Q: What is Neuromyelitis optica spectrum disorder?

A: Neuromyelitis Optica Spectrum Disorder (NMOSD) is an inflammatory, demyelinating, antibody-mediated disease of the central nervous system (CNS) that predominantly targets the optic nerves, brainstem and spinal cord. The term neuromyelitis optica was first described by Devic and Gault in 1894 (1). The disease was, therefore, previously referred to as Devic’s disease. It was considered for years as a variant of multiple sclerosis but, more recently, demonstrated to represent a distinct clinical and pathophysiologic entity. Moreover, the identification of a serum autoantibodies specific for the aquaporin-4 (AQP4) (2), a water channel present on astrocytic foot processes heavily expressed in the optic nerves, brainstem, and spinal cord, unified a spectrum of NMO-related disorders and distinguished them from multiple sclerosis (MS). NMOSD encompasses patients who fulfill the diagnostic criteria below and are either AQP4 seropositive or AQP4/myelin oligodendrocyte glycoprotein (MOG) seronegative (testing discussed below).

Q: How common is NMOSD? Who gets it?

A: The reported incidence and prevalence of NMOSD are dependent on geographical location and ethnicity. The prevalence in the United States and Europe range between 3.9-4.1/100,000 but higher in African and Asian populations. Females are more affected than males (3:1–9:1) (3). The median age at presentation is 39 years, but 18% of cases occur in children or the elderly (4). It is generally regarded as a non-familial disease.

Q: How do patients with NMOSD present?

A: NMOSD has three cardinal manifestations: optic neuritis, transverse myelitis, and area postrema syndrome. Optic neuritis is often associated with severe bilateral vision involvement, and incomplete recovery. Transverse myelitis in NMOSD is typically complete with profound bilateral motor weakness, prominent dysesthesias, a sensory level, and sphincter dysfunction (5). Other useful clinical clues include pain, pruritis, and tonic spasms (brief recurrent, usually painful episodes of increased muscle tone with abnormal posturing of the affecting limb). NMOSD transverse myelitis is often disabling and associated with poor recovery despite treatment. The third common presentation is area postrema syndrome, which is characterized by nausea, vomiting with or without hiccup, and patients are often evaluated first by gastroenterologists. It may occur in isolation, have other accompanying brainstem features, or evolve into a myelitis episode. Other less common presentations include symptomatic diencephalic syndrome (narcolepsy, autonomic dysfunction, anorexia and syndrome of inappropriate antidiuretic hormone secretion), symptomatic cerebral syndrome with presentation similar to posterior reversible encephalopathy syndrome (PRES) or acute disseminated encephalomyelitis (ADEM), myalgia and hyperCKemia.

Q; Are any other diseases associated with NMOSD?

A: NMOSD is commonly associated with organ specific autoimmune disease myasthenia gravis (pernicious anemia, autoimmune thyroiditis, ulcerative colitis and type 1 diabetes) and non-organ specific autoimmune disease or their autoantibody biomarkers such as systemic lupus erythematosus, Sjogren syndrome, and antiphospholipid antibody syndrome (6). The presence of any core manifestations of NMOSD in any patient with these diseases is likely due to NMOSD rather than neurological manifestations of connective tissue disease and should promote testing for AQP4-IgG. NMOSD can rarely be a paraneoplastic presentation.

Q: How are NMOSD different from MS?

A: Although NMOSD has distinct immunopathogenesis and treatment options, both NMOSD and MS may have similar clinical presentations and imaging features. It is essential to differentiate NMOSD and MS, especially in patients with both optic nerve and spinal cord involvement, as some MS therapies (e.g. interferon beta, natalizumab, fingolimod) can exacerbate NMOSD. Optic neuritis is generally more severe, and recovery poorer in NMOSD than in MS, with complete remission in only 32%. Transverse myelitis in NMOSD is usually extensive, with complete clinical remission in only 17% of attacks (7). Unlike MS, the disability in NMOSD is mostly driven by relapses rather than disease progression. MRI of the brain is usually normal or shows changes that differ from MS (See below).

The longitudinally extensive cord lesions (typically 3 vertebral segments long) characteristic of NMO are rarely seen in MS (MS lesions are usually one vertebral segment long).  CSF may show a striking lymphocytic pleocytosis or a neutrophilic predominance, whereas a CSF pleocytosis >50 cells/mm3 is rare in multiple sclerosis. Oligoclonal bands are found in only 15-30% with NMO versus 90% with MS (8).

