July 27, 2022
Years published: 1987, 1988, 1989, 2000, 2006, 2008, 2012, 2015, 2018
NORD gratefully acknowledges Brian Weinshenker, MD, FRCP(C), Professor of Neurology, Mayo Clinic, for assistance in the preparation of this report.
Neuromyelitis optica spectrum disorder (NMOSD), also known as Devic disease, is a chronic disorder of the brain and spinal cord dominated by inflammation of the optic nerve (optic neuritis) and inflammation of the spinal cord (myelitis). Classically, it was felt to be a monophasic illness, consisting of episodes of inflammation of one or both optic nerves and the spinal cord over a short period of time (days or weeks) but, after the initial episode, no recurrence. It is now recognized that most patients satisfying current criteria for NMOSD experience repeated attacks separated by periods of remission. The interval between attacks may be weeks, months or years. In its early stages, NMOSD may be confused with multiple sclerosis (MS).
The characteristic symptoms of NMOSD are either optic neuritis or myelitis; either may occur as the first symptom. Optic neuritis is inflammation, of the optic nerve (optic neuritis) leading to pain inside the eye which rapidly is followed by loss of clear vision (acuity). Usually, only one eye is affected (unilateral) although both eyes may be involved simultaneously (bilateral). NMOSD may or may not be preceded by a prodromal upper respiratory infection.
The other cardinal syndrome is inflammation of the spinal cord, a condition known as transverse myelitis because the symptoms tend to affect some, and often all motor, sensory and autonomic functions (bladder and bowel) below a certain level on the body, although, not infrequently, symptoms may be confined to one side of the body. Affected individuals may experience pain in the spine or limbs, and mild to severe paralysis (paraparesis to paraplegia) of the lower limbs, and loss of bowel and bladder control. Deep tendon reflexes may be exaggerated, or may be diminished or absent initially and later become exaggerated. A variable degree of sensory loss may occur. Affected individuals may also have a stiff neck, back or limb pain, and/or headaches. This syndrome may be indistinguishable from other cases of “idiopathic” transverse myelitis.
Early in the course of the disease, it may be difficult to distinguish between NMOSD and multiple sclerosis because both may cause optic neuritis and myelitis as symptoms. However, the optic neuritis and myelitis tend to be more severe in NMOSD; the brain MRI is more commonly normal, and the spinal fluid analysis does not usually show oligoclonal bands in NMOSD, which are features that help distinguish it from MS.
In most cases of NMOSD, the initial symptoms of vision loss or paralysis improve with standard treatment with high dose corticosteroids, and partial recovery of vision, motor, sensory, or bladder function occurs. However, in recurring cases, NMOSD frequently causes significant permanent disturbances of vision and/or spinal cord function leading to blindness or impaired mobility.
NMOSD includes limited versions of neuromyelitis associated with positive test for aquaporin-4 autoantibodies and NMOSD brain syndromes associated with positive test for aquaporin-4 autoantibodies (AQP4-IgG), as well as similar clinical conditions where AQP4-IgG is not detected, but rigorous criteria distinguish them from multiple sclerosis and other conditions that may mimic NMOSD (see below for differential diagnosis). An international panel established diagnostic criteria for NMOSD in 2015.
Some patients with NMOSD have only recurrent myelitis or only recurrent optic neuritis. When patients have antibodies to aquaporin-4 with just these manifestations, most investigators would argue that they should be treated as having NMOSD. Brain lesions may occur in patients with NMOSD, typically, but not always, in later phases of the disease. Intractable vomiting or hiccups is now a generally accepted specific syndrome of this condition and is the result of inflammation in the dorsal medulla of the brainstem and may be the initial symptom of NMOSD. Brainstem and hypothalamic syndromes are particularly common, but inflammation of the forebrain may also occur, often associated with prominent brain swelling (edema). Clinicians suspecting this disorder must have a strong index of suspicion for this condition especially in patients with a history of severe myelitis or optic neuritis.
NMOSD can also be associated with systemic or brain autoimmune diseases, and this may lead to diagnostic confusion (e.g. “lupus myelitis” is most often NMOSD coexisting with systemic lupus erythematosus).
Greater than 95% of patients with NMOSD report no relatives with the disease, but approximately 3% report having other relatives with the condition. There is a strong association with a personal or family history of autoimmunity, which are present in 50% of cases. NMOSD is regarded as an autoimmune disease though the exact cause for the autoimmunity is unknown.
Autoimmune disorders occur when the body’s natural defenses against disease or invading organisms (such as bacteria), for unknown reasons, suddenly begin to attack healthy tissue. These defenses, for reasons not at all understood, attack proteins in the central nervous system, especially aquaporin-4. In some patients with NMOSD, especially those with the non-relapsing variant, antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) have been discovered. Patients who are seropositive for MOG differ in some respects from those with AQP4-IgG antibodies: they do not have as striking a predilection for women, attacks are less severe and recover better, optic neuritis tends to be associated with more swelling of the optic nerve head and occurs in the anterior optic nerve, whereas myelitis has a somewhat greater predilection for the caudal spinal cord. NMOSD may be immunologically heterogeneous.
NMOSD occurs in individuals of all races. The prevalence of NMOSD is approximately 1-10 per 100,000 individuals and seems to be similar worldwide, although somewhat higher rates have been reported in countries with a higher proportion of individuals of African ancestry. Relative to MS that it mimics, it occurs with greater frequency in individuals of Asian and African descent, but the majority of patients with this illness in Western countries are Caucasian. Individuals of any age may be affected, but typically NMOSD, especially cases seropositive for AQP4-IgG, occur in late middle-aged women. Equal numbers of men and women have the form that does not recur after the initial flurry of attacks, but women, especially those with AQP4-IgG, are four or five times more likely to be affected than men by the recurring (relapsing) form. Children represent may also be affected by this condition; children more commonly develop brain symptoms at onset and seem to have a higher frequency of monophasic presentation than adults.
