Neuromyelitis optical spectrum disorder

Initially described as a syndrome manifested by selective severe optic nerve and spinal cord inflammation.

Devic’s disease.

A rare autoimmune disorder with multifocal CNS inflammation primarily affecting the optic nerves and spinal cord.

Accounts for 1 to 2% of all cases of CNS inflammatory demyelinating disease in the US, while multiple sclerosis is much more common.

The initial attack involves the optic nerve or spinal cord in more than 85% of affected adults.

Patients present with unilateral or bilateral visual loss or scotoma, the synchronized dyschromatopsis, and ocular pain exacerbated by eye movement.

Acute transverse myelitis causes limb weakness, numbness, sensory loss or pain below the lesion level, along with bowel and bladder dysfunction.

NMSOD however, accounts one third or more cases of CNS inflammation in Asia and other non-white populations.

Incidence and prevalence estimates range from. 037 to .73 cases for 100,000 person years and 0.7 to 10 cases per hundred thousand persons, respectively.

Patients may have Lhermitte’s sign elicited by neck flexion and episodes of paroxysmal tonic spasms with painful muscle contractions.

Highest rates occur among Africans and the Afro Caribbean region, and the lowest rates among Whites and persons in Australasia, reflecting genetic environmental influences in difference is in ascertainment message.

In the US it has a higher prevalence for Blacks than for Whites by greater than three times.

It typically results in visual loss  and paralysis.

Approximately 50% of people with NMOSD have permanent visual impairment and paralysis caused by NMOSD attacks.
The area poststrema syndrome is a presenting feature in 10% of patients and occurs at some time during the disease in 15 to 40% of patients with vomiting lasting weeks and presages an attack of optic neuritis or myelitis.

It is thought to impact approximately 4,000 to 8,000 Americans.

The median age of onset is 40 years, but can affect people of any age and up to 20% of cases are in children or in adults over the age of 65 years.

An autoimmunologic neurologic disease of the CNS associated with a highly specific, greater than 99%, serum biomaker and pathogenic autoantibody, aquaporin-4 immunoglobulin G.

Aquaporin-4 immunoglobulin G is pathogenic, initiating the inflammatory CNS lesions and clinical manifestations of the disease.

AQP4 is expressed on astrocytic in feet that abut endothelial cells, which form the glia limitans component of the blood brain barrier.

When the barrier is breached, or in areas such as the area posttema where it is lacking, circulating AQP4 – IgG gains  access and bonds to its target antigen initiating inflammatory responses that generate neuromyelitis optica spectrum disorder lesions.

The pathological hallmark of NMOSD with AQP4-IgG is a focal inflammatory CNS lesion with marked to complete loss of AQP4.

Complement activation is a consequence of binding of AQP4-IgG to its antigen and together with interleukin-6 increases the permeability of the blood brain barrier and is a chemoattractantvsignaling eosinophils and neutrophils to enter the evolving lesion and degranulate.

Astrocytevinjury occurs from the effects of C5 and membrane attack complex components of complement.

Demyelination occurs as a secondary consequence of myelinolysis and oligodendrocyte injury.

A chronic relapsing autoimmune, inflammatory disorder that typically affects the optic nerves and spinal cord.

Possibly affects the brain stem and cerebrum.

Binding of aquaporin-4 immunoglobulin G to aquaporin 4 results in a cascade of the immune-mediated CNS damage accompanied by secondary CNS demyelinization.

Aquaporin-4 is a water channel protein expressed mainly by astrocytes in the CNS.

Aquaporin-4 is abundant on astrocytic membranes and that is proximate to the blood brain barrier.

Aquaporin-4 triggers the complement cascade, leading to inflammation and the formation of membrane attack complex implicated in astrocyte destruction and neuronal injuries.

Clinically seronegative patients cannot be distinguished from seopositive patients.

At least 2/3 of cases are associated with aquaporin-4 antibodies and complement mediated damage to the CNS.

Interleukin 6 is involved in the pathogenesis.

