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INTRODUCTION — Neuromyelitis optica (NMO, previously known as Devic disease) and neuromyelitis optica spectrum disorders (NMOSD) are inflammatory disorders of the central nervous system characterized by severe, immune-mediated demyelination and axonal damage predominantly targeting optic nerves and spinal cord. Traditionally considered a variant of multiple sclerosis, NMO is now recognized as a distinct clinical entity based on unique immunologic features. The discovery of a disease-specific serum NMO-IgG antibody that selectively binds aquaporin-4 (AQP4) has led to increased understanding of a diverse spectrum of disorders.
The epidemiology, pathogenesis, clinical manifestations, diagnosis, treatment, and prognosis of NMO and NMOSD will be reviewed here.
BACKGROUND — The first clinical descriptions of NMO emerged over a century ago when Devic and Gault [1,2] documented a series of patients with a monophasic course of bilateral (or rapidly sequential) optic neuritis and myelitis. Disability following these attacks was often severe. Over time, however, significant variation in the presenting features, clinical course, and the degree of accumulated disability in patients with presumed NMO made its distinction from multiple sclerosis less clear [3-8]. It was previously believed that NMO and multiple sclerosis represented one disease entity, with variable phenotypes and expression. However, mounting evidence suggests that NMO is distinct from classic relapsing-remitting multiple sclerosis with respect to pathogenesis, imaging features, biomarkers, neuropathology, and response to treatment.
PATHOGENESIS — The cause of NMO and NMOSD is unknown. As in multiple sclerosis, an autoimmune inflammatory cascade leads to demyelination and axonal injury through diverse pathways . (See "Pathogenesis and epidemiology of multiple sclerosis", section on 'Pathogenesis'.)
In NMO, florid demyelination and inflammation involve multiple spinal cord segments and the optic nerves with associated axonal loss, perivascular lymphocytic infiltration, and vascular proliferation . Unlike multiple sclerosis, necrosis and cavitation typically involve both gray and white matter . The neuropathologic features of NMO at autopsy are those of a much more severe necrotic lesion of the cord rather than incomplete demyelination.
Whereas multiple sclerosis is mostly a cell-mediated disorder, the pathophysiology of NMO is thought to be primarily mediated by the humoral immune system [9-12]. Several lines of evidence support an autoimmune pathogenesis for NMO. The most important of these was the identification of a NMO disease-specific autoantibody, the NMO-IgG antibody, also referred to as the aquaporin-4 (AQP4) autoantibody (see 'AQP4 autoantibody' below) . Serum AQP4 autoantibody titers at the nadir of clinical attacks have been shown to correlate with the length of longitudinally extensive spinal cord lesions [14,15]. In addition, serum anti-AQP4 titers have been shown in several studies to correlate with clinical disease activity, drop after immunosuppressive treatment, and remain low during remissions [14-16].
Aquaporin-4 (AQP4), the target antigen of NMO-IgG, is a water channel protein highly concentrated in spinal cord gray matter, periaqueductal and periventricular regions, and astrocytic foot processes at the blood-brain barrier [17,18]. It is now clear that NMO-IgG (anti-AQP4) plays a direct role in the pathogenesis of NMO [19-21]. In MS lesions, the distribution of AQP4 protein expression depends upon the stage of demyelination, while in NMO lesions, there is a loss of AQP4 expression that is unrelated to the stage of demyelination . In addition, intrathecal anti-AQP4 antibodies have been identified in a patient with NMO at disease onset; monoclonal recombinant antibodies generated from this patient induced NMO-specific immunopathology in rats, demonstrating a direct pathogenic role of AQP4 antibodies . The inflammatory processes in NMO primarily targets astrocytes [23-25]; the area postrema appears to be a preferential target of NMO-IgG antibodies that bind to astrocyte AQP4 water channels, leading to astrocyte dysfunction and the clinical manifestations of nausea and vomiting [26,27]. (See 'Brainstem syndromes' below.)
Additional data supporting an autoimmune pathogenesis for NMO include the following observations:
●Histopathologic examination of NMO lesions shows immunoglobulin and complement deposits in a characteristic vasculocentric rim and rosette pattern around hyalinized blood vessels [11,22].
