Neuromyelitis Optica Spectrum Disorder

Neuromyelitis optica spectrum disorder (NMOSD) is an uncommon autoimmune inflammatory demyelination disorder of the central nervous system (CNS).
It is a clinical syndrome defined by predilection to affect particular regions of the CNS: Specifically the optic nerve, spinal cord (typically with longitudinally extensive transverse myelitis), and some areas of the brain including periependymal regions (most strikingly the area postrema).
The clinical syndrome is further subdivided into seropositive NMOSD (AQP4-IgG+- 80% of patients) and seronegative NMOSD (MOG-IgG+, negative for both AQP4-IgG and MOG-IgG, or unknown serologic status). ¹

Synonyms

NMOSD
Neuromyelitis Optica (NMO)
Devic’s Disease

Epidemiology & Demographics

Incidence

Wide variety of estimated incidence, ranging from 0.037 per 100,000 in Australia and New Zealand to 0.73 per 100,000 in Afro-Caribbean region. ²

Prevalence

Wide variety of estimated prevalence, ranging from 0.7 per 100,000 in Australia and New Zealand to 10 per 100,000 in Afro-Caribbean region. ²
In the U.S., the estimated prevalence was 13 per 100,000 in Black Americans and 4 per 100,000 in White Americans. ³

Predominant Sex & Age

Median age of onset is 40 years old. ⁴
10:1 female to male (seropositive AQP4-IgG+)
1:1 and 1:2 female to male (seronegative AQP4-IgG+) ⁵

Peak Incidence

Peak incidence appears to be in the African and Afro-Caribbean populations.

Risk Factors

Other autoimmune diseases including systemic lupus erythematosus. ⁴

Genetics

Though presently not well understood, there has been postulated a genetic predisposition towards NMOSD.
Specifically relevant to seropositive NMOSD, associations with AQP4-IgG seropositivity and HLA-DRB1∗03 (DR3) in French and Brazilian populations and HLA-DPB1∗0501 in Japanese and Chinese populations have been described. ⁶

Physical Findings & Clinical Presentation

Findings depend on the location of the CNS lesion(s) and may include the following:

Common: Nonspecific complaints such as fatigue (most common, with 80% lifetime prevalence), blurred vision, diplopia, vertigo, falls, hemiparesis, paraparesis, monoparesis, numbness, paresthesias, ataxia, cognitive impairment, depression, anxiety, pseudobulbar affect (involuntary crying or laughing out of context), sexual dysfunction, and bowel/bladder dysfunction
Optic neuritis: Unilateral or bilateral
Corticospinal tract(s) involvement: Transverse myelitis often involving three or more segments of the spinal cord, upper motor neuron signs such as spasticity (particularly leg spasms at night or after prolonged immobility), hyperreflexia, clonus, extensor plantar responses, tonic spasms, upper motor neuron pattern of weakness
Area postrema syndrome: Intractable hiccupping and/or vomiting (occurs in up to 60% of patients during their disease course)
Brainstem syndromes including combinations of cranial nerve palsies, weakness, sensory loss, and ataxia.
Diencephalic syndromes: Narcolepsy, thalamic/hypothalamic-mediated dysfunction
Sensory involvement: May include partial or full dermatomal loss of pain and temperature, loss of vibration (common) and position sense, temperature dysregulation, thoracic band of sensory loss, paresthesias, trigeminal neuralgia
Bladder dysfunction: Due to spinal cord involvement.

Etiology

As AQP4 is expressed in the central nervous system most abundantly on the foot processes of astrocytes, seropositive NMOSD should be understood as an antibody-mediated astrocytopathy.
In a clinical relapse, accumulation of AQP4-IgG stimulates an inflammatory response mediated by such factors as complement activation and interleukins such as interleukin-6 (IL-6), leading to the influx of granulocytes.
This cascades into a substantial local inflammatory response, leading to bystander damage of local cells and cell products such as myelin or axons themselves.
On the other hand, MOG-IgG associated NMOSD is more clearly demyelinating, with some histopathologic studies bearing features similar to type II MS pattern demyelinating lesions. ⁶
The specifics of non-MOG-IgG seronegative NMOSD pathophysiology are less well understood.

Differential Diagnosis

Optic Neuritis

Inflammatory: MS, sarcoidosis, granulomatosis with polyangiitis, lupus, Sjögren syndrome, acute disseminated encephalomyelitis, paraneoplastic (CRMP-5, CV-2), autoimmune optic neuropathy, autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy
Infectious: Neurosyphilis, tuberculosis (TB), Lyme disease, HIV, cytomegalovirus, herpes simplex virus, varicella-zoster virus, Epstein-Barr virus, West Nile virus, dengue fever, Bartonella henselae, Rickettsia spp., Toxocara spp., Q fever, histoplasmosis, toxoplasmosis, helminths, periorbital infections
Ischemic: Anterior and posterior ischemic optic neuropathies, diabetic papillopathy, branch or central retinal artery or vein occlusion
Drugs and toxins: Arsenic, methanol, ethambutol, cyclosporine, etc.
Mitochondrial: Leber hereditary optic neuropathy, other mitochondrial

Transverse Myelitis

Multiple sclerosis
Acute demyelinating encephalomyelitis (where TM tends to be monophasic)
Autoimmune syndromes: systemic lupus, Sjögren syndrome, antiphospholipid antibody syndrome, sarcoidosis, and paraneoplastic conditions, which can be progressive or relapsing.
Infectious causes of myelitis include HIV, syphilis, varicella zoster (associated with shingles), human T-cell leukemia virus type 1, Lyme disease, COVID-19, arboviruses such as West Nile virus (typically causing a poliomyelitis-type acute flaccid paralysis), or enteroviruses (typically causing acute flaccid paralysis mainly in children).