Interleukin 6 levels are elevated in the CSF of patients with NMOSD.

This process resembles multiple sclerosis, which is also characterized by acute self limited attacks of optic neuritis and myelitis.

Symptoms include: visual impairment, paralysis, sensory loss, bladder dysfunction, nausea, vomiting, and hiccups from lesions involving the area postrema.

About half the patients have permanent vision loss and paralysis.

Pain and fatigue are coming during and after relapses.

Disability following one attack can be aacumulative with each relapse.

Prevalence 0.5-10 persons per hundred thousand population.

Predominates in women.

Seropositive disease has a female predominance that approaches 90%, whereas seronegative cases have an equal sex distribution.

Up to 3% of cases are familial.

Acute attacks of NMOSD, including the initial episode usually occur in the absence of an identifiable inciting event.

Approximately 1/3 of cases are preceded by infection, which is often viral, and in rare cases an acute attack follows vaccination, and the use of checkpoint inhibitor therapies.

Demyelinating disorders, mediated by the humoral immune system, that predominately targets the optic nerve and spinal cord.

Aquaporin 4 IgG-associated NMOSD is an immune astrocytopathy with lytic and nonlytic clinical consequences to astrocytes.

Believed that the disease involves selective binding of the neuromyelitis optica IgG antibody, also known as anti-AQP4 antibody , to aquaporin-4.

Acqaporin-4 is a water channel protein highly concentrated in the spinal cord gray matter and in the periaqueductal gray matter and area postrema of the brain.

 Some of the pro-inflammatory processes involved in NMOSD are thought to involve IL-6, including the formation of pathological autoantibodies against aquaporin-4 (AQP4), and the permeability of the blood-brain barrier to mediators of inflammation.

Autoantibodies targeting myelin oligodendrocyte glycoprotein (MOG) are recognized as defining an overlapping clinical syndrome of the clinical diagnosis of NMOSD.

MOG IgG- associated NMOSD target myelin and does not lead to elevation of markers of astrocyte injury.

A positive titer of neuromyelitis optica IgG antibodies is highly specific for diagnosis.

Diagnosis requires manifestations of one or more of the six typical syndromes and emphasizes clinical and radiologic correlations, and a positive serological test for AQP4-IgG.

About 80% of cases are seropositive.

Patients usually present with transverse myelitis and unilateral or bilateral optic neuritis.

Patients with the spectrum disorder present with evidence of longitudinally extensive transverse myelitis, brainstem syndromes and brain lesions involving hypothalamus, corpus callosum, and periventricular areas.

Six core clinical syndromes have been identified and are classified by their location: optic nerve, spinal cord, area postrema of the dorsal medulla, brainstem regions, diencephalon, or cerebrum.

Refer to an inflammatory, demyelinating disease of the central nervous system.

It is characterized by severe relapsing attacks of optic neuritis and transverse myelitis, and attacks commonly spare the brain in the early stages.

Attacks usually reach peak severity in several days, plateau, and then spontaneously subside, frequently leaving moderate to severe functional deficits.

In more than 90% of cases the disease has a relapsing course.

There may be periods of months to years between attacks.

Symptoms typically evolve over a period of days, with the most common syndromes being optic neuritis and transverse myelitis, as well as area postrema syndrome, which causes intractable or repetitive vomiting and hiccups.

Neurologic impairment is stable or may diminish doing remission time, but relapses may have increasing disability.

The type, frequency, and severity of relapses are influenced by patient’s age, sex and ethnic group.

Among women with seropositive NMOSD, relapse rates are higher in the first three months postpartum and the risk of miscarriage is increased.

The sentinel attack involves the optic nerve or spinal cord in more than 85% of affected adults.

Five years after the onset of disease almost 1/4 of untreated patients require gait existence, more than 40% are blind in at least one eye, and mortality approaches 10%

Multiple lesions may result in a simultaneous or rapidly sequential combination of syndromes.