●NMO is frequently associated with systemic autoimmune disorders. Organ-specific disorders include hypothyroidism, pernicious anemia, ulcerative colitis, myasthenia gravis, and idiopathic thrombocytopenic purpura. Nonorgan-specific disorders include systemic lupus erythematosus, antiphospholipid syndrome, and Sjögren syndrome [19,28,29]. In addition, some cases of NMO may be associated with neoplasms .
●Antinuclear autoantibodies are common in patients with NMO patients who lack evidence of a systemic disorder. In one cohort of 78 patients with NMO, seropositivity for antinuclear antibodies (ANA) and Sjögren's syndrome A/Sjögren's syndrome B (SSA/SSB) was found in 53 and 17 percent, respectively .
●Among Japanese patients, Asian optic-spinal multiple sclerosis, now considered one of the NMOSD, is associated with the HLA-DPB1-0501 allele of the major histocompatibility complex , while conventional multiple sclerosis is associated with the HLA-DRB1-1501 allele. Anti-AQP4 antibody-positive patients are more likely to bear the HLA-DPB1 allele .
●Clinical experience suggests that therapeutic plasma exchange and immunosuppressive therapies are beneficial for treatment and prevention of acute NMO attacks. (See 'Treatment' below.)
EPIDEMIOLOGY — The prevalence of NMO in various studies ranges from 0.5 to 10 per 100,000 [34-39]. Ethnic, geographic and gender disparities are recognized. The reported incidence of NMO in women is up to 10 times higher than in men [40-42]. In monophasic NMO (1 to 10 percent of patients) men and women are affected equally, but in typical recurrent NMO, women predominate over men by 5:1 to 10:1 . The median age of onset is 32 to 41 years, but cases are described in children and older adults [16,34,40,42,43]. Comparatively, multiple sclerosis has a median age of onset of 24 years and an estimated female to male incidence of 2.3:1. (See "Pathogenesis and epidemiology of multiple sclerosis", section on 'Epidemiology and risk factors'.)
NMO may be overrepresented in some non-European populations worldwide, including Africans, East Asians, and Latin Americans, among whom conventional multiple sclerosis is less common [16,44]. In a study that determined AQP4-IgG seroprevalence, the incidence and prevalence of NMO/NMOSD and AQP4 autoimmunity were substantially higher among black compared with white patients who had inflammatory demyelinating central nervous system disease . As an example, the study found that overall prevalence of NMO/NMOSD in the Caribbean island of Martinique (predominantly black) compared with Olmstead County, Minnesota (predominantly white) was 10.0/100,000 versus 3.9/100,000, respectively. However, the ethnic predilection of NMO was not supported by some earlier studies [35,45], suggesting it could represent the relative rarity of multiple sclerosis among these groups rather than a true excess of NMO .
In Japan, optic-spinal multiple sclerosis (OSMS), clinically and immunologically similar to NMO, represents approximately 15 to 40 percent of multiple sclerosis cases and has been historically identified as a separate disorder, though on a spectrum with conventional Western multiple sclerosis . Whether NMO and Asian OSMS are the same entity remains uncertain [47,48]. Nevertheless, Asian OSMS is now considered as one of the NMOSD. (See 'NMO spectrum disorders' below.)
NMO is usually sporadic, though a few familial cases have been reported .
CLINICAL FEATURES — Hallmark features of NMO include acute attacks of bilateral or rapidly sequential optic neuritis (leading to severe visual loss) or transverse myelitis (often causing limb weakness, sensory loss, and bladder dysfunction) with a typically relapsing course [1,2,9,40,42,49]. Attacks most often occur over days, with variable degrees of recovery over weeks to months .
Central nervous system involvement outside of the optic nerves and spinal cord is recognized in patients with NMO and NMOSD. Other suggestive symptoms include episodes of intractable nausea, vomiting, hiccups, excessive daytime somnolence or narcolepsy, reversible posterior leukoencephalopathy syndrome, neuroendocrine disorders, and (in children) seizures. While no clinical features are disease-specific, some are highly characteristic.
Optic neuritis — Optic neuritis is reviewed here briefly, and is discussed in detail separately. (See "Optic neuritis: Pathophysiology, clinical features, and diagnosis" and "Optic neuritis: Prognosis and treatment".)
