Neuromyelitis Optica Spectrum Disorder (NMOSD)


Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disorder characterized by inflammation and demyelination of nerves in the central nervous system (CNS), especially the optic nerves and spinal cord. It manifests as episodic flare-ups of optic neuritis and longitudinally extensive transverse myelitis.1 

In 2006, after subject matter experts gathered to review the various criteria for a diagnosis of NMOSD, revised diagnostic criteria were published in the journal Neurology.1,2 In 2008, the National Multiple Sclerosis Society (NMSS) task force revised the specific criteria for a correct NMO diagnosis and listed characteristic features of the disorder.1 

Between October of 2011 and November of 2013, 18 individuals from 9 countries gathered on 7 separate occasions to review and revise the existing guidelines for NMOSD. As members of the International Panel for NMO Diagnosis Criteria, they published updated guidelines in the journal Neurology in 2015. They clarified the terminology “neuromyelitis optica spectrum disorder” and revised the recommendations for treatment.3 

Diagnostic Features of NOSD

Genetics

Although NMOSD is rarely inherited within families, genetic predisposition plays a role in disease manifestation. NMOSD affects ethnic groups with limited or no European genetic make-up. NMOSD is 10 times more likely to occur in women than in men.1

Disease Types

Approximately 80% to 90% of individuals with NMOSD have the recurrent type, whereas 10% to 20% have the monophasic type. Rarely, patients have either a primary or secondary progressive form of NMOSD. Longer time between the first 2 episodes, older age at disease onset, female gender, and relatively mild motor deficits following the sentinel myelitis event all predict a recurrent course of the disease.1,4   

Clinical Features

In comparison with the vision loss in multiple sclerosis (MS), the vision loss due to optic neuritis in NMOSD is more severe and typically develops in both eyes at the same time.1,3 Typically, the 2 optic nerves are involved simultaneously along with the optic chiasm, the altitudinal visual field is affected, and severe vision loss develops.3 

In NMOSD, myelitis manifests as complete (rather than partial) transverse myelitis with para- or tetraparesis, often accompanied by paroxysmal tonic spasms.1,3 In MS, the spinal cord symptoms are typically mild and asymmetric.1

Area postrema clinical syndrome is another feature of NMOSD, with an incidence of 16% to 43%. The syndrome is characterized by intractable hiccups, nausea, and/or vomiting.3

Diagnostic Criteria

According to the most recent 2015 guideline recommendations, NMOSD may be diagnosed if 1 of 6 existing core clinical criteria is met. An additional requirement is serum positivity for immunoglobulin G (IgG) autoantibodies that attack aquaporin-4 (AQP4) water channels. The core clinical characteristics affect 6 different regions in the CNS: the optic nerves, spinal cord, brainstem, area postrema of the dorsal medulla, diencephalon, and cerebrum.3

Individuals without a positive serum AQP4-IgG test result must exhibit 2 of the 6 core clinical criteria for a diagnosis of NMOSD. One of the 2 criteria that are met must be optic neuritis, transverse myelitis with magnetic resonance imaging (MRI) evidence of longitudinally extensive transverse myelitis, or an area postrema clinical syndrome with MRI evidence of an associated medullary lesion. The 2 core characteristics may appear with a single or multiple CNS attacks.3

The International Panel recommends that clinicians use a cell-based serum assay such as microscopy or a flow cytometry-based method when performing AQP4-IgG serologic testing because their sensitivity is higher and they yield fewer false-positive results than indirect immunofluorescence assays and enzyme-linked immunosorbent assays (ELISAs). The International Panel also highly recommends confirmation testing with a different AQP4-IgG assay technique. Individuals with the monophasic type of NMOSD are more likely to lack AQP4-IgG antibodies than those with the recurrent type.3 

Additionally, the International Panel concluded the following3

  • At least one clinical attack must occur for a diagnosis of NMOSD.
  • MNOSD cannot be diagnosed in an asymptomatic patient even if NMOSD-like lesions are visible on MRI.
  • No clinical characteristic specifically indicates NMOSD.
  • Multiple clinical characteristics must be present in the absence of AQP4-IgG seropositivity for a diagnosis.
  • No single characteristic rules out NMOSD, but certain red flags may indicate an alternative diagnosis.

Most of the red flags are related to the temporal course of NMOSD symptoms; others involve imaging or laboratory findings. Typically, in NMOSD, a gradual disease course in which symptoms progressively worsen over a period of months to years without any relationship to CNS attacks is very rare, occurring in 1% to 2% of cases. Clinicians must rule out comorbidities with neurological symptoms that mimic NMOSD, including MS, sarcoidosis, cancers, vasculitis, and other chronic systemic infections.3,5 

Physicians should consider MS when symptoms progressively worsen in the absence of clinical episodes, when transverse myelitis is only partial, or when oligoclonal bands are found in the cerebrospinal fluid (in >80% of MS cases and <20% of NMOSD cases).3 

Features on T2-weighted brain MRI more indicative of MS than of NMOSD include lesions with a perpendicular orientation to the lateral ventricular surfaces, lesions next to the lateral ventricles within the inferior temporal lobes, cortical lesions, and juxtacortical lesions with involvement of subcortical U-fibers.3

Spinal MRI features that suggest MS over NMOSD include lesions that affect fewer than 3 adjacent vertebral segments on sagittal T2-weighted sequences, lesions with more than 70% occurring in the peripheral spinal cord on T2-weighted axial sequencing, and unclear, diffuse signal changes on T2-weighted sequencing.3

