What makes UpToDate so powerful?

  • over 10,000 topics
  • 22 specialties
  • 5,700 physician authors
  • evidence-based recommendations
See more sample topics
Find Print
0 Find synonyms

Find synonyms Find exact match

Neuromyelitis optica spectrum disorders
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
Neuromyelitis optica spectrum disorders
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2016. | This topic last updated: May 11, 2016.

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 NMO spectrum disorders 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 NMO spectrum disorders is unknown. As in multiple sclerosis, an autoimmune inflammatory cascade leads to demyelination and axonal injury through diverse pathways [9]. (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 [9]. Unlike multiple sclerosis, necrosis and cavitation typically involve both gray and white matter [7]. 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) [13]. 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 [22]. 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 [19]. 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 [30].

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 [31].

Among Japanese patients, Asian optic-spinal multiple sclerosis, now considered one of the NMO spectrum disorders, is associated with the HLA-DPB1-0501 allele of the major histocompatibility complex [32], while conventional multiple sclerosis is associated with the HLA-DRB1-1501 allele. Anti-AQP4 antibody-positive patients are more likely to bear the HLA-DBP1 allele [33].

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 [34-38]. Ethnic, geographic and gender disparities are recognized. The reported incidence of NMO in women is up to 10 times higher than in men [39-41]. 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 [40]. The median age of onset is 32 to 41 years, but cases are described in children and older adults [16,34,39,41,42]. 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 [16,43]. 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 [38]. 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 [35,44], suggesting it could represent the relative rarity of multiple sclerosis among these groups rather than a true excess of NMO [45].

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 [46]. Whether NMO and Asian OSMS are the same entity remains uncertain [46,47]. Nevertheless, Asian OSMS is now considered as one of the NMO spectrum disorders. (See 'NMO spectrum disorders' below.)

NMO is usually sporadic, though a few familial cases have been reported [45].

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 [1,2,9,39,41,48]. Attacks most often occur over days, with variable degrees of recovery over weeks to months [49].

Central nervous system involvement outside of the optic nerves and spinal cord is recognized in patients with NMO and NMO spectrum disorders. 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 [8,16,43,48,50]. 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 [16].

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 [16,48]. Accompanying symptoms may include paroxysmal tonic spams of the trunk or extremities, radicular pain, or Lhermitte sign [48,51]. 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 [39,48], 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 [52]. However, a minority of patients with NMO or NMO spectrum disorders present with a shorter extent of spinal cord involvement [53]. (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 [52,54,55]. Brainstem involvement may lead to acute neurogenic respiratory failure and death [48].

NMO spectrum disorders — A spectrum of NMO disorders is recognized, based upon clinical, imaging, and antibody findings. This spectrum includes the following [16,41,53,55-58]:

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 [59]. In addition, there are several reports of transiently elevated serum creatine kinase (ie, "hyper-CKemia") associated with attacks of NMOSD [58,60-63].

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 [57].

Other symptoms — Other manifestations that can develop with NMO and NMOSD include encephalopathy, fulminant cerebral demyelination, hypothalamic dysfunction, and posterior reversible leukoencephalopathy [16,27,64,65]. 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 [66,67]. In rare cases, fulminant diffuse vasogenic edema can lead to brain herniation and death [65].

Pain is a common symptom with NMO. In retrospective studies of patients with NMO or NMO spectrum disorders, 80 percent or more of patients report pain, most often involving the trunk and legs [68,69].

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 [70-75].

Disease patterns — NMO has a relapsing course in 90 percent or more of cases [34,39,48]. 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 [48]. 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 [48,76,77]. 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 [78].

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 [55]:

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 [55].

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) [55]. The criteria recognize six core clinical characteristics, which are:

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

The diagnosis of NMOSD with AQP4 IgG antibodies (table 1) requires the following [55]:

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

The diagnostic criteria for NMOSD are more exacting in the setting of negative or unknown AQP4-IgG antibody status (table 1) and require [55]:

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

The additional MRI requirements for NMOSD negative or unknown AQP4-IgG antibody status are determined by the clinical presentation (table 1) [55].

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) [48,79,80]. 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 [16]. The cervical cord is affected in approximately 60 percent of cases, and lesions may extend into the medulla [81]. Occasionally, the spinal cord inflammation and swelling have been so severe that the lesion can mimic a tumor [82-84]. Gadolinium enhancement disappears with treatment and spinal cord lesions diminish during remissions [16].