Symptoms of the following disorders can be similar to those of NMOSD. Comparisons may be useful for a differential diagnosis:
Acute disseminated encephalomyelitis (postinfectious encephalitis) is a central nervous system disorder characterized by inflammation of the brain and spinal cord caused by damage to the fatty sheath surrounding the nerves. This can occur spontaneously, but usually follows a viral infection or inoculation such as a bacterial or viral vaccine. Individuals with acute disseminated encephalomyelitis may have MOG-IgG, adding extra confusion.
Multiple sclerosis is a chronic disease of the brain and spinal cord (central nervous system) which may be progressive, relapsing and remitting, or stable. The pathology of MS consists of small lesions called plaques that form randomly throughout the brain and spinal cord. In these plaques, the fatty sheath surrounding nerves is lost, which prevents proper transmission of nervous system signals and thus result in a variety of neurological symptoms. Most individuals with MS have a near normal life span. Symptoms often include visual difficulties as well as speech impairment, abnormal skin sensations or numbness, gait disturbance, and difficulties with bladder and bowel function. In a small number of cases, selective involvement of the optic nerves and spinal cord may occur in early stages of MS, but in these situations rarely would the spinal cord information extend over long segments of the spinal cord as occurs in NMOSD. (For more information on this disorder, choose “Multiple Sclerosis” as your search term in the Rare Disease Database.)
Systemic lupus erythematosus (also known as lupus) is an inflammatory connective tissue disease that can affect many parts of the body including the joints, skin and internal organs. Lupus is a disease of the body’s immune system, most often striking young women between the ages of fifteen and thirty-five years. (For more information on this disorder, choose “Lupus” as your search term in the Rare Disease Database.) Transverse myelitis and optic neuritis have been reported to occur in patients with systemic lupus erythematosus, but recent research demonstrates that a high proportion of such individuals have the NMO-IgG antibody, and likely have coexisting NMOSD.
Paraneoplastic disorders are conditions in which patients develop inflammation or cell injury caused by autoimmune reactions to a cancer that leads to production of autoantibodies or cell-mediated autoimmunity. In some paraneoplastic syndromes, particularly those associated with collapsin response mediated protein 5 (CRMP5), optic neuritis and extensive myelitis may occur that may closely simulate NMOSD.
Sarcoidosis is a granulomatous disorder that may affect the optic nerves and spinal cord when it affects the central nervous system. This condition frequently presents with pulmonary disease, either symptomatic or asymptomatic, or enlarged lymph nodes, often present on chest xray. Many patients with central nervous system involvement do not have demonstrable sarcoidosis in other organs. Sarcoidosis may result in long inflammatory spinal cord lesions that mimic the myelitis in NMOSD, but symptoms usually develop more insidiously and regress more slowly following corticosteroid treatment.
A diagnosis of NMOSD is made based upon a detailed patient history, a thorough clinical evaluation, identification of characteristic physical findings, and a variety of specialized tests. Such tests include blood tests, examination of cerebrospinal fluid (CSF), spinal taps, or x-ray procedures such as magnetic resonance imaging (MRIs) or computed tomography (CT or CAT) scans. A blood test, AQP4-IgG, is highly specific and moderately sensitive for NMOSD. It has been shown that it detects antibodies that are specific for an astrocyte protein, aquaporin-4. This is very helpful to request this test at the first significant suspicion of NMOSD, as it is frequently positive at the time of the very first symptom even before a confident clinical diagnosis is possible. A recently discovered antibody, MOG-IgG, is present in about half of those who do not have AQP4-IgG; while it seems specific for a form of NMOSD, and is rarely seen in typical MS, it also occurs in some patients with recurrent optic neuritis and in some patients with acute disseminated encephalomyelitis; in the latter patients, it is often transient. Successful diagnosis of NMOSD depends on distinguishing it from MS.
In 2019, Soliris (eculizumab) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of NMOSD in adult patients who are anti-aquaporin-4 (AQP4) antibody positive. In 2020, Uplizna (inebilizumab-cdon) and Enspryng (satralizumab-mwge) were approved for the treatment of NMOSD in adult patients with the same AQP4 antibody.
For acute attacks, the standard treatment is high-dose intravenous corticosteroids, typically methylprednisolone. Plasma exchange may be effective in patients who experience acute severe attacks that do not response to intravenous corticosteroids. This procedure involves removing some blood and mechanically separating the blood cells from the fluid (plasma). Blood cells are then mixed with a replacement solution and returned to the body.
For long-term suppression of the disease, a variety of immunosuppressive drugs are regarded by many clinicians as first-line therapy. Corticosteroids, azathioprine, mycophenolate mofetil and rituximab are the treatments most widely prescribed treatments. Typically, azathioprine or mycophenolate mofetil are prescribed along with low doses of corticosteroids. Rituximab has been shown to be helpful in retrospective studies, including in patients who fail first-line immunosuppressive treatments. Immunomodulatory drugs for multiple sclerosis are ineffective, and in the case of interferon beta, there is some evidence that suggest that it may be harmful.
Symptom treatment may also involve the use of low doses of carbamazepine to control paroxysmal (sudden) tonic spasms that often occur during attacks of NMOSD and antispasticity agents to treat long term complication of spasticity that frequently develops in those with permanent motor deficits.
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