B, Shroff M. Diagnosing neuromyelitis optica. Neuroimaging Clin N Am. 2013;23:279–91.
Pekcevik Y et al. What do we know about brain contrast enhancement patterns in neuromyelitis optica? Clin Imaging. 2016;40:573–80.
Cassinotto C et al. MRI of the spinal cord in neuromyelitis optica and recurrent longitudinal extensive myelitis. J Neuroradiol. 2009;36(4):199–205.
Asgari N et al. Modifications of longitudinally extensive transverse myelitis and brainstem lesions in the course of neuromyelitis optica (NMO): a population-based, descriptive study. BMC Neurol. 2013;13:33.
•• Kim HJ et al. MRI characteristics of neuromyelitis optica spectrum disorder: an international update. Neurology. 2015;84(11):1165–73. This publication emphasizes distinctions in imaging findings between NMOSD and other pathology such as MS, which has important implications in appropriate treatment.
Stankewitz A et al. Trigeminal nociceptive transmission in migraineurs predicts migraine attacks. J Neurosci. 2011;31(6):1937–43.
•• Bradl M et al. Pain in neuromyelitis optica—prevalance, pathogenesis and therapy. Nat Rev Neurol. 2014;10:529–36. This publication extensively reviewed the pathophysiology of pain in NMO and proposed specific therapies for treatment.
O’Connor AB et al. Pain associated with multiple sclerosis: systematic review and proposed classification. Pain. 2008;137(1):96–111.
Ceylan M et al. Serum levels of pentraxin-3 and other inflammatory biomarkers in migraine: association with migraine characteristics. Cephalalgia. 2016;36(6):518–25.
Wang H et al. Increased plasma levels of pentraxin 3 in patients with multiple sclerosis and neuromyelitis optica. Mult Scler. 2013;19(7):926–31.
Seok JM et al. Clinical characteristics of disabling attacks at onset in patients with neuromyelitis optica spectrum disorder. J Neurol Sci. 2016;368:209–13.
Wang F et al. Association of serum levels of intercellular adhesion molecule-1 and interleukin-6 with migraine. Neurol Sci. 2015;36(4):535–40.
Chavarro VS et al. Insufficient treatment of severe depression in neuromyelitis optica spectrum disorder. Neurol Neuroimmunol Neuroinflamm. 2016;3(6):286. –abstract.
Igel C et al. Neuromyelitis optica in pregnancy complicated by posterior reversible encephalopathy syndrome, eclampsia and fetal death. J Clin Med Res. 2015;7(3):193–5.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
Alina Masters-Israilov declares no conflicts of interest.
Matthew S. Robbins declares he is a site PI for clinical trials with eNeura, Inc., and the funds were given directly to his institution; he also declares book royalties from Wiley.
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.
Additional information
This article is part of the Topical Collection on Secondary Headache
Rights and permissions
About this article
Cite this article
Masters-Israilov, A., Robbins, M.S. Headache in Neuromyelitis Optica. Curr Pain Headache Rep 21, 20 (2017). https://doi.org/10.1007/s11916-017-0620-1
Published:
DOI: https://doi.org/10.1007/s11916-017-0620-1
Keywords
- Neuromyelitis optica
- Headache
- Aquaporin 4
- MRI
- Medulla
- Cervical spine