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) [16] (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 [85-88]. 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 NMO spectrum disorders 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 [89]. 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 [90].

AQP4 autoantibody — The aquaporin-4 (AQP4) serum autoantibody, also known as NMO-IgG, is a specific biomarker for NMOSD [55,58]. 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 [55,58]. Ideally, testing for AQP4 antibody status should be performed during attacks and before immunosuppressive therapy, since conversion to seronegative status may occur with immunosuppression [91]. 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) [13,92]. 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 [14]. 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 [93].

Even using the most sensitive assays, 12 percent of patients with a clinical diagnosis of NMO or NMOSD are seronegative for NMO-IgG [91]. 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 [91,94].

A minority of AQP4-seronegative patients with a phenotype of NMO spectrum disorders has antibodies against myelin oligodendrocyte glycoprotein (MOG) [95-97], but the clinical relevance of anti-MOG antibodies in NMO spectrum disorders is uncertain [98,99].

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 [16,39,48]. Notably, oligoclonal bands are typically absent (70 to 85 percent of cases) [16,39].

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 [100,101]. Microcystic macular edema of the inner nuclear appears to be common among patients with NMO and a history of optic neuritis [102]. 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 [103-105].

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 [105-107]. 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), and radiation therapy.

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 [16,79]. 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 [85-87]. 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 [88]:

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 [108].

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 NMO spectrum disorders (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 [109,110]. 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 [16,111].  

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 [16,112,113]. (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 [16,112,113]. 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 [114]. 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 [16,113,115]. Data on the efficacy of preventive therapies is based upon observational studies. The cornerstone of treatment is systemic immunosuppression with agents including azathioprine [116,117], mycophenolate mofetil [118,119], rituximab [120-124], methotrexate [125,126], mitoxantrone [127], and oral glucocorticoids [128].

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 [56,112,115]. Comparative data are scant, but one retrospective, nonrandomized study from two tertiary centers in the United States analyzed relapses among patients with NMO or NMO spectrum disorder 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 [129]. 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 [109]. 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 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 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 [135].

Limited observational evidence suggests that treatment of NMO with interferon beta, natalizumab, or fingolimod is not effective and may be harmful [136-141].

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 [39,48,142,143]. 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 [16]. 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 [43,77,142]. 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 [144-146], though the available data are inconsistent [91]. In patients with recurrent optic neuritis, retrospective evidence suggests that NMO-IgG seropositivity is associated with poor visual outcome and development of NMO [145]. 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 [146]. In contrast, a subsequent report noted that seronegative and seropositive NMO were similar in terms of relapse rate, severity, and long-term outcomes [91]. 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 [147], and that the annualized relapse rate of NMOSD is increased in the first three to six months of the postpartum period [148,149].


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 NMO spectrum disorder, 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 NMO spectrum disorder, 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.)

Use of UpToDate is subject to the Subscription and License Agreement.


