Neuromyelitis Optica Spectrum Disorders

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 affects 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 (MS) but is now known to represent a distinct clinical and pathophysiologic entity. The identification of serum autoantibodies specific for 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 CNS demyelinating disorders and distinguished them from MS. NMOSD encompasses patients who are either AQP4-IgG seropositive or AQP4-IgG seronegative (testing discussed below) with core clinical features (optic neuritis, transverse myelitis, brainstem syndrome, area postrema syndrome). AQP4-IgG seropositive NMOSD (e.g. NMOSD in patients who are AQP4-IgG seropositive) is an autoimmune astrocytopathy characterized by perivascular deposition of immunoglobulin, complement activation, demyelination, and axonal loss. ³ In general, the population of patients with AQP4-IgG seronegative NMOSD is considered more heterogeneous and may represent different clinical entities.

Q: How common is NMOSD? Who gets it?

A: The prevalence of NMOSD is comparatively similar across the globe and rarely exceeds 5/100,000.4 The relative difference in the proportion of MS and NMOSD patients is more a function of the variability in prevalence of MS than NMOSD. Females are more affected than males (3:1 in MS vs. 9:1 in NMOSD). ⁴ The median age at presentation is 39 years, but 18% of cases occur in children or the elderly. ⁵ It is generally regarded as a non-familial disease.

Q: How do patients with NMOSD present?

A: NMOSD has four cardinal manifestations: optic neuritis, transverse myelitis, area postrema syndrome, and acute brainstem syndrome. Clinical attacks often evolve rapidly and may be associated with incomplete recovery despite treatment. Compared to patients with MS, optic neuritis is more likely to have simultaneous bilateral involvement on first attack, is more likely to recur, and tends to have poorer long-term visual outcomes. ⁶ Transverse myelitis in NMOSD is typically complete with profound bilateral motor weakness, prominent dysesthesias, a sensory level, and sphincter dysfunction. ⁷ The third common presentation is area postrema syndrome, ⁸ which is characterized by nausea, vomiting with or without hiccups, and patients are often evaluated first by gastroenterologists. Brainstem syndromes are also a common feature of NMOSD and may include vomiting, hiccups, facial nerve palsy, oculomotor dysfunction, or vertigo. Other useful clinical clues include pain, pruritus, and tonic spasms (brief recurrent, usually painful episodes of increased muscle tone with abnormal posturing of the affecting limb).

Q; Are any other diseases associated with NMOSD?

A: NMOSD is commonly associated with antibody-mediated autoimmune diseases including myasthenia gravis, systemic lupus erythematosus, Sjogren syndrome, and antiphospholipid antibody syndrome. ⁹ 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 prompt testing for AQP4-IgG. NMOSD can present, albeit rarely, as a paraneoplastic presentation and may have an older age of presentation. ^{10, 11}

Q: How are NMOSD clinically different from MS?

A: Although NMOSD has distinct immunopathogenesis and treatment options, NMOSD and MS may have some overlapping 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) may exacerbate NMOSD. As mentioned above, 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. ¹² Unlike MS, the disability in NMOSD is mostly driven by relapses rather than gradual accrual of disease progression. Magnetic resonance imaging (MRI) of the brain has distinct features as compared to MS, and typically total lesion volume is lower (see below).

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 diagnostic criteria for MS. ¹³ 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 NMOSD, such as pencil-thin linear ependymal enhancement (thin ependymal enhancement of lateral ventricular surfaces), leptomeningeal enhancement, and cloud-like poorly marginated enhancement.

MRI findings of NMOSD optic neuritis include extensive T2 hyperintense lesions, which may be 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. ¹⁴  Imaging of the acute myelitis of NMOSD typically reveals a longitudinally extensive T2-hyperintense lesion spanning three or more contiguous vertebral segments. However, lesions may be short in 14% of first myelitis episodes (92% long at relapse). ¹⁵ Extensive cord edema, central cord involvement with necrosis and cavitation, and a long segment cord atrophy are other common features with NMOSD. It can be difficult at times to distinguish multiple cord lesions in MS patients coalescing over time from longitudinally extensive lesions in NMOSD. Conversely, longitudinally extensive lesions in NMOSD may break up over time, giving the appearance of multiple shorter cord lesions.

Q: What is the workup of suspected NMOSD?