Optic neuritis – inflammation of the optic nerve – can be caused by any inflammatory condition or may be idiopathic. Optic neuritis presents with varying degrees of vision loss and is almost always associated with eye pain that worsens with movement of the eye.
Individual optic neuritis attacks in NMO are indistinguishable from isolated syndromes of optic neuritis or those related to multiple sclerosis, though visual loss is generally more severe in NMO [8,16,44,49,51]. While the majority of optic neuritis attacks in NMO are unilateral, sequential optic neuritis in rapid succession or bilateral simultaneous optic neuritis is highly suggestive of NMO .
Transverse myelitis — Transverse myelitis is defined as spinal cord dysfunction developing over hours or days in the absence of a structural spinal cord lesion. Transverse myelitis is reviewed here briefly and discussed in greater detail separately. (See "Transverse myelitis".)
Spinal cord involvement in NMO typically presents with transverse myelitis, characterized by symmetric paraparesis or quadriparesis, bladder dysfunction, and sensory loss below the level of the spinal cord lesion [16,49]. Accompanying symptoms may include paroxysmal tonic spams of the trunk or extremities, radicular pain, or Lhermitte sign [49,52]. In contrast, myelitis in multiple sclerosis tends to be incomplete and asymmetric. Patients with NMO typically have a longer extent of spinal cord demyelination than patients with multiple sclerosis [40,49], often involving three or more vertebral segments on MRI, a condition termed longitudinally extensive transverse myelitis (LETM). LETM represents an inaugural or limited form of NMO in a high proportion of patients . However, a minority of patients with NMO or NMOSD present with a shorter extent of spinal cord involvement . (See 'NMO spectrum disorders' below.)
Brainstem syndromes — Some patients with NMOSD present with brainstem symptoms due to medullary involvement. In particular, the area postrema clinical syndrome of nausea and vomiting or hiccups, sometimes intractable, with associated medullary lesions on MRI occurs with an incidence of 16 to 43 percent in NMOSD [53,55,56]. Brainstem involvement may lead to acute neurogenic respiratory failure and death .
NMO spectrum disorders — A spectrum of NMO disorders is recognized, based upon clinical, imaging, and antibody findings. This spectrum includes the following [16,42,54,56-59]:
●Limited or partial forms of NMO:
•Single or recurrent episodes of myelitis, usually but not always involving longitudinally extensive spinal cord lesions (ie, a spinal cord lesion on MRI involving >3 vertebral segments)
•Single or recurrent unilateral or simultaneous bilateral optic neuritis
•Optic neuritis or transverse myelitis in isolation
●Asian optic-spinal multiple sclerosis
●Optic neuritis or longitudinally extensive spinal cord lesions associated with systemic autoimmune disease
●Optic neuritis or myelitis associated with distinct brain MRI lesions typical of NMO (ie, with hypothalamic, corpus callosal, periventricular, or periependymal brainstem lesions on T2 images)
In addition to the central nervous system involvement characteristic of NMOSD, muscle may be a target of attacks in rare cases. There is at least one case report of a patient with NMO who had recurrent myalgias and evidence of an autoimmune myopathy with targeting of sarcolemmal AQP4 in skeletal muscle by complement-activating IgG . In addition, there are several reports of transiently elevated serum creatine kinase (ie, "hyper-CKemia") associated with attacks of NMOSD [59,61-64].
Over time, the NMO spectrum disorder category has expanded to include patients with AQP4 antibody positivity who have single or recurrent attacks of optic neuritis, myelitis, brainstem syndromes, or brain syndromes, often indistinguishable from multiple sclerosis .
Other manifestations — Other manifestations that can develop with NMO and NMOSD include encephalopathy, fulminant cerebral demyelination, hypothalamic dysfunction, and posterior reversible leukoencephalopathy [16,27,65,66]. Symptoms related to bilateral hypothalamic lesions may include symptomatic narcolepsy or excessive daytime sleepiness, obesity, and various autonomic manifestations such as hypotension, bradycardia, and hypothermia [67,68]. In rare cases, fulminant diffuse vasogenic edema can lead to brain herniation and death .
Pain is a common symptom with NMO. In retrospective studies of patients with NMO or NMOSD, 80 percent or more of patients report pain, most often involving the trunk and legs [69,70].