Workup

NMOSD remains a clinical diagnosis, supported by serologic studies for the antibodies and/or characteristic MRI findings

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 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 1/2 optic nerve length or involving optic chiasm
2.Acute myelitis: requires associated intramedullary MRI lesion extending over at least three contiguous segments (LETM) OR at least three 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 lesions

Laboratory Tests

•AQP4-IgG (serum)
•MOG-IgG (serum)
•Consider antinuclear antibody (ANA), angiotensin-converting enzyme (ACE; a test with low specificity and sensitivity for sarcoidosis), antineutrophil cytoplasmic antibodies, antiphospholipid and anticardiolipin antibodies, Sjögren antibodies, thyroid-stimulating hormone (TSH), free T ₄
•Lumbar puncture to evaluate for elevated protein (>100 mg/dl), pleocytosis (often with neutrophilic or eosinophilic predominance in NMOSD). Oligoclonal bands (OCBs) can be seen in NMOSD but much less commonly than in multiple sclerosis. Evaluate for other causes of transverse myelitis.
•Serum: Complete blood count (CBC) with differential, comprehensive metabolic panel, liver function tests (LFTs), vitamin B ₁₂, copper, 25-OH vitamin D ₃
•In some cases, optical coherence tomography can be helpful, which may demonstrate thinning of the retinal nerve fiber layer and ganglion cell inner plexiform layer.

Imaging Studies

Magnetic resonance imaging (MRI) of the brain and spinal cord with and without contrast is recommended in all cases. There are some imaging patterns to recognize in NMOSD:

•In the spinal cord, transverse myelitis is most frequently longitudinally extensive (that is, a single lesion involving three or more vertebral segments), though shorter segment lesions can occur in a minority of cases.
•In the optic nerve, >50% of the length of the nerve is commonly involved, with a preference for the posterior portion. Optic chiasm may be involved. Bilateral optic nerve involvement is less common

In the brain, there is preferential involvement of the periependymal regions, including diencephalic and periventricular tissue. Involvement of the area postrema is especially characteristic. Lesions can occur elsewhere in both the supratentorial and infratentorial compartments, but these are less specific.

Treatment

Nonpharmacologic Therapy

Patient education regarding disease characteristics, treatment options, risks and benefits of treatment, and prognosis. Often, patients need to incorporate intermittent rest periods on a daily basis and when physically active (for energy conservation), and avoid exposure to heat, which typically worsens symptoms (but not the disease).

Recommend physical therapy for new or worsening weakness, incoordination, or spasticity.

Acute General Rx

Given the potential for significant morbidity associated with acute NMOSD relapses, early recognition and intervention are considered important.
For acute relapses or worsening, treat with 1 gram of methylprednisolone intravenously (IVMP) for 3-5 days.
Plasma exchange (PLEX) should be considered in those who do not respond briskly to IVMP. This strategy has been found to significantly reduce the likelihood of residual deficits. ⁷

Chronic Rx

•Chronic immunomodulation is indicated in most cases.
•Chronic steroids, azathioprine, mycophenolate mofetil, intravenous immunoglobulins, ⁸ and rituximab ⁹ can be used, especially for seronegative NMOSD.
•For seropositive (AQP4-IgG +) NMOSD, there are FDA approved therapies. In choosing between these therapies, a variety of factors should be considered including dosing frequency, comorbidities, and risk of opportunistic infections.
- 1.Eculizumab ¹⁰
- 2.Inebilizumab ¹¹
- 3.Satralizumab ¹²

Drugs With Phase II/III Trials in NMOSD

Drugs with Phase II/III Trials in NMOSD
Name	Mechanism of Action	Dose and Delivery	Side Effects/Monitoring
Eculizumab ¹⁰	Inhibits the terminal complement protein C5 and prevents its cleavage into C5a, which is pro-inflammatory, and C5b, which coordinates the formation of membrane cytolytic attack complex.	900 mg intravenously weekly for the first 4 doses starting on day 1, followed by 1200 mg every 2 weeks starting at week 4	–Approved for AQP4-IgG positive NMOSD –Increased infections with leukopenia and lymphopenia –Increased risk of infection with encapsulated bacteria, especially Neisseria meningitidis (meningococcal vaccination is mandatory before starting treatment)
Inebilizumab ¹¹	Binds to the B-cell surface antigen CD19 targeting B cells and CD19+ plasmablasts	300 mg administered intravenously on days 1 and 15 every 6 months	–Approved for AQP4-IgG positive NMOSD –Lymphopenia, reduced immunoglobulin levels –Increased infections
Satralizumab ¹²¹³	Binds to membrane-bound and soluble IL-6 receptors, preventing IL-6 from binding and inhibiting the IL-6 signaling pathways involved in inflammation	120 mg subcutaneously at weeks 0, 2, and 4 and every 4 weeks thereafter	–Approved for AQP4-IgG positive NMOSD –Leukopenia, increased infections
Rituximab ⁹	Binds to the B-cell surface antigen CD20 surface expressed on B-lymphocytes	375 mg/m ²intravenously every week for 4 weeks, then 6-month interval dosing (alternatively, 2 doses of 1,000 mg with 2 weeks interval)	Extralabel use for NMOSD