A: Patients suspected of having NMOSD should obtain brain, cervical and thoracic MRI, as well as be tested for AQP4-IgG antibodies and antibodies to myelin oligodendrocyte glycoprotein (MOG), given clinical overlap between MS, NMOSD, and MOG antibody disorder (MOGAD). As mentioned above, AQP4-IgG is highly specific for NMOSD.2 Serum testing for AQP4-IgG should be performed before immunotherapy is initiated. Of available AQP4-IgG assays, the live cell-based assay has the highest sensitivity (76.7%) and specificity (99.8%).¹⁶ The older-generation enzyme-linked immunosorbent assay technique is less sensitive and more prone to yield false-positive results. Therefore, at the Mellen Center, we test for both MOG-IgG and AQP4-IgG using cell-based assays. With the most sensitive assays, testing is negative in 10-25% of clinically diagnosed NMOSD. Up to 42% of patients meeting clinical criteria for AQP4-IgG seronegative NMOSD will actually test positive for MOG-IgG, ¹⁷ and are therefore considered to have MOGAD. Conversely, 23% of adults and 31% of children with MOGAD were found to meet criteria for AQP4-IgG seronegative NMOSD. ¹⁸ Please refer to the Mellen Center Approach on MOGAD 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. ¹⁹ Positive oligoclonal bands are found in less than 30 % of patients with AQP4-IgG. Testing for AQP4-IgG in the CSF is less sensitive and not recommended. ²⁰

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. ²¹

Q: What is 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. ²² 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. ²³ 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.

There is some evidence that prognosis differs between patients who are AQP4-IgG seropositive and AQP4-IgG seronegative, although data is mixed. ^12,24 In one prospective cohort study of 594 patients, NMOSD patients who were AQP4-IgG seronegative had less severe clinical attacks and better prognoses, including lower EDSS scores and a lower proportion of disability compared to patients with NMOSD who were AQP4-IgG seropositive. ²⁴ In general the population of NMOSD who are AQP4-IgG seronegative is considered more heterogeneous and may represent different clinical entities.

Diagnostic criteria for NMOSD with AQP4-IgG

At least one core clinical characteristic Positive test for AQP4-IgG using best available detection method (cell-based assay strongly recommended) 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

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

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

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 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 Area postrema syndrome: Requires associated dorsal medulla/area postrema lesions Acute brainstem syndrome: Requires associated periependymal brainstem lesion

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 being 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). ²⁵ As in adults, AQP4-IgG seropositivity is usually associated with a severe, relapsing course. Brain lesions occur more commonly in pediatric NMOSD compared to adult NMOSD. ²⁶ 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. ²⁷ 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 pediatrics with a caveat that LETM is probably less specific and can be observed in children with MS or ADEM. ²⁸ We recommend that any pediatric patient presenting with ADEM be tested for the presence of AQP4-IgG and MOG-IgG, given the importance of distinguishing these entities due to long-term treatment implications. 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 the 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. Oral prednisone should be tapered slowly and continued until maintenance therapy has been established (typically 1-2 months post-initiation of maintenance therapy). An equivalent dose of high dose oral steroids (1250mg PO prednisone daily, divided into 2-3 morning/early afternoon doses) can be used in place of IV methylprednisolone. Concurrent PPI or H2 blocker should be prescribed while on steroids for GI protection. Patients with severe myelitis or brainstem symptoms may need hospitalization. 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. Intravenous immunoglobulin (IVIG) has also been used as a second-line treatment, although its evidence is not as robust.

Q: How do we prevent relapses in NMOSD?

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. The risk of relapse does not diminish with age and patients with NMOSD require long-term immunotherapy for decades. Any decision to stop chronic immunotherapy must be taken with caution. Until 2019, there was no approved medication for NMOSD, and immunosuppressive medications were used off-label. However, the FDA has now approved eculizumab, ²⁹ inebilizumab, ³⁰ and satrilizumab³¹ for treatment of adult patients with NMOSD who are seropositive for AQP4-IgG antibodies. Although not FDA-approved, rituximab has been widely used off-label to prevent relapses in NMOSD, driven by robust effects in several retrospective studies³² and a recent small, randomized control trial (33). Azathioprine and mycophenolate mofetil have been used for years although systematic literature review suggests that rituximab demonstrates better efficacy. ³⁴ Tocilizumab has also shown improved efficacy compared to azathioprine in an open-label phase II trial. ³⁵

At the Mellen Center, we treat all AQP4-IgG seropositive NMOSD patients at their first attack with long-term immunosuppression due to the risk of incomplete recovery from relapses. The current treatment options are summarized in table 2 below; please refer to individual Mellen Center Approaches on these medications for more details. There have been no head-to-head studies to compare the safety and efficacy of the 3 FDA-approved medications (inebilizumab, satralizumab, eculizumab) and rituximab in NMOSD. In addition, efficacy rates between trials are difficult to directly compare due to differences in individual trial details (e.g., inclusion of AQP4-IgG seronegative patients, and whether concomitant immunosuppressive medications were allowed). The decision of which medication to begin with is ultimately up to the treating neurologist and patient and includes considerations such as route of administration, side effect profile, and cost. At the Mellen Center, we most commonly use rituximab as first-line therapy due to our experience with the medication, cost effectiveness, and well-established long-term efficacy and tolerability. Eculizumab, inebulizumab, and satralizumab can also be considered as first line therapy, although we generally reserve these for cases where rituximab has been ineffective or not tolerated. In the presence of breakthrough disease activity, we generally switch to a medication with a different mechanism of action.