Brain MRI may reveal NMO-typical lesions localized in areas where AQP4 water channels are highly expressed, particularly the hypothalamus and brainstem. Brain MRI must also demonstrate gadolinium enhancement of the optic nerves, which is often seen during acute flare-ups of optic neuritis but also may be present during periods of remission in individuals with the recurrent type of NMOSD.1

Parameters of nerve function, including visual evoked potentials (VEPs), somatosensory evoked potentials (SEPs), and brainstem acoustic evoked potentials (BAEPs), commonly indicate electrophysiological abnormalities, whereas the results of peripheral nerve conduction tests are likely to be normal.1 

The presence of other systemic autoimmune disorders, specifically systemic lupus erythematosus (SLE) or Sjögren syndrome (SS), as well as specific pathological findings and CSF data, may increase the likelihood of a diagnosis of NMOSD.3

Although analysis of the CSF is helpful in supporting a diagnosis of NOSD, especially following an acute attack, it is not highly sensitive or specific. Lymphomononuclear pleocytosis (>50 cells per microliter), the presence of white blood cells, and the absence of oligoclonal bands in the CSF may indicate NMOSD but are not diagnostic.1 

During acute injury to nerve axons, both neurofilament heavy chains (NfHs) and glial fibrillary acidic proteins (GFAPs) accumulate in the CSF. It has been noted that levels of these 2 substances are significantly higher in individuals with NMOSD than in those with MS, acute disseminated encephalomyelitis, or spinal cord infarctions; however, their value in diagnosing NMOSD must be more rigorously examined in future studies.1  

Treatment Guidelines

No cure for NMO exists at present.6,7 According to the 2015 International Panel guidelines, an early and accurate diagnosis is critical to differentiate NMOSD from MS and to differentiate AQP4-IgG seropositive from AQP4-IgG seronegative NMOSD, primarily because recent data have indicated that the use of MS immunotherapies such as interferon-β, fingolimod, and natalizumab may worsen NMOSD.3 

The main goals in treating NOSD are to alleviate symptoms during relapses, prevent relapses to stabilize the long-term course of the disease, and treat residual symptoms.7 

Current treatment guidelines during an initial attack in NMOSD include the intravenous administration of a high-dose corticosteroid such as methylprednisolone, followed by plasma exchange (PLEX) if the corticosteroid proves ineffective. In the PLEX procedure, blood is removed from the body, blood cells are filtered from the plasma, the plasma is replaced with an artificial substitute, and the combined blood cells and artificial plasma are returned to the body intravenously. Because most individuals with NMO have the recurring type, continuous immunosuppressive treatment is deemed essential to prevent recurrent attacks.6 

The US Food and Drug Administration (FDA) has approved 3 drugs to target anti-AQP4 NMO, including Soliris (eculizumab), Uplizna (inebilizumab), and Enspryng (satralizumab-mwge). Drugs used off label to prevent future episodes include Rituxan (rituximab), CellCept (mycophenolate mofetil), Imuran or Azasan (azathioprine), prednisone, and methotrexate.6 

Although the NMSS suggests the use of intravenous high-dose steroids, Trebst and colleagues state that depending on the severity of an attack, a tapered dose of an oral steroid combined with a proton pump inhibitor and thrombosis prophylaxis may be used for 5 days. Therapeutic PLEX for 5 to 7 cycles is recommended if the neurological symptoms worsen or do not improve following steroid use.7 

As of 2014, according to Trebst and colleagues, 2 of the most frequently used first-line therapies in NMO are azathioprine and rituximab. Second-line therapies include mycophenolate mofetil, mitoxantrone, and methotrexate. Third-line therapies include combination therapies and tocilizumab. Intravenous immunoglobulin, cyclophosphamide, interferon-beta/glatiramer acetate, natalizumab, and fingolimod comprise other potential treatments for NMO.7

Current experimental therapies include anti-interleukin 6 treatment; competitive, nonpathogenic AQP4-specific antibodies (aquaporumab); neutrophil elastase inhibitors; antihistamines with stabilization of eosinophilic actions; and enzymatic deglycosylation or cleavage of AQP4-IgG antibodies.7

References

  1. Sellner J, Boggild M, Clanet M, et al. EFNS guidelines on diagnosis and management of neuromyelitis optica. Eur J Neurol. 2010;17(8):1019-1032. doi:10.1111/j.1468-1331.2010.03066.x
  2. Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology. 2006;66(10):1485-1489. doi:10.1212/01.wnl.0000216139.44259.74
  3. Wingerchuk DM, Banwell B, Bennett JL, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85(2):177-189. doi:10.1212/WNL.0000000000001729
  4. Wingerchuk DM, Weinshenker BG. Neuromyelitis optica: clinical predictors of a relapsing course and survival. Neurology. 2003;60(5):848-853. doi:10.1212/01.wnl.0000049912.02954.2c
  5. Miller D, Weinshenker B, Filippi M, et al. Differential diagnosis of suspected multiple sclerosis: a consensus approach. Mult Scler. 2008;14(9):1157-1174. doi:10.1177/1352458508096878
  6. Treatments of NMO. National Multiple Sclerosis Society. Accessed October 26, 2021.
  7. Trebst C, Jarius S, Berthele A, et al. Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the neuromyelitis optica study group (NEMOS). J Neurol. 2014;261(1):1-16. doi:10.1007/s00415-013-7169-7

Reviewed by Kyle Habet, MD, on 11/1/2021.