Adapted from Mora Cuervo DL et al: Immunobiology of neuromyelitis optica spectrum disorders, Curr Opin Neurobiol 76(102618):102618, 2022.

Disposition

NMOSD, like MS, follows a relapsing clinical course in the vast majority of cases.
Disability is largely accrued over time as a direct consequence of damage sustained during relapses. In cases of untreated seropositive NMOSD at 5 years after onset, more than 40% of patients are blind in at least one eye, nearly 25% require assistance to walk, and mortality is close to 10%. ⁴

Referral

Timely referral to a neurologist is critical. Given the prospect of significant residual deficits, a multidisciplinary approach to mitigating disability is advisable.
Consider consultation with physical therapy/occupational therapy/speech therapy, neuro-ophthalmology, PM&R, and urology as well as engaging the services of social work.

Pearls & Considerations

•NMOSD is a relapsing inflammatory autoimmune disorder of the central nervous system with preferential involvement of the optic nerve, spinal cord, and periependymal regions of the brain including the area postrema.
•Each relapse can result in permanent disability. Prompt recognition and treatment for relapses should be adopted, with steroids and early consideration for escalation to plasma exchange.
•Chronic preventative immunomodulation plays an important role in reducing the frequency of relapses and thus reducing disability. There are presently three FDA approved medications for seropositive (AQP4-IgG +) NMOSD with many more in development, and effective options including rituximab can be utilized for seronegative (MOG-IgG +, dual negative, or serologic status unknown) NMOSD.

Patient & Family Education

Multiple organizations exist to spread awareness, fund research, and support patients with NMOSD. Among these are the Siegel Rare Neuroimmune Association ( https://wearesrna.org/ ), the Sumaira Foundation ( https://www.sumairafoundation.org/ ), and the Guthy-Jackson Charitable Foundation ( https://guthyjacksonfoundation.org/ ).

References

1.Wingerchuk D.M., et al.: International consensus diagnostic criteria for neuromyelitis optica spectrum disorders . Neurology 2015; 85 (2): pp. 177-189.

2.Papp V., et al.: Worldwide incidence and prevalence of neuromyelitis optica: a systematic review . Neurology 2021; 96 (2): pp. 59-77.

3.Flanagan E.P., et al.: Epidemiology of aquaporin-4 autoimmunity and neuromyelitis optica spectrum . Ann Neurol 2016; 79 (5): pp. 775-783.

4.Wingerchuk D.M., Lucchinetti C.F.: Neuromyelitis optica spectrum disorder . N Engl J Med 2022; 387 (7): pp. 631-639.

5.Jarius S., et al.: Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: a multicentre study of 175 patients . J Neuroinflammation 2012; 9 (1): pp. 14.

6.Paul S., et al.: Neuromyelitis optica spectrum disorders . J Neurol Sci 2021; 420 (117225): pp. 117225.

7.Abboud H., et al.: Treatment of acute relapses in neuromyelitis optica: steroids alone versus steroids plus plasma exchange . Mult Scler 2016; 22 (2): pp. 185-192.

8.Mora Cuervo D.L., et al.: Immunobiology of neuromyelitis optica spectrum disorders . Curr Opin Neurobiol 2022; 76 (102618): pp. 102618.

9.Tahara M., et al.: Safety and efficacy of rituximab in neuromyelitis optica spectrum disorders (RIN-1 study): a multicentre, randomised, double-blind, placebo-controlled trial . Lancet Neurol 2020; 19 (4): pp. 298-306.

10.Pittock S.J., et al.: Eculizumab in aquaporin-4-positive neuromyelitis optica spectrum disorder . N Engl J Med 2019; 381 (7): pp. 614-625.

11.Cree B.A.C., et al.: Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial . Lancet 2019; 394 (10206): pp. 1352-1363.

12.Yamamura T., et al.: Trial of satralizumab in neuromyelitis optica spectrum disorder . N Engl J Med 2019; 381 (22): pp. 2114-2124.

13.Traboulsee A., et al.: Safety and efficacy of satralizumab monotherapy in neuromyelitis optica spectrum disorder: a randomised, double-blind, multicentre, placebo-controlled phase 3 trial . Lancet Neurol 2020; 19 (5): pp. 402-412.

Neuromyelitis Optica Spectrum Disorder