Children — Although firm conclusions are limited by small numbers of patients, the available data suggest that a substantial minority of children with NMO have brain involvement at presentation associated with clinical features of encephalopathy, seizures, and/or lesions on brain MRI resembling those typically seen with multiple sclerosis or acute disseminated encephalomyelitis [71-76].
Disease patterns — NMO has a relapsing course in 90 percent or more of cases [34,40,49]. In some patients, optic neuritis and transverse myelitis occur concurrently; in others, clinical episodes are separated by a variable time delay. Relapse occurs within the first year following an initial event in 60 percent of patients and within three years in 90 percent . As a rule, severe residual deficits follow initial and subsequent attacks, leading to rapid development of disability due to blindness and paraplegia within five years [49,77,78]. Unlike multiple sclerosis, a secondary progressive phase of the disease is rare. Patients with cerebral presentations may have continued brain attacks without involvement of the optic nerves or spinal cord .
EVALUATION AND DIAGNOSIS — In addition to a comprehensive history and examination, the evaluation of suspected NMOSD entails brain and spinal cord neuroimaging with MRI, determination of aquaporin-4 (AQP4) IgG serum autoantibody status, and often cerebrospinal fluid analysis. The detection of AQP4 IgG antibodies is specific for confirming the diagnosis (table 1) in appropriate clinical settings.
Clinical presentations that should raise suspicion for NMOSD include the following :
●Optic neuritis that is simultaneously bilateral, involves the optic chiasm, causes an altitudinal visual field defect, or causes severe residual visual loss
●A complete (rather than partial) spinal cord syndrome, especially with paroxysmal tonic spasms
●An area postrema clinical syndrome consisting of intractable hiccups or nausea and vomiting
However, none of these presentations are diagnostic for NMOSD when AQP4 IgG antibodies are not detected and, conversely, the NMO spectrum can be wider, based upon the presence of AQP4 IgG antibodies in milder spinal cord syndromes .
Other clinical and imaging manifestations are considered "red flags" (table 2) that raise the likelihood of alternative diagnoses. Of these, a gradual progressive course of neurologic worsening over months or years is very unusual in NMOSD.
Diagnostic criteria — Revised consensus criteria published in 2015 (table 1) unify the concepts of NMO and NMOSD and base the diagnosis on the presence of core clinical characteristics, AQP4 antibody status, and MRI neuroimaging features (table 3) . The criteria recognize six core clinical characteristics, which are:
●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
●At least one core clinical characteristic
●A positive test for AQP4-IgG using the best available detection method (cell-based assay strongly recommended)
●Exclusion of alternative diagnoses
●At least two core clinical characteristics occurring as a result of one or more clinical attacks and meeting all of the following requirements:
•At least one core clinical characteristic must be optic neuritis, acute myelitis with longitudinally extensive transverse myelitis, or area postrema syndrome
•Dissemination in space (two or more different core clinical characteristics)
•Fulfillment of additional MRI requirements (table 1) as applicable
●Negative tests for AQP4-IgG using best available detection method, or testing unavailable
●Exclusion of alternative diagnoses
Spinal cord MRI — Longitudinally extensive spinal cord lesions on T2-weighted MRI, particularly those extending for three or more vertebral segments and primarily involving the central cord gray matter on axial sections, are highly suggestive of NMO (table 3 and image 1) [49,80,81]. Acute lesions generally involve most of the cross-sectional area of a spinal segment, with edema and gadolinium enhancement. The "owl-eye" sign is due to hyperintensities of the anterior horn cells in the spinal gray matter, suggesting spinal artery ischemia; it may be seen acutely and cavitation is present in severe cases . The cervical cord is affected in approximately 60 percent of cases, and lesions may extend into the medulla . Occasionally, the spinal cord inflammation and swelling have been so severe that the lesion can mimic a tumor [83-85]. Gadolinium enhancement disappears with treatment and spinal cord lesions diminish during remissions .