  1. Devic E. Myélite aiguë compliquée de névrite optique. Bull Med (Paris) 1894; 8:1033.
  2. Gault F. De la neuromyélite optique aiguë, Lyon 1894.
  3. Goulden C. Optic neuritis and myelitis. Ophthal Rev 1914; 34:193.
  4. Beck GM. A case of diffuse myelitis associated with optic neuritis. Brain 1927; 50:687.
  5. STANSBURY FC. Neuromyelitis optica; presentation of five cases, with pathologic study, and review of literature. Arch Ophthal 1949; 42:292; passim.
  6. SCOTT GI. Neuromyelitis optica. Am J Ophthalmol 1952; 35:755.
  7. Mandler RN, Davis LE, Jeffery DR, Kornfeld M. Devic's neuromyelitis optica: a clinicopathological study of 8 patients. Ann Neurol 1993; 34:162.
  8. O'Riordan JI, Gallagher HL, Thompson AJ, et al. Clinical, CSF, and MRI findings in Devic's neuromyelitis optica. J Neurol Neurosurg Psychiatry 1996; 60:382.
  9. Wingerchuk DM, Lennon VA, Lucchinetti CF, et al. The spectrum of neuromyelitis optica. Lancet Neurol 2007; 6:805.
  10. Wingerchuk DM. Evidence for humoral autoimmunity in neuromyelitis optica. Neurol Res 2006; 28:348.
  11. Lucchinetti CF, Mandler RN, McGavern D, et al. A role for humoral mechanisms in the pathogenesis of Devic's neuromyelitis optica. Brain 2002; 125:1450.
  12. Correale J, Fiol M. Activation of humoral immunity and eosinophils in neuromyelitis optica. Neurology 2004; 63:2363.
  13. Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 2004; 364:2106.
  14. Takahashi T, Fujihara K, Nakashima I, et al. Anti-aquaporin-4 antibody is involved in the pathogenesis of NMO: a study on antibody titre. Brain 2007; 130:1235.
  15. Jarius S, Aboul-Enein F, Waters P, et al. Antibody to aquaporin-4 in the long-term course of neuromyelitis optica. Brain 2008; 131:3072.
  16. Sellner J, Boggild M, Clanet M, et al. EFNS guidelines on diagnosis and management of neuromyelitis optica. Eur J Neurol 2010; 17:1019.
  17. Lennon VA, Kryzer TJ, Pittock SJ, et al. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med 2005; 202:473.
  18. Jung JS, Bhat RV, Preston GM, et al. Molecular characterization of an aquaporin cDNA from brain: candidate osmoreceptor and regulator of water balance. Proc Natl Acad Sci U S A 1994; 91:13052.
  19. Bennett JL, Lam C, Kalluri SR, et al. Intrathecal pathogenic anti-aquaporin-4 antibodies in early neuromyelitis optica. Ann Neurol 2009; 66:617.
  20. Papadopoulos MC, Verkman AS. Aquaporin 4 and neuromyelitis optica. Lancet Neurol 2012; 11:535.
  21. Hinson SR, McKeon A, Lennon VA. Neurological autoimmunity targeting aquaporin-4. Neuroscience 2010; 168:1009.
  22. Roemer SF, Parisi JE, Lennon VA, et al. Pattern-specific loss of aquaporin-4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis. Brain 2007; 130:1194.
  23. Parratt JD, Prineas JW. Neuromyelitis optica: a demyelinating disease characterized by acute destruction and regeneration of perivascular astrocytes. Mult Scler 2010; 16:1156.
  24. Hinson SR, Romero MF, Popescu BF, et al. Molecular outcomes of neuromyelitis optica (NMO)-IgG binding to aquaporin-4 in astrocytes. Proc Natl Acad Sci U S A 2012; 109:1245.
  25. Takano R, Misu T, Takahashi T, et al. Astrocytic damage is far more severe than demyelination in NMO: a clinical CSF biomarker study. Neurology 2010; 75:208.
  26. Popescu BF, Lennon VA, Parisi JE, et al. Neuromyelitis optica unique area postrema lesions: nausea, vomiting, and pathogenic implications. Neurology 2011; 76:1229.
  27. Magaña SM, Pittock SJ, Lennon VA, et al. Neuromyelitis optica IgG serostatus in fulminant central nervous system inflammatory demyelinating disease. Arch Neurol 2009; 66:964.
  28. Leite MI, Coutinho E, Lana-Peixoto M, et al. Myasthenia gravis and neuromyelitis optica spectrum disorder: a multicenter study of 16 patients. Neurology 2012; 78:1601.
  29. Iyer A, Elsone L, Appleton R, Jacob A. A review of the current literature and a guide to the early diagnosis of autoimmune disorders associated with neuromyelitis optica. Autoimmunity 2014; 47:154.