Associated with an antibody that targets aquaporin-4, the water channel on astrocytes and is a sensitive and specific biomarker for NMO.

NMOSD (spectrum disorder) includes patients who are seropositive for aquaporin-4-IgG but have more diverse neurological manifestations.

Neurological Manifestations

Extensive transverse myelitis 60-80%

Single occurrence transverse myelitis 40%

Recurrent Optic Neuritis 20%

Single Occurrence of Optic Neuritis <5%

Intractable Vomiting <5%

Acute disseminated Encephalomyelitis

Posterior reversible encephalopathy syndrome occurs in <5%.


Sleep Disorder<5%,

SIAD <5%

Hearing Loss <5%

Ataxia, Diplopia <5%

NMO spectrum disorders have very similar clinical and radiologic characteristics to MS, but the diseases are treated differently.

A majority of NMO patients, typically women, are initially misdiagnosed with MS.

NMO is treated by immunosuppressant therapy, while MS is treated by immunomodulation therapy, which may worsen NMO.

Neurological disability caused by NMO spectrum disorders is based on the number of attacks rather than a progressive phase of the illness.

Initiating therapy early in the course to eliminate recurrence of attacks will minimize patient disability.

Preventing relapses is a key strategy in disease management.

If not treated within 5 years, 50% of patients lose functional vision in at least 1 eye or are unable to walk.

Serum is more sensitive than CSF for detection of NMO/Aquaporin-4-IgG.

NMO/Aquaporin-4-IgG.should be ordered when any of the symptoms below are present in combination with either a single episode of optic neuritis or short spinal cord lesions

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

Confirmation that an attack is due to NMOSD is aided by MRI characterization of the lesions of the brain, optic nerve, optic chiasm, or spinal cord.

MRI may show new or enlarging inflammatory lesions and may show enhancement with gadolinium in actively inflamed lesions.

Abnormalities on MRI have a predilection for the optic chiasm or adjacent posterior optic nerves.

MRI of the spinal cord typically shows longitudinally extensive transverse myelitis.

Multiple sclerosis is a separate disease with a less rapid progress of course, and a higher likelihood of recovery.

Treatment as for multiple sclerosis is not beneficial and can be harmful.


The primary goal is prevention of relapse.

Acute relapses initially are treated intravenous glucocorticoids but only about 20% of patients have short-term remission of symptoms.

Plasma exchange may ameliorate symptoms with its early administration.

Early initiation of immunosuppressive therapy can prevent disability in neuromyelitis optica spectrum disorder.

May be associated with intractable nausea, vomiting, and hiccups months before neurologic signs and symptoms are evident.

Immunosuppressive treatments, including rituximab are used for relapse prevention, but 25-60% of patients continue to have recurrent attacks.

Mycophenolate mofetil,  and azothioprine, along with low-dose prednisone, methotrexate, mitoxanthone  or cyclophosphamide have been used.

Plasmapheresis may be indicated to decrease risk for long-term disability and mortality.

Satralizumab a subcutaneous administered humanized monoclonal antibody that binds to both membrane found in soluble interleukin-6 receptors and prevents the binding of interleukin-6, thus blocking interleukin-6-signaling pathways that are involved in inflammation.

Inebilizumab Targets CD19 can reduce the risk of relapse and disability.

Among patients with AQP4-IgG positive neuromyelitis optica spectrum disorder, received eculizumab had a significantly lower risk of relapse in those who received placebo.

Satralizumab (Enspryng), is a humanized monoclonal antibody medication that is used for the treatment of neuromyelitis optica spectrum disorder (NMOSD), a rare autoimmune disease.

Up to half of patients with NMOSD and AQP4-IgG have other serum autoantibodies – thyroid peroxidase, anti-nuclear, and Ro/SS-A antibodies, and 1/3 have an auto immune disease most commonly thyroiditis, systemic lupus erythematosus, or Sjogren’s syndrome.

Up to 5% of antibody positive NMOSD cases are paraneoplastic.


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