MRI of the brain and orbits — At presentation, MRI of the brain is normal in 55 to 84 percent of patients with NMO, aside from gadolinium enhancement of the optic nerves (table 3)  (see "Optic neuritis: Pathophysiology, clinical features, and diagnosis", section on 'Magnetic resonance imaging'). Over time, however, MRI evidence of brain involvement develops in up to 85 percent of patients with NMO [86-89]. Lesions are described in the central medulla, hypothalamus, and diencephalon, corresponding to regions of high AQP4 expression, but are also found within subcortical white matter (image 2 and image 3). These lesions in patients with NMO or NMOSD occasionally fulfill multiple sclerosis diagnostic criteria for dissemination in space. (See "Diagnosis of multiple sclerosis in adults", section on 'McDonald criteria' and "Diagnosis of multiple sclerosis in adults", section on 'Magnetic resonance imaging'.)
Similar to the way that spinal cord lesions of NMOSD are longitudinally extensive, lesions of the optic nerve tend to be longitudinally extensive . Inflammation in the optic nerves extends more posteriorly than in multiple sclerosis, often involving the optic chiasm and tracts. In a small retrospective study reporting imaging of optic neuritis with MRI, contrast enhancement of the optic chiasm was observed in some patients diagnosed with NMO but was not found in patients diagnosed with multiple sclerosis, suggesting it is a reliable differentiator between the two conditions .
AQP4 autoantibody — The aquaporin-4 (AQP4) serum autoantibody, also known as NMO-IgG, is a specific biomarker for NMOSD [56,59]. The aquaporin-4 receptor is the target antigen of NMO-IgG, which has a direct role in the pathogenesis of NMO (see 'Pathogenesis' above). Therefore, patients suspected of having NMO should be tested for serum AQP4 IgG antibodies [56,59]. Ideally, testing for AQP4 antibody status should be performed during attacks and before immunosuppressive therapy, since conversion to seronegative status may occur with immunosuppression . In addition, patients who are initially seronegative for AQP4 antibody should be retested if there is suspicion for NMO.
The early NMO-IgG serum assay demonstrated moderate sensitivity and high specificity for the detection of NMO (73 and 91 percent, respectively) in addition to Asian optic-spinal multiple sclerosis (58 and 100 percent, respectively) [13,93]. Antigen specific anti-AQP4 antibody assays may be more sensitive than the original NMO-IgG assay. A case-control study found 91 percent sensitivity and 100 percent specificity of anti-AQP4 antibody for NMO . A blinded, multicenter trial confirmed a high specificity (100 percent) but only moderate sensitivity (72 percent) using combined commercial cell–based assay (CBA) and enzyme-linked immunosorbent assay (ELISA) against AQP4 .
Even using the most sensitive assays, 12 percent of patients with a clinical diagnosis of NMO or NMOSD are seronegative for NMO-IgG . Limited data suggest that seronegative NMOSD may differ from seropositive NMOSD on certain features, including an equal male to female ratio, predominantly Caucasian ethnicity, and greater likelihood of simultaneous optic neuritis and transverse myelitis at first presentation [92,95].
MOG autoantibody — A minority of AQP4-seronegative patients with a phenotype of NMOSD has antibodies against myelin oligodendrocyte glycoprotein (MOG) [96-99], but the clinical relevance of anti-MOG antibodies in NMOSD is uncertain [100,101]. MOG autoantibodies may define an overlapping clinical syndrome that often meets the clinical criteria for NMOSD but has some differences in features compared with AQP4 antibody-associated NMOSD or seronegative NMOSD, including [97,102]:
●Proportionally more men affected
●More likely to involve the optic nerve than the spinal cord
●More frequent simultaneous bilateral optic neuritis
●More likely to be monophasic
●Spinal cord lesions mainly occur in the lower portion of the spinal cord
Cerebrospinal fluid — During acute attacks of NMO, cerebrospinal fluid (CSF) abnormalities are common, including pleocytosis and elevated protein levels. Pleocytosis is detected in 14 to 79 percent of patients with NMO, typically monocytes or lymphocytes, though neutrophils may predominate. A CSF white blood count >50 cells/mm3 is reported in 13 to 35 percent of patients with NMO; those with longitudinally extensive spinal cord lesions show a higher incidence than those with optic neuritis [16,40,49]. Notably, oligoclonal bands are typically absent (70 to 85 percent of cases) [16,40].
In contrast, a CSF pleocytosis >50 cells/mm3 is rare in multiple sclerosis while oligoclonal bands are present in over 90 percent of patients. (See "Diagnosis of multiple sclerosis in adults", section on 'Cerebrospinal fluid analysis'.)