  30. Figueroa M, Guo Y, Tselis A, et al. Paraneoplastic neuromyelitis optica spectrum disorder associated with metastatic carcinoid expressing aquaporin-4. JAMA Neurol 2014; 71:495.
  31. Pittock SJ, Lennon VA, de Seze J, et al. Neuromyelitis optica and non organ-specific autoimmunity. Arch Neurol 2008; 65:78.
  32. Yamasaki K, Horiuchi I, Minohara M, et al. HLA-DPB1*0501-associated opticospinal multiple sclerosis: clinical, neuroimaging and immunogenetic studies. Brain 1999; 122 ( Pt 9):1689.
  33. Matsushita T, Matsuoka T, Isobe N, et al. Association of the HLA-DPB1*0501 allele with anti-aquaporin-4 antibody positivity in Japanese patients with idiopathic central nervous system demyelinating disorders. Tissue Antigens 2009; 73:171.
  34. Mealy MA, Wingerchuk DM, Greenberg BM, Levy M. Epidemiology of neuromyelitis optica in the United States: a multicenter analysis. Arch Neurol 2012; 69:1176.
  35. Cabrera-Gómez JA, Kurtzke JF, González-Quevedo A, Lara-Rodríguez R. An epidemiological study of neuromyelitis optica in Cuba. J Neurol 2009; 256:35.
  36. Uzawa A, Mori M, Kuwabara S. Neuromyelitis optica: concept, immunology and treatment. J Clin Neurosci 2014; 21:12.
  37. Asgari N, Lillevang ST, Skejoe HP, et al. A population-based study of neuromyelitis optica in Caucasians. Neurology 2011; 76:1589.
  38. Flanagan EP, Cabre P, Weinshenker BG, et al. Epidemiology of aquaporin-4 autoimmunity and neuromyelitis optica spectrum. Ann Neurol 2016.
  39. Ghezzi A, Bergamaschi R, Martinelli V, et al. Clinical characteristics, course and prognosis of relapsing Devic's Neuromyelitis Optica. J Neurol 2004; 251:47.
  40. Wingerchuk DM. Neuromyelitis optica: effect of gender. J Neurol Sci 2009; 286:18.
  41. Kim SH, Kim W, Li XF, et al. Clinical spectrum of CNS aquaporin-4 autoimmunity. Neurology 2012; 78:1179.
  42. Maraş H, Kara B, Anık Y. Seropositive neuromyelitis optica: a pediatric case report and 6-year follow-up. Pediatr Neurol 2013; 49:198.
  43. Papais-Alvarenga RM, Carellos SC, Alvarenga MP, et al. Clinical course of optic neuritis in patients with relapsing neuromyelitis optica. Arch Ophthalmol 2008; 126:12.
  44. Marignier R, De Sèze J, Vukusic S, et al. NMO-IgG and Devic's neuromyelitis optica: a French experience. Mult Scler 2008; 14:440.
  45. Matiello M, Kim HJ, Kim W, et al. Familial neuromyelitis optica. Neurology 2010; 75:310.
  46. Kira J. Neuromyelitis optica and asian phenotype of multiple sclerosis. Ann N Y Acad Sci 2008; 1142:58.
  47. Kira J. Multiple sclerosis in the Japanese population. Lancet Neurol 2003; 2:117.
  48. Wingerchuk DM, Hogancamp WF, O'Brien PC, Weinshenker BG. The clinical course of neuromyelitis optica (Devic's syndrome). Neurology 1999; 53:1107.
  49. Drori T, Chapman J. Diagnosis and classification of neuromyelitis optica (Devic's syndrome). Autoimmun Rev 2014; 13:531.
  50. Hokari M, Yokoseki A, Arakawa M, et al. Clinicopathological features in anterior visual pathway in neuromyelitis optica. Ann Neurol 2016; 79:605.
  51. Kim SM, Go MJ, Sung JJ, et al. Painful tonic spasm in neuromyelitis optica: incidence, diagnostic utility, and clinical characteristics. Arch Neurol 2012; 69:1026.
  52. Apiwattanakul M, Popescu BF, Matiello M, et al. Intractable vomiting as the initial presentation of neuromyelitis optica. Ann Neurol 2010; 68:757.
  53. Flanagan EP, Weinshenker BG, Krecke KN, et al. Short myelitis lesions in aquaporin-4-IgG-positive neuromyelitis optica spectrum disorders. JAMA Neurol 2015; 72:81.
  54. Misu T, Fujihara K, Nakashima I, et al. Intractable hiccup and nausea with periaqueductal lesions in neuromyelitis optica. Neurology 2005; 65:1479.
  55. Wingerchuk DM, Banwell B, Bennett JL, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 2015; 85:177.
