Kyle Habet, MD, is a physician at Belize International Institute of Neuroscience where he is a member of a multidisciplinary group of healthcare professionals involved in the care of patients with an array of neurological and psychiatric diseases. He is a published author, researcher and instructor of neuroscience and clinical medicine at Washington University of Health and Science.
Neuromyelitis optica spectrum disorder (NMOSD), formerly known as “Devic disease,” is a rare, chronic, immune-mediated demyelinating disease of the central nervous system (CNS).1 As the name suggests, the optic nerve is frequently involved, and the second most common site of involvement is the spinal cord. The NMOSD spectrum includes acute attacks of bilateral or rapidly sequential optic neuritis, transverse myelitis, brainstem syndromes, and encephalopathy. There is no pathognomonic symptom for NMOSD, however, this combination of symptoms is highly characteristic. The relapsing and remitting pattern of transverse myelitis and optic neuritis may resemble the clinical course of multiple sclerosis (MS). For this reason, it was once considered a phenotypic variant of MS.1 The discovery of autoantibodies to aquaporin-4 (AQP4) in the serum of affected patients recognized NMOSD as an immunologically distinct entity separate from MS.1 Other autoantibodies have since been discovered and are used to further characterize the disease.
The core clinical characteristics of the spectrum are2:
- Optic neuritis
- Acute myelitis
- Area postrema syndrome
- Acute brainstem syndrome
- Symptomatic narcolepsy or acute diencephalic clinical syndrome with -typical diencephalic magnetic resonance imaging (MRI) lesions
- Symptomatic cerebral syndrome with -typical brain lesions
AQP4 Autoantibody-Positive NMOSD
Most patients with NMOSD are anti-AQP4-positive. AQP4 is the most widely expressed water channel in the CNS, and it is dispersed throughout the brain, spinal cord, and optic nerves. It is found in regions that contact cerebrospinal fluid and is specifically localized to the foot processes of astrocytes.1 AQP4 autoantibody-positive disease affects women more than men at a ratio of approximately 9:1, and typical age of onset is around 40 years. From a pathological standpoint, it is more of an astrocytopathic disease than a demyelinating disease.3
Patients that present with at least 1 core characteristic, AQP4 positivity, and a diagnosis that is not explained by another disease meet the criteria for AQP4-positive NMOSD.2
Approximately 12% of patients are seronegative for AQP4 autoantibodies.4 Interestingly, in this group, prevalence shows no predilection for sex. However, it is more common in Caucasians, and the incidence of simultaneous optic neuritis and transverse myelitis at the first episode is comparatively higher.5 The significance of this finding is debatable, suggesting that seronegative NMOSD may be a distinct entity due to its unique pathophysiology.
AQP4-Negative, MOG-Positive NMOSD
Anti-myelin oligodendrocyte glycoprotein (MOG) antibodies may be positive in some seronegative NMOSD patients.6 Symptoms in both groups are overlapping, however, there are some key differences between MOG-positive patients and seronegative and anti-AQP4-positive patients. Patients with MOG positivity have more involvement of the optic nerve than the spinal cord. Optic nerve involvement is more frequently bilateral and simultaneous in this group. Additionally, while a relapsing and remitting course may be present, it is frequently monophasic. Spinal cord lesions are usually distributed in the lower portion of the spinal cord and display better functional recovery following an attack.7 MOG-positive patients are also more likely to have brainstem involvement.8 The most frequent presentations of MOG-positive disease are acute disseminated encephalomyelitis in children under 7 years of age, which can provoke seizures, and optic neuritis in older children and adults.1
The diagnosis of seronegative patients is more diligent. Patients meet criteria if they present with at least 2 core characteristics (one must be optic neuritis, acute myelitis with longitudinally extensive transverse myelitis lesions, or area postrema syndrome) that are disseminated in space and time, and they must meet additional MRI requirements as outlined by the American Academy of Neurology.2
Clinical Spectrum of the Disease
NMOSD is a spectrum that assumes various clinical forms and can be categorized accordingly. Phenotypic variants include:
- Limited disease – Includes a single episode or recurrent episodes of myelitis (usually involving longitudinally extensive spinal cord lesions), a single episode or recurrence of unilateral or simultaneous bilateral optic neuritis, and optic neuritis or transverse myelitis in isolation.9
- Asian opticospinal MS – Presents with selective, bilateral, and severe demyelination of the optic nerve in Asian populations, and it shares a close phenotypic resemblance to MS with AQP4-antibody positivity.10
- Optic neuritis or longitudinally extensive spinal cord lesions associated with systemic autoimmune disease.11
- Optic neuritis or myelitis associated with distinct brain MRI lesions typical of .2
1. Huda S, Whittam D, Bhojak M, Chamberlain J, Noonan C, Jacob A. Neuromyelitis optica spectrum disorders. Clin Med (Lond). 2019;19(2):169-176. doi:10.7861/clinmedicine.19-2-169
2. Wingerchuk DM, Banwell B, Bennett JL, et al.; International Panel for NMO Diagnosis. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85(2):177-189. doi:10.1212/WNL.0000000000001729
3. Hor JY, Asgari N, Nakashima I, et al. Epidemiology of neuromyelitis optica spectrum disorder and its prevalence and incidence worldwide. Front Neurol. 2020;11:501. doi:10.3389/fneur.2020.00501
4. Jiao Y, Fryer JP, Lennon VA, et al. Updated estimate of AQP4-IgG serostatus and disability outcome in neuromyelitis optica. Neurology. 2013;81(14):1197-1204. doi:10.1212/WNL.0b013e3182a6cb5c
5. Marignier R, Bernard-Valnet R, Giraudon P, et al.; NOMADMUS Study Group. Aquaporin-4 antibody-negative neuromyelitis optica: distinct assay sensitivity-dependent entity. Neurology. 2013;80(24):2194-2200. doi:10.1212/WNL.0b013e318296e917
6. Kitley J, Woodhall M, Waters P, et al. Myelin-oligodendrocyte glycoprotein antibodies in adults with a neuromyelitis optica phenotype. Neurology. 2012;79(12):1273-1277. doi:10.1212/WNL.0b013e31826aac4e
7. Sato DK, Callegaro D, Lana-Peixoto MA, et al. Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders. Neurology. 2014;82(6):474-481. doi:10.1212/WNL.0000000000000101
8. Jurynczyk M, Messina S, Woodhall MR, et al. Clinical presentation and prognosis in MOG-antibody disease: a UK study. Brain. 2017;140(12):3128-3138. doi:10.1093/brain/awx276
9. Kim SH, Kim W, Li XF, Jung IJ, Kim HJ. Clinical spectrum of CNS aquaporin-4 autoimmunity. Neurology. 2012;78(15):1179-1185. doi:10.1212/WNL.0b013e31824f8069
10. Kira J. Neuromyelitis optica and Asian phenotype of multiple sclerosis. Ann N Y Acad Sci. 2008;1142:58-71. doi:10.1196/annals.1444.002
11. Pittock SJ, Lucchinetti CF. Neuromyelitis optica and the evolving spectrum of autoimmune aquaporin-4 channelopathies: a decade later. Ann N Y Acad Sci. 2016;1366(1):20-39. doi:10.1111/nyas.12794
Reviewed by Harshi Dhingra, MD, on 10/12/2021.
Reviewed by Harshi Dhingra, MD, on 10/12/2021.