Optical coherence tomography — Optical coherence tomography studies in NMO report significantly greater retinal nerve fiber layer thinning in patients with NMO than multiple sclerosis, reflecting more severe axonal insult [103,104]. Microcystic macular edema of the inner nuclear appears to be common among patients with NMO and a history of optic neuritis . However, the utility of optical coherence tomography as a diagnostic tool is not well established. (See "Optic neuritis: Pathophysiology, clinical features, and diagnosis", section on 'Optical coherence tomography'.)
DIFFERENTIAL DIAGNOSIS — NMO syndromes must be distinguished from multiple sclerosis, which is the most common disorder likely to cause central nervous system demyelination. Acute disseminated encephalomyelitis and other autoimmune diseases such as systemic lupus erythematosus and Behçet disease may rarely have similar presentations [106-108].
Of note, longitudinally extensive spinal cord lesions are not specific for NMO. They have been described in patients with other autoimmune or inflammatory diseases, including systemic lupus erythematosus, Sjögren syndrome, neuro-Behçet disease, sarcoidosis, multiple sclerosis, parainfectious disorders (eg, acute disseminated encephalomyelitis), and anti-NMDA receptor encephalitis [108-110]. Additional etiologies of longitudinally extensive spinal cord lesions include intrathecal tumors, vascular causes (eg, spinal dural arteriovenous fistula and infarcts due to occlusion of the anterior spinal artery), metabolic conditions (eg, vitamin B12 deficiency causing subacute combined degeneration of the spinal cord), radiation therapy, and viral infections (eg, HIV-1, HTLV-1).
Differentiating NMO from other demyelinating disorders is based upon important differences with respect to clinical course, prognosis, and underlying pathophysiology (table 2) as well as responsiveness to multiple sclerosis disease-modifying therapies [16,80]. Several features appear to distinguish NMO from classic relapsing-remitting multiple sclerosis:
●Brain MRI is often normal in patients with NMO, particularly at onset, and spinal cord MRI typically exhibits extensive lesions spanning three or more vertebral segments. However, clinical or MRI evidence of brain involvement, particularly in the brainstem, occurs in a substantial proportion of patients with NMO [86-88]. Findings on brain MRI that suggest the diagnosis of multiple sclerosis rather than NMO include T2-weighted lesions in one or more of the following locations :
•Lesions adjacent to lateral ventricle
•Inferior temporal lobe white matter lesions
•Ovoid (ie, "Dawson finger") periventricular lesions
•U-fiber juxtacortical lesions
However, these neuroimaging findings do not necessarily exclude the diagnosis of NMO, as they can occur in patients with NMO who are seropositive for AQP4 antibodies .
●During acute attacks of NMO, the cerebrospinal fluid (CSF) may exhibit a neutrophilic pleocytosis, but it is usually (70 to 85 percent of cases) negative for oligoclonal bands.
●The detection of AQP4 antibody positivity is specific for NMO and NMOSD (see 'AQP4 autoantibody' above)
●The myelopathy and optic neuritis associated with NMO tends to be more severe than with multiple sclerosis, with less likelihood of recovery.
TREATMENT — Acute attacks and relapses of NMO are generally treated with intravenous glucocorticoids followed soon by therapeutic plasma exchange for refractory or progressive symptoms [112,113]. For prevention of recurrent attacks, treatment with systemic immunosuppression is the mainstay. However, there are no controlled trials evaluating the treatment of NMO, and recommendations are primarily supported by data from observational studies and by the clinical experience of experts.
The rationale for treatment of acute and recurrent attacks in NMO is based upon evidence that humoral autoimmunity plays a role in the pathogenesis of NMO, and is driven by the high attack-related disability, poor prognosis, and overall high risk of mortality in untreated patients [16,114].
Initial and subsequent acute attacks — All patients with suspected NMO should be treated for acute attacks. We suggest initial treatment with high-dose intravenous methylprednisolone (1 gram daily for three to five consecutive days), in agreement with expert panel recommendations and based upon studies of multiple sclerosis and idiopathic optic neuritis [16,115,116]. (See "Treatment of acute exacerbations of multiple sclerosis in adults", section on 'Glucocorticoids' and "Optic neuritis: Prognosis and treatment", section on 'Treatment'.).