  56. Jacob A, McKeon A, Nakashima I, et al. Current concept of neuromyelitis optica (NMO) and NMO spectrum disorders. J Neurol Neurosurg Psychiatry 2013; 84:922.
  57. Sato DK, Nakashima I, Takahashi T, et al. Aquaporin-4 antibody-positive cases beyond current diagnostic criteria for NMO spectrum disorders. Neurology 2013; 80:2210.
  58. Pittock SJ, Lucchinetti CF. Neuromyelitis optica and the evolving spectrum of autoimmune aquaporin-4 channelopathies: a decade later. Ann N Y Acad Sci 2016; 1366:20.
  59. Guo Y, Lennon VA, Popescu BF, et al. Autoimmune aquaporin-4 myopathy in neuromyelitis optica spectrum. JAMA Neurol 2014; 71:1025.
  60. Deguchi S, Deguchi K, Sato K, et al. HyperCKemia related to the initial and recurrent attacks of neuromyelitis optica. Intern Med 2012; 51:2617.
  61. Di Filippo M, Franciotta D, Massa R, et al. Recurrent hyperCKemia with normal muscle biopsy in a pediatric patient with neuromyelitis optica. Neurology 2012; 79:1182.
  62. Yokoyama N, Niino M, Takahashi T, et al. Seroconversion of neuromyelitis optica spectrum disorder with hyperCKemia: a case report. Eur J Neurol 2012; 19:e143.
  63. Suzuki N, Takahashi T, Aoki M, et al. Neuromyelitis optica preceded by hyperCKemia episode. Neurology 2010; 74:1543.
  64. Matsushita T, Isobe N, Matsuoka T, et al. Extensive vasogenic edema of anti-aquaporin-4 antibody-related brain lesions. Mult Scler 2009; 15:1113.
  65. Newey CR, Bermel RA. Fulminant cerebral demyelination in neuromyelitis optica. Neurology 2011; 77:193.
  66. Kanbayashi T, Shimohata T, Nakashima I, et al. Symptomatic narcolepsy in patients with neuromyelitis optica and multiple sclerosis: new neurochemical and immunological implications. Arch Neurol 2009; 66:1563.
  67. Suzuki K, Nakamura T, Hashimoto K, et al. Hypothermia, hypotension, hypersomnia, and obesity associated with hypothalamic lesions in a patient positive for the anti-aquaporin 4 antibody: a case report and literature review. Arch Neurol 2012; 69:1355.
  68. Kanamori Y, Nakashima I, Takai Y, et al. Pain in neuromyelitis optica and its effect on quality of life: a cross-sectional study. Neurology 2011; 77:652.
  69. Qian P, Lancia S, Alvarez E, et al. Association of neuromyelitis optica with severe and intractable pain. Arch Neurol 2012; 69:1482.
  70. McKeon A, Lennon VA, Lotze T, et al. CNS aquaporin-4 autoimmunity in children. Neurology 2008; 71:93.
  71. Banwell B, Tenembaum S, Lennon VA, et al. Neuromyelitis optica-IgG in childhood inflammatory demyelinating CNS disorders. Neurology 2008; 70:344.
  72. Lotze TE, Northrop JL, Hutton GJ, et al. Spectrum of pediatric neuromyelitis optica. Pediatrics 2008; 122:e1039.
  73. Collongues N, Marignier R, Zéphir H, et al. Long-term follow-up of neuromyelitis optica with a pediatric onset. Neurology 2010; 75:1084.
  74. Tillema JM, McKeon A. The spectrum of neuromyelitis optica (NMO) in childhood. J Child Neurol 2012; 27:1437.
  75. Chitnis T, Ness J, Krupp L, et al. Clinical features of neuromyelitis optica in children: US Network of Pediatric MS Centers report. Neurology 2016; 86:245.
  76. Merle H, Olindo S, Bonnan M, et al. Natural history of the visual impairment of relapsing neuromyelitis optica. Ophthalmology 2007; 114:810.
  77. Cabre P, González-Quevedo A, Bonnan M, et al. Relapsing neuromyelitis optica: long term history and clinical predictors of death. J Neurol Neurosurg Psychiatry 2009; 80:1162.
  78. Kim HJ, Paul F, Lana-Peixoto MA, et al. MRI characteristics of neuromyelitis optica spectrum disorder: an international update. Neurology 2015; 84:1165.
  79. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69:292.
  80. Scott TF, Frohman EM, De Seze J, et al. Evidence-based guideline: clinical evaluation and treatment of transverse myelitis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2011; 77:2128.
  81. Cassinotto C, Deramond H, Olindo S, et al. MRI of the spinal cord in neuromyelitis optica and recurrent longitudinal extensive myelitis. J Neuroradiol 2009; 36:199.