Table 2: Therapies currently available for treatment of NMOSD

Medication	Mechanism of action	Study Details	Efficacy	Treatment Dosing	Safety and tolerability	Pre-medication Recommendations
Eculizumab (FDA approved)	C5 complement inhibitor	PREVENT -AQP4-Ab seropositive -phase III trial: compared to placebo; adjunctive IS allowed, no RTX	Relapses: 3% vs 43% HR 0.06	Initial dose: 900 mg IV weekly for 4 weeks Maintenance: 1200 mg IV every 2 weeks	Increased risk of meningococcal infections, headache, URTI, nasopharyngitis	Pre-testing: CBC w diff, CMP Monitoring: CBC w diff, CMP Meningococcal vaccines ≥ 2 weeks prior to the first dose
Inebilizumab (FDA approved)	anti-CD19	N-MOmentum -NMOSD -Phase III RCT: compared to placebo; no other IS allowed	Relapses: 12% vs 39% HR 0.27	Initial dose: 300 mg IV on days 1 and 15. The total dose of in the trial period was 600 mg IV Maintenance: 300mg Q6 mos	UTI, nasopharyngitis, infusion reactions and hypogammaglobulinemia	Pre-testing: HBV, HCV, latent Tb, IgG/IgM
Satralizumab (FDA approved)	anti-IL-6 receptor	SAkuraSky -NMOSD -Phase III RCT: compared to placebo; adjunctive IS allowed, no RTX -55-62% overall population relapse risk reduction	Relapses: 20% vs 42% HR 0.38	Initial dose: 120 mg SC at weeks 0, 2, and 4 Maintenance: 120 mg every four weeks	URTI, nasopharyngitis, headache	Pre-testing: HBV, HCV, latent Tb, CBC with diff, LFTs Monitoring: LFTs, CBC with diff
Rituximab	anti-CD20	RIN-1 -AQP4-Ab seropositive -RCT: compared to placebo; no other IS allowed -No relapses in rituximab group for 72 weeks.	Relapses: 0% vs 37%	Initial dose: two doses of 1000 mg IV, 2 weeks apart Maintenance: 1000 mg IV every 6 months	Infusion reactions, myelosuppression, UTI, URTI, hepatitis B reactivation, tuberculosis reactivation	Pre-testing: HBV, HCV, latent Tb, IgG/IgM, CBC with diff, CMP, CD19, serum hCG
Tocilizumab	Anti-IL6	TANGO: -highly relapsing NMOSD* -Open label RCT: compared to azathioprine; no other IS allowed	Relapses: 14% versus 47% HR 0.24	8 mg/kg IV every 4 weeks	Hepatitis B reactivation, increased liver enzymes, anemia, leukopenia, upper respiratory tract and urinary tract infections	Pre-testing: CBC with diff, CMP, lipids, latent Tb, HBV Monitoring: CBC with diff, CMP, lipids
Azathioprine	Guanosine nucleotide biosynthesis inhibition	-NMOSD -Retrospective studies		Target dose: 2.5–3 mg/kg/d orally in divided doses	malignancies, infections hepatotoxicity, myelosuppression, hypersensitivity reaction, gastrointestinal upset, and	Pre-testing: CBC with diff, CMP, TPMT, serum hCG Monitoring: CBC with diff, CMP
Mycophenolate mofetil	Inosine monophosphate dehydrogenase inhibition	-NMOSD -Retrospective studies		Target dose: 1000 mg 2 times a day orally (start at 500 mg 2 times a day)	Opportunistic infections, myelosuppression, malignancy, gastrointestinal upset, peripheral edema and elevated blood pressure	Pre-testing: serum hCG, CBC with diff, CMP, HBV/HCV**

CBC, complete blood count; LFT, liver function test; Tb, tuberculosis; HBV, hepatitis B virus; HCV, hepatitis C virus; CMP, complete metabolic panel; URTI, upper respiratory tract infection; UTI, urinary tract infection; TPMT thiopurine transferase

* Subgroup analysis showed no difference in outcomes based on AQP4 status

** Not recommended specifically in insert, but are at risk for reactivation

Q: Are seronegative NMOSD patients treated differently?

A: The initiation of immunotherapy in AQP4-IgG seronegative patients requires additional deliberation. As highlighted above, inebilizumab, satralizumab, and eculizumab are FDA-approved specifically for NMOSD patients who are AQP4-IgG seropositive. Patients seronegative for AQP4-Ab may be a more heterogeneous population reflecting other etiologies of disease. Of interest, the trials of inebilizumab and satralizumab both included AQP4-IgG seronegative patients, however there was insufficient evidence to support a risk reduction in this AQP4-IgG seronegative population. Although the data are less clear and each case must be considered individually, we often recommend initiation of immunosuppressive therapy in patients with NMOSD who are AQP4-Ab seronegative.

Approach last updated: April, 8 2021

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