For patients with severe symptoms, unresponsive to glucocorticoids, therapeutic plasma exchange is the suggested treatment [16,115,116]. Limited retrospective and uncontrolled data suggest that initial treatment with intravenous glucocorticoids plus therapeutic plasma exchange is associated with improved outcomes compared with glucocorticoid treatment alone . Exchanges are carried out every other day up to a total of seven exchanges.
Seronegative NMO is managed in the same way as seropositive NMO.
Intravenous immune globulin has not been specifically evaluated for acute attacks of NMO and is rarely used in this setting.
Attack prevention — We recommend initiation of long-term immunosuppression treatment for the prevention of attacks as soon as the diagnosis of NMO is made [16,116,118]. Data on the efficacy of preventive therapies is based upon observational studies. The cornerstone of treatment is systemic immunosuppression with agents including azathioprine [119,120], mycophenolate mofetil [121,122], rituximab , methotrexate [124,125], mitoxantrone , and oral glucocorticoids .
The optimal drug regimen and treatment duration are yet to be determined. Although there is no strict consensus, agents most often considered as first-line monotherapy treatments for NMO are azathioprine, rituximab, and mycophenolate mofetil [57,115,118,128]. Comparative data are scant, but one retrospective, nonrandomized study from two tertiary centers in the United States analyzed relapses among patients with NMO or NMOSD who were treated with azathioprine and concomitant prednisone (n = 32) for at least six months, or mycophenolate (n = 28) for at least six months, or with rituximab (n = 30) for at least one month, and followed-up after treatment for at least six months . Treatment with all three agents was associated with significant reductions in annualized relapse rates ranging from 72 to 88 percent compared with baseline. As an example, the annualized relapse rate decreased from 2.26 before azathioprine treatment to 0.63 after treatment, a reduction of 72 percent. Treatment failure was defined as the development of any new central nervous system inflammatory event that occurred despite immunosuppressive treatment; treatment failure rates with these drugs varied from 33 to 53 percent.
Immunosuppression is usually continued for at least five years for patients who are AQP4 seropositive, including those presenting with a single attack, because they are at high risk for relapse or conversion to NMO . However, there is no consensus with regard to the duration of immunosuppressive treatment. Some experts suggest that life-long therapy is appropriate, given the often devastating nature of the disease. Others suggest that the length of immunosuppression should be tailored to the severity of attacks and disability.
Treatment with tocilizumab (an IL-6 receptor antagonist) has been associated with clinical stabilization or improvement in a small number of patients with refractory NMO who failed one or more of the "standard" treatments discussed above [130-134]. Similarly, eculizumab (a complement-inhibiting antibody) treatment of NMO was associated with a significant reduction in attack frequency in a small uncontrolled open-label study, though complicated by meningococcal sepsis with full recovery in 1 of the 14 treated patients . In an observational study of five Chinese patients with highly active NMOSD that was poorly responsive to "standard" immunosuppressive agents, treatment with bortezomib (a proteosome inhibitor that depletes plasma cells) was associated with relapse-free status in four and clinical stabilization in all five .
Limited observational evidence suggests that treatment of NMO with interferon beta, natalizumab, or fingolimod is not effective and may be harmful [137-142]. There is no published evidence regarding the treatment of NMO with ocrelizumab.
PROGNOSIS — The natural history of NMO is one of stepwise deterioration due to accumulating visual, motor, sensory, and bladder deficits from recurrent attacks (see 'Disease patterns' above). Most acute attacks or relapses worsen over days to a nadir and recover over several weeks to months with significant sequelae. Predictors of a worse prognosis include the number of relapses within the first two years, the severity of the first attack, older age at disease onset, and (perhaps) an association with other autoimmune disorders including autoantibody status [40,49,143,144]. These prognostic factors need to be confirmed in larger independent prospective studies.
Mortality rates are high in NMO, most frequently secondary to neurogenic respiratory failure, which occurs with extension of cervical lesions into the brainstem or from primary brainstem lesions . Cohort studies of North American, Brazilian, and French West Indies populations reported mortality rates of 32 percent, 50 percent, and 25 percent, respectively in NMO [44,78,143]. These studies may be biased towards more severe cases. Progress in the diagnosis and treatment of NMO is expected to decrease mortality rates.