Q: What are the MRI features of NMOSD disorders?

A: Brain MRI is abnormal in 55-80% of patients with NMOSD, but only 10% to 20% will satisfy Barkhof MS criteria (9). Typical brain involvement in NMOSD occurs at regions of high AQP4 expression (periaqueductal, hypothalamic, and periventricular regions) but can also involve the deep and subcortical white matter. Different patterns of white matter involvement have been reported in NMOSD, such as marbled appearance of the acute callosal lesion, involvement of the entire thickness of the corpus callosum (arch bridge appearance), tumefactive lesion and spindle-like appearance following white matter tracts. On occasion, lesions ascending from the spinal cord into the brainstem can occur. In addition, different patterns of enhancement have been reported to be typical for NMO, such as pencil-thin linear ependymal enhancement (thin ependymal enhancement of lateral ventricular surfaces), leptomeningeal enhancement, and cloud-like poorly marginated enhancement. Cases of PRESS have also been reported in association with NMOSD.

MRI findings of NMOSD optic neuritis include extensive T2 hyperintense lesions, commonly bilateral, extending over the posterior part of the optic nerve or involving the optic chiasm, with enhancement usually extending more than half the length of the nerve (11). Imaging of the acute myelitis of NMOSD typically reveals a longitudinally extensive T2-hyperintense lesion spanning three or more contiguous vertebral segments. However, lesions are short in 14% of first myelitis episodes (92% long at relapse) (10). Extensive cord edema, central cord involvement with necrosis and cavitation, and a long segment cord atrophy are other common features with NMOSD.

Q: What are the laboratory findings in NMOSD?

A: Patients suspected of having NMOSD should be tested for AQP4-IgG antibodies. AQP4-IgG binds to AQP4, which is located on the end-feet of astrocytes, initiating a cascade of immune-mediated inflammation resulting in secondary demyelination. Blood testing is recommended for AQP4-IgG and should be performed during the attack, before immunotherapy. Of available AQP4-Ab assays, the live cell-based assay has the highest sensitivity (76.7%) and specificity (99.8%) (12). The older-generation enzyme-linked immunosorbent assay technique is less sensitive and more prone to yield false-positive results. With the most sensitive assays, testing is negative in 10-25% of clinically diagnosed NMO. Up to 25% of patients with seronegative NMOSD will have antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG). Please refer to the Mellen Center Approach (MCA) on Myelin oligodendrocyte glycoprotein antibody disorders for more information on that topic.

CSF findings in NMOSD typically include a mixed pleocytosis (lymphocytes, neutrophils, and monocytes) with a median cell count of 19 cells/μl (range: 6-380) and elevated protein, especially in the setting of relapse. Positive oligoclonal bands are found in less than 30 % of patients with AQP4-IgG. Testing for AQP4-IgG in the CSF is less useful and is not the preferred method.

Q: Who do we test for NMOSD IgG?

A: We test any patient with any of these clinical presentations: longitudinally extensive or severe transverse myelitis, severe unilateral, recurrent, or bilateral optic neuritis. We also test AQP4-IgG in patients with intractable vomiting, hiccup, vertigo, unusual brain or brainstem lesions or undiagnosed inflammatory CNS disorder.

Q: What are the criteria for the diagnosis of NMOSD?

A: Revised consensus criteria published in 2015 base the diagnosis of NMOSD on the presence of core clinical characteristics, AQP4 antibody status, and magnetic resonance imaging (MRI) neuroimaging features (13).

Diagnostic criteria for NMOSD with AQP4-IgG

  1. At least one core clinical characteristic
  2. Positive test for AQP4-IgG using best available detection method (cell-based assay strongly recommended)
  3. Exclusion of alternative diagnoses

Diagnostic criteria for NMOSD without AQP4-IgG or NMOSD with unknown AQP4-IgG status

1. At least two core clinical characteristics occurring as a result of one or more clinical attacks and meeting all of the following requirements:

a. At least one core clinical characteristic must be optic neuritis, acute myelitis with longitudinally extensive transverse myelitis (LETM), or area postrema syndrome

b. Dissemination in space (two or more different core clinical characteristics)

c. Fulfillment of additional MRI requirements, as applicable

2. Negative tests for AQP4-IgG using best available detection method, or testing unavailable

3. Exclusion of alternative diagnoses

Core clinical characteristics

  1. Optic neuritis
  2. Acute myelitis
  3. Area postrema syndrome: Episode of otherwise unexplained hiccups or nausea and vomiting
  4. Acute brainstem syndrome
  5. Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical diencephalic MRI lesions
  6. Symptomatic cerebral syndrome with NMOSD-typical brain lesions