  82. Tsivgoulis G, Kontokostas S, Boviatsis E, et al. Teaching neuroimages: neuromyelitis optica misdiagnosed as spinal cord tumor. Neurology 2014; 82:e33.
  83. Habek M, Adamec I, Brinar VV. Spinal cord tumor versus transverse myelitis. Spine J 2011; 11:1143.
  84. Brinar M, Rados M, Habek M, Poser CM. Enlargement of the spinal cord: inflammation or neoplasm? Clin Neurol Neurosurg 2006; 108:284.
  85. Pittock SJ, Lennon VA, Krecke K, et al. Brain abnormalities in neuromyelitis optica. Arch Neurol 2006; 63:390.
  86. Chan KH, Tse CT, Chung CP, et al. Brain involvement in neuromyelitis optica spectrum disorders. Arch Neurol 2011; 68:1432.
  87. Cabrera-Gómez JA, Quevedo-Sotolongo L, González-Quevedo A, et al. Brain magnetic resonance imaging findings in relapsing neuromyelitis optica. Mult Scler 2007; 13:186.
  88. Matthews L, Marasco R, Jenkinson M, et al. Distinction of seropositive NMO spectrum disorder and MS brain lesion distribution. Neurology 2013; 80:1330.
  89. Mealy MA, Whetstone A, Orman G, et al. Longitudinally extensive optic neuritis as an MRI biomarker distinguishes neuromyelitis optica from multiple sclerosis. J Neurol Sci 2015; 355:59.
  90. Khanna S, Sharma A, Huecker J, et al. Magnetic resonance imaging of optic neuritis in patients with neuromyelitis optica versus multiple sclerosis. J Neuroophthalmol 2012; 32:216.
  91. Jiao Y, Fryer JP, Lennon VA, et al. Updated estimate of AQP4-IgG serostatus and disability outcome in neuromyelitis optica. Neurology 2013; 81:1197.
  92. Jarius S, Franciotta D, Bergamaschi R, et al. NMO-IgG in the diagnosis of neuromyelitis optica. Neurology 2007; 68:1076.
  93. Waters PJ, McKeon A, Leite MI, et al. Serologic diagnosis of NMO: a multicenter comparison of aquaporin-4-IgG assays. Neurology 2012; 78:665.
  94. Marignier R, Bernard-Valnet R, Giraudon P, et al. Aquaporin-4 antibody-negative neuromyelitis optica: distinct assay sensitivity-dependent entity. Neurology 2013; 80:2194.
  95. Kitley J, Woodhall M, Waters P, et al. Myelin-oligodendrocyte glycoprotein antibodies in adults with a neuromyelitis optica phenotype. Neurology 2012; 79:1273.
  96. Sato DK, Callegaro D, Lana-Peixoto MA, et al. Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders. Neurology 2014; 82:474.
  97. Kitley J, Waters P, Woodhall M, et al. Neuromyelitis optica spectrum disorders with aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies: a comparative study. JAMA Neurol 2014; 71:276.
  98. Weinshenker BG, Wingerchuk DM. The two faces of neuromyelitis optica. Neurology 2014; 82:466.
  99. Levy M. Does aquaporin-4-seronegative neuromyelitis optica exist? JAMA Neurol 2014; 71:271.
  100. Naismith RT, Tutlam NT, Xu J, et al. Optical coherence tomography differs in neuromyelitis optica compared with multiple sclerosis. Neurology 2009; 72:1077.
  101. Ratchford JN, Quigg ME, Conger A, et al. Optical coherence tomography helps differentiate neuromyelitis optica and MS optic neuropathies. Neurology 2009; 73:302.
  102. Sotirchos ES, Saidha S, Byraiah G, et al. In vivo identification of morphologic retinal abnormalities in neuromyelitis optica. Neurology 2013; 80:1406.
  103. Graham D, McCarthy A, Kavanagh E, et al. Teaching NeuroImages: longitudinally extensive transverse myelitis in neuro-Behcet disease. Neurology 2013; 80:e189.
  104. White C, Leonard B, Patel A. Longitudinally extensive transverse myelitis: a catastrophic presentation of a flare-up of systemic lupus erythematosus. CMAJ 2012; 184:E197.
  105. Kitley JL, Leite MI, George JS, Palace JA. The differential diagnosis of longitudinally extensive transverse myelitis. Mult Scler 2012; 18:271.
  106. Outteryck O, Baille G, Hodel J, et al. Extensive myelitis associated with anti-NMDA receptor antibodies. BMC Neurol 2013; 13:211.