The AQP4 autoantibody (NMO-IgG) may be a marker for disease course and prognosis [145-147], though the available data are inconsistent . In patients with recurrent optic neuritis, retrospective evidence suggests that NMO-IgG seropositivity is associated with poor visual outcome and development of NMO . A prospective study of 29 patients presenting with longitudinally extensive spinal cord lesions found 55 percent of the patients seropositive for NMO-IgG relapsed within one year or converted to NMO, while none of seronegative patients relapsed . In contrast, a subsequent report noted that seronegative and seropositive NMO were similar in terms of relapse rate, severity, and long-term outcomes . The discrepancy in these results may be due in part to small numbers of patients with seronegative NMO and to differences in the sensitivities of the AQP4 antibody assays.
There are only limited and retrospective data on the relationship of NMOSD and pregnancy. These suggest that NMOSD is associated with an increased risk of miscarriage , and that the annualized relapse rate of NMOSD is increased in the first three to six months of the postpartum period [149,150].
SUMMARY AND RECOMMENDATIONS
●Neuromyelitis optica (NMO) and NMO spectrum disorders (NMOSD) are inflammatory disorders of the central nervous system characterized by severe, immune-mediated demyelination and axonal damage predominantly targeting the optic nerves and spinal cord, but also the brain and brainstem. NMO and NMOSD are distinguished from multiple sclerosis and other central nervous system inflammatory disorders by the presence of the disease-specific anti-aquaporin-4 (AQP4) antibody, which plays a direct role in the pathogenesis of NMOSD. (See 'Background' above and 'Pathogenesis' above.)
●The incidence of NMOSD in women is up to 10 times higher than in men. The median age of onset is 32 to 41 years, but cases are described in children and older adults. (See 'Epidemiology' above.)
●Hallmark features of NMOSD include acute attacks characterized by bilateral or rapidly sequential optic neuritis (leading to visual loss), acute transverse myelitis (often causing limb weakness and bladder dysfunction), and the area postrema syndrome (with intractable hiccups or nausea and vomiting). Other suggestive symptoms include episodes of excessive daytime somnolence or narcolepsy, reversible posterior leukoencephalopathy syndrome, neuroendocrine disorders, and (in children) seizures. While no clinical features are disease-specific, some are highly characteristic. NMO has a relapsing course in 90 percent or more of cases. (See 'Clinical features' above.)
●In addition to a comprehensive history and examination, the evaluation of suspected NMOSD entails brain and spinal cord neuroimaging with MRI (table 3), determination of AQP4 antibody status, and often cerebrospinal fluid analysis. Diagnostic criteria for NMOSD (table 1) require the presence of at least one core clinical characteristic (eg, optic neuritis, acute myelitis, area postrema syndrome), a positive test for AQP4-IgG, and exclusion of alternative diagnoses. The diagnostic criteria are more exacting in the setting of negative or unknown AQP4-IgG antibody status (table 1). (See 'Evaluation and diagnosis' above.)
●NMO syndromes must be distinguished from multiple sclerosis, which is the most common disorder likely to cause central nervous system demyelination. Other conditions that should be considered in the differential diagnosis include systemic lupus erythematosus, Sjögren's syndrome, neuro-Behçet disease, acute disseminated encephalomyelitis, and intrathecal spinal cord tumors. (See 'Differential diagnosis' above.)
●For patients with acute or recurrent attacks of NMO or NMOSD, we suggest initial treatment with high-dose intravenous methylprednisolone (1 gram daily for three to five consecutive days) (Grade 2C). For patients with severe symptoms, unresponsive to glucocorticoids, we suggest treatment with plasma exchange (Grade 2C). (See 'Initial and subsequent acute attacks' above.)
●For patients with NMO or NMOSD, we recommend initiation of long-term immunosuppression treatment with azathioprine, rituximab, or mycophenolate for the prevention of attacks as soon as the diagnosis is made (Grade 1C). The optimal drug regimen and treatment duration are yet to be determined. Immunosuppression is usually continued for at least five years for patients who are AQP4 seropositive, including those presenting with a single attack, because they are at high risk for relapse. (See 'Attack prevention' above.)
●The natural history of NMO is one of stepwise deterioration due to accumulating visual, motor, sensory, and bladder deficits from recurrent attacks. Long-term disability and mortality rates are high. (See 'Prognosis' above.)
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