Additional MRI requirements for NMOSD without AQP4-IgG and NMOSD with unknown AQP4-IgG status

1. Acute optic neuritis: Requires brain MRI showing (a) normal findings or only nonspecific white matter lesions, or (b) optic nerve MRI with T2-hyperintense lesion or T1-weighted gadolinium enhancing lesion extending over more than one-half the optic nerve length or involving optic chiasm

2. Acute myelitis: Requires associated intramedullary MRI lesion extending over ≥3 contiguous segments (LETM) or ≥3 contiguous segments of focal spinal cord atrophy in patients with history compatible with acute myelitis

3. Area postrema syndrome: Requires associated dorsal medulla/area postrema lesions

4. Acute brainstem syndrome: Requires associated periependymal brainstem lesion

Q: What is the expected course and prognosis of NMOSD?

A: Approximately 90% of NMOSD patients have a relapsing course, with around 50% have their first relapse within 1 year and 90% within 5 years (14). Predictors of relapsing course include older age of onset, longer interval between first and second clinical attack, female gender, and less severe motor disability with the index event (15). If untreated, 50% of patients with relapsing NMOSD become blind in one or both eyes and require ambulatory help within 5 years of disease onset.

Q: What are the differences between pediatric and adult onset NMOSD?

A: Approximately 4% of NMOSD cases are reported to be pediatric onset. The age of onset is typically around 10–12 years, with the youngest reported patient with NMOSD was 16 months old. The marked female predominance seen in adult-onset disease is less evident (∼3:1 female: male ratio compared with up to 9:1 for adults). As in adults, AQP4 IgG seropositivity is usually associated with a severe, relapsing course, but is sometimes monophasic. In pediatric cases, the brain tends to be more involved, and brain lesions are commonly symptomatic, most common are encephalopathy, intractable nausea, hiccups, diplopia, and vertigo. With regard to spine MRI, both long and short segment myelitis were reported. However, LETM is less specific for NMOSD in children as 15% of pediatric MS patients have LETM. Other clinical, neuroimaging, and laboratory characteristics of pediatric NMOSD are similar to those of adult-onset disease. The International Panel for NMO Diagnosis (IPND) suggested that adult criteria are utilizable in pediatric with a caveat that LETM is probably less specific and can be observed in children with MS or ADEM. Current therapeutic options are similar to those of NMOSD for adults (see below). However, there is no FDA approved drug for pediatric patients with NMOSD.

Q: What is the general approach to an NMO relapse? Is it different from an MS relapse?

A: At the Mellen Center we treat NMO relapses urgently because of the rapidity, severity, as well as potential irreversibility of relapses in this disorder. Brainstem and cervical cord involvement may lead to fulminant neurogenic respiratory failure. We also make sure the patient is started on long term disease therapy as well (See below).

Intravenous corticosteroids are our initial treatment for an acute attack. The typical Mellen Center regimen is methylprednisolone 1000mg IV as a single daily dose on 3-5 consecutive days followed by an oral prednisone taper of one to 6 months depending on the severity of the attack and the maintenance immunotherapy plan. Patients with severe myelitis or brainstem symptoms should be given steroids in an inpatient setting.  We consider plasmapheresis as an early second line treatment with a low threshold in those with no or minimal response to corticosteroids or if the attack is severe.

Q: Other than medication, what types of support are needed in an NMO relapse?

A: Other considerations during an NMO relapse with spinal cord involvement include attention to skin hygiene, DVT prophylaxis, symptomatic treatment for painful spasms, and early physical therapy.  Patients with cervical cord and/or brainstem involvement may require close monitoring of pulmonary mechanics and cardiac telemetry. Tonic spasms following transverse myelitis can often effectively be treated with a low dose of carbamazepine. Central neuropathic pain is also more frequent in NMOSD and early involvement of a local pain team is helpful if typical neuropathic agents are not effective.

Q: How do we prevent relapses in NM OSD?

