Etiology/Pathophysiology

Patients with NMOSD have an increased risk of systemic autoimmune disorders (approximately 40% of patients), such as systemic lupus erythematosus, Sjögren syndrome, myasthenia gravis, and Hashimoto thyroiditis.9 The primary immune-mediated event underlying NMOSD is currently unknown.  The disorder is characterized by astrocytic damage, demyelination, and necrosis that is more severe than that seen in MS.4 The cascade of events leading to NMOSD include4,14:

  • Initial trigger: an unknown trigger activates the mature B-cells to produce aquaporin-4 immunoglobulin antibodies (AQP4-IgGs)
  • AQP4-IgG penetration: AQP4-IgGs enter through the blood-brain barrier and bind selectively to AQP4 on astrocytes
  • Complement-dependent cytotoxicity: the binding of AQP4-IgGs to AQP4 causes the activation of the complements and induces astrocyte damage
  • Inflammation in the CNS: in response to cellular cytotoxicity, there is an increase in macrophages, neutrophils, and eosinophils penetrating through the blood-brain barrier
  • Oligodendrocyte injury and demyelination: mechanisms of damage to the oligodendrocytes and myelin are not fully understood.

Clinical Presentation

Common symptoms of NMOSD result from damage to the optic nerve, spinal cord, and brainstem. These include optic neuritis with symptoms of loss or blurred vision in 1 or both eyes, eye pain, and loss of color vision. Myelitis causes paralysis or paresis of the extremities, loss of bladder and/or bowel control, and numbness or paresthesia with location dependent on the spinal cord level(s) that are affected.2,4

Other symptoms in NMOSD occur in CNS areas besides the optic nerve and spinal cord, including intractable nausea, vomiting, and intractable hiccups in area postrema syndrome (APS, a specific brainstem syndrome).4 APS is considered a disease manifestation that is highly specific for NMOSD and is the initial presenting symptom in more than 10% of cases.14,16 Fatigue, memory loss, and narcolepsy may also be present and are suggestive of NMOSD.3,4,17


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Signs of NMOSD on neurologic examination include decreased visual acuity and possible altitudinal visual field defects due to optic neuritis, typically seen bilaterally.3,9,15 Weakness and hyper-reflexia (or initial hyporeflexia) is seen in affected extremities due to transverse myelitis.2,15 Sensory deficits may be seen on physical examination; location correlates to the level of the spinal cord involvement.2,15

Most cases of NMOSD present with symptoms of either optic neuritis or transverse myelitis, if not symptoms of both, but some cases of brain abnormalities without optic neuritis or longitudinally extensive transverse myelitis (LETM) have been described.6,8 This variable presentation further highlights the importance of ruling out mimicking disorders when considering a diagnosis of NMOSD (Table 2).4,6-8,12,14,17-21

Table 2. Differential Diagnosis of NMOSD

DiseaseDescription of Disease6,18-19,21Overlapping Symptoms4,6,14,17,18,20Differential Diagnosis4,6,7,12,14,18,19
Multiple sclerosisMS is an autoimmune disorder in which demyelination occurs in the CNS and inflammation can occur in the optic nervesOptic neuritis and transverse myelitis are both symptoms of MS and NMOSD.15 Both MS and NMOSD can present with short spinal cord lesions.MS is predominately T-cell driven and is negative for AQP4-IgG. Multifocal lesions of MS have specific MRI features that are absent in NMOSD. MS cases often have a positive OCB test and MRZ reaction.
Neuro-Behḉet diseaseThis autoimmune syndrome presents with oral and genital ulcers affecting predominately Mediterranean and Middle Eastern countriesReports of weakness, visual symptoms, and longitudinally extensive lesions could resemble those of NMSODBiopsy of mucocutaneous ulcers is definitive. It is rare in North America; the CSF is negative for IgG abnormalities.
CNS lymphomaCNS lymphomas can be seen in patients who are immunocompromised or immunocompetentLongitudinally extensive spinal cord lesions and focal neurologic deficitsBiopsy confirms CNS lymphoma. PET scan can be used as a diagnostic tool.
HIV infection/AIDSRetroviral infection with HIV-1 that can involve the nervous systemCan cause optic neuritis, focal deficits with white matter changes, and abnormal CSFOccurs in high-risk populations who may have diminished CD4 cell counts and positive HIV serology. AQP4-Ab is not detected in the sera of patients.
Lyme disease
(neuroborreliosis)
Infection by tick-borne spirochete that transmit the bacteria Borrelia burgdorferiCan cause persistent focal neurologic findings and signal abnormalities on MRI of the brainMay have a history of erythema migrans rash. CSF may show positive results for polymerase chain reaction (PCR).
Progressive multifocal leukoencephalopathyCNS infection by the John Cunningham virus in an immunosuppressed patient, which causes progressive deficits leading to death within a few monthsCan have multifocal CNS deficits; MRI scans can show similar lesions. Patients with NMOSD may be predisposed to this condition because of immunosuppressant use.Occurs primarily in immunosuppressed patients and the deficits are usually progressive, not relapsing. Brain lesions are usually large and confluent. Brain biopsy may be necessary for diagnosis.
SarcoidosisA systemic granulomatous disease that commonly involves the lymph node, skin, lung, eye, and nervous systemOptic nerve, brain, and spinal cord involvement; can be bilateral and longitudinally extensive (seen in neurosarcoidosis patients)Systemic symptoms, in the lungs, primarily. Biopsy of skin, lymph node, or lung is definitive. MRI may show meningeal enhancement.
Sjӧgren syndromeAn autoimmune disease associated with dry eyes and dry mouthMRI may have longitudinally extensive spinal cord lesionsProminent dry eyes and mouth. Salivary gland biopsy can be definitive.
Systemic lupus erythematosusAn autoimmune disease involving multiple systems that commonly affects the CNSCommon in young women. Affects the optic nerves and spinal cord. Headaches, optic neuritis, and myelitis are diagnosed in some patients. Some patients with SLE may have AQP4-IgG antibody.Systemic involvement  includes kidneys, skin, and hematologic changes
Myasthenia gravisCharacterized by muscle weakness and fatigueMyelitis can be present in the CNS and the presence of AQP4 antibodies has been discovered. It has been reported that Myasthenia gravis is more commonly found in patients with NMOSD than in the general population.Most commonly acquired at the neuromuscular junction and is caused by autoantibodies targeting mainly the acetylcholine receptor
Syphilis (neurosyphilis)Chronic CNS infection by the spirochete bacteria, Treponema pallidumCan cause optic neuritis and other neurologic findings that can mimic NMOSD visual loss and pain  Negative for AQP4-IgG  
Idiopathic optic neuritisCharacterized by inflammation of the optic nervesPredominant in women, reduces visual acuity, impairs color vision, and can cause ocular painMRI does not show lesions (other than optic nerve enhancement). Tests for MOG-Ab and AQP4-IgG antibodies are negative.
ADLDProgressive disorder of the CNS white matter that presents in the fourth or fifth decade, characterized by cerebellar dysfunctionDemyelinating disorder, T2-weighted hyperintensity, autonomic dysfunction including bladder dysfunction, spasticity.ADLD is inherited in an autosomal dominant manner, individuals have a LMNB1 gene mutation, and MRI depicts demyelination of white matter in the brain is symmetrical.
ADLD, autosomal dominant leukodystrophy disease; CNS, central nervous system; CSF, cerebrospinal fluid; IgG, immunoglobulin G; MRZ, measles, rubella, and varicella zoster virus; MS, multiple sclerosis; SLE, systemic lupus erythematosus