A: Given the natural history of NMOSD, long-term immunotherapy is indicated as soon as the diagnosis is made to prevent recurrent relapses and disability accrual. Unlike MS where the risk of relapses diminishes with age, patients with NMOSD require long term immunotherapy-for decades and any decision to stop chronic immunotherapy must be taken with caution. Until recently, there was no approved medication for NMOSD, and all of the medications were used off label. In June 2019, the FDA approved eculizumab (Soliris) for treatment of adult patients with NMOSD who are seropositive for AQP4 IgG antibodies (16). Rituximab has been widely used off label as first-line treatment to prevent relapses in NMOSD, driven by robust effects in several retrospective studies and a recent small randomized control trial  (17). Azathioprine and mycophenolate mofetil have been used for years but prospective data in support of their efficacy are lacking. Other therapies, such as methotrexate, mitoxantrone, cyclo- phosphamide, and cyclosporine have less supporting data for use in NMOSD.

Inebilizumab and Satralizumab showed positive outcomes in phase III with reduction in relapse rates between 70–90% but are not yet licensed or available outside of clinical trials at the time of this review.

At the Mellen Center, we treat all patients with AQP4-Abs at their first attack with long-term immunosuppression. We also recommend initiating therapy with Eculizumab or Rituximab as a first line therapy for AQP4-IgG-seropositive NMOSD. Rituximab has the potential benefits of infrequent administration, cost effectiveness and long-term efficacy and tolerability. Table 2 summarizes current treatment options.

Table 2:  Therapies currently available for treatment of NMOSD

Medication: Eculizumab (FDA approved)

Mechanism of action: C5 complement inhibitor

Study population/efficacy:
-Anti-AQP4 Ab- seropositive
-phase III trial
-94% reduction of relapse risk compared to placebo

Typical dose/precaution:
Initial dose: 900 mg IV weekly for 4 weeks
Maintenance: 1200 mg IV every 2 weeks 
Meningococcal vaccines ≥ 2 weeks prior to the first dose

Safety and tolerability: Increased risk of meningococcal infections, headache, upper respiratory tract infections, nasopharyngitis

Medication: Rituximab

Mechanism of action: anti-CD20

Study population/efficacy:
-Anti-AQP4 Ab- seropositive
-RCT
-No relapses in rituximab group for 72 weeks.

Typical dose/precaution:
Initial dose: two doses of 1000 mg IV, 2 weeks apart
Maintenance: 1000 mg IV every 6 months

Safety and tolerability: Infusion reactions, myelosuppression, hepatitis B reactivation, tuberculosis reactivation

Medication: Azathioprine

Mechanism of action: Guanosine nucleotide biosynthesis inhibition

Study population/efficacy:
-NMOSD
-Retrospective studies

Typical dose/precaution: Target dose: 2.5–3 mg/kg/d orally in divided doses

Safety and tolerability: malignancies, infections, hepatotoxicity, myelosuppression, hypersensitivity reaction, gastrointestinal upset, and hair thinning

Medication: Mycophenolate mofetil

Mechanism of action: Inosine monophosphate dehydrogenase inhibition

Study population/efficacy:
-NMOSD
-Retrospective studies

Typical dose/precaution: Target dose: 1000 mg 2 times a day orally (start at 500 mg 2 times a day

Safety and tolerability: Opportunistic infections, myelosuppression, gastrointestinal upset, peripheral edema and elevated blood pressure

Medication: Tocilizumab

Mechanism of action: Anti-IL6

Study population/efficacy:
-NMOSD
-Open label RCT

Typical dose/precaution: 8 mg/kg IV every 4 weeks

Safety and tolerability: Increased liver enzymes, anemia, leukopenia, upper respiratory tract and urinary tract infections

Therapies with promising results in phase III trials

Medication: Inebilizumab

Mechanism of action: anti-CD19

Study population/efficacy:
-NMOSD
-Phase III
-73% overall population relapse risk reduction

Typical dose/precaution: Initial dose: 300 mg on days 1 and 15. The total dose of in the trial period was 600 mg

Safety and tolerability: Urinary tract infection, nasopharyngitis, infusion-related reactions and IgG-hypogammaglobulinemia

Medication: Satralizumab

Mechanism of action: anti-IL-6 receptor

Study population/efficacy:
-NMOSD
-Phase III
-55-62% overall population relapse risk reduction

Typical dose/precaution: Initial dose: 120 mg SC at weeks 0, 2, and 4; Maintenance: 120 mg every four weeks

Safety and tolerability: upper respiratory tract infections, nasopharyngitis, headache

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