  107. Flanagan EP, Kaufmann TJ, Krecke KN, et al. Discriminating long myelitis of neuromyelitis optica from sarcoidosis. Ann Neurol 2016; 79:437.
  108. Braksick SA, Cutsforth-Gregory JK, Black DF, et al. Teaching neuroimages: MRI in advanced neuromyelitis optica. Neurology 2014; 82:e101.
  109. Carroll WM, Fujihara K. Neuromyelitis optica. Curr Treat Options Neurol 2010; 12:244.
  110. Kleiter I, Gahlen A, Borisow N, et al. Neuromyelitis optica: Evaluation of 871 attacks and 1,153 treatment courses. Ann Neurol 2016; 79:206.
  111. Collongues N, de Seze J. Current and future treatment approaches for neuromyelitis optica. Ther Adv Neurol Disord 2011; 4:111.
  112. Trebst C, Jarius S, Berthele A, et al. Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS). J Neurol 2014; 261:1.
  113. Sherman E, Han MH. Acute and Chronic Management of Neuromyelitis Optica Spectrum Disorder. Curr Treat Options Neurol 2015; 17:48.
  114. Merle H, Olindo S, Jeannin S, et al. Treatment of optic neuritis by plasma exchange (add-on) in neuromyelitis optica. Arch Ophthalmol 2012; 130:858.
  115. Kimbrough DJ, Fujihara K, Jacob A, et al. Treatment of Neuromyelitis Optica: Review and Recommendations. Mult Scler Relat Disord 2012; 1:180.
  116. Costanzi C, Matiello M, Lucchinetti CF, et al. Azathioprine: tolerability, efficacy, and predictors of benefit in neuromyelitis optica. Neurology 2011; 77:659.
  117. Bichuetti DB, Lobato de Oliveira EM, Oliveira DM, et al. Neuromyelitis optica treatment: analysis of 36 patients. Arch Neurol 2010; 67:1131.
  118. Jacob A, Matiello M, Weinshenker BG, et al. Treatment of neuromyelitis optica with mycophenolate mofetil: retrospective analysis of 24 patients. Arch Neurol 2009; 66:1128.
  119. Huh SY, Kim SH, Hyun JW, et al. Mycophenolate mofetil in the treatment of neuromyelitis optica spectrum disorder. JAMA Neurol 2014; 71:1372.
  120. Pellkofer HL, Krumbholz M, Berthele A, et al. Long-term follow-up of patients with neuromyelitis optica after repeated therapy with rituximab. Neurology 2011; 76:1310.
  121. Kim SH, Huh SY, Lee SJ, et al. A 5-year follow-up of rituximab treatment in patients with neuromyelitis optica spectrum disorder. JAMA Neurol 2013; 70:1110.
  122. Bedi GS, Brown AD, Delgado SR, et al. Impact of rituximab on relapse rate and disability in neuromyelitis optica. Mult Scler 2011; 17:1225.
  123. Weinfurtner K, Graves J, Ness J, et al. Prolonged Remission in Neuromyelitis Optica Following Cessation of Rituximab Treatment. J Child Neurol 2015; 30:1366.
  124. Kim SH, Jeong IH, Hyun JW, et al. Treatment Outcomes With Rituximab in 100 Patients With Neuromyelitis Optica: Influence of FCGR3A Polymorphisms on the Therapeutic Response to Rituximab. JAMA Neurol 2015; 72:989.
  125. Kitley J, Elsone L, George J, et al. Methotrexate is an alternative to azathioprine in neuromyelitis optica spectrum disorders with aquaporin-4 antibodies. J Neurol Neurosurg Psychiatry 2013; 84:918.
  126. Ramanathan RS, Malhotra K, Scott T. Treatment of neuromyelitis optica/neuromyelitis optica spectrum disorders with methotrexate. BMC Neurol 2014; 14:51.
  127. Cabre P, Olindo S, Marignier R, et al. Efficacy of mitoxantrone in neuromyelitis optica spectrum: clinical and neuroradiological study. J Neurol Neurosurg Psychiatry 2013; 84:511.
  128. Watanabe S, Misu T, Miyazawa I, et al. Low-dose corticosteroids reduce relapses in neuromyelitis optica: a retrospective analysis. Mult Scler 2007; 13:968.
  129. Mealy MA, Wingerchuk DM, Palace J, et al. Comparison of relapse and treatment failure rates among patients with neuromyelitis optica: multicenter study of treatment efficacy. JAMA Neurol 2014; 71:324.
  130. Kieseier BC, Stüve O, Dehmel T, et al. Disease amelioration with tocilizumab in a treatment-resistant patient with neuromyelitis optica: implication for cellular immune responses. JAMA Neurol 2013; 70:390.
  131. Lauenstein AS, Stettner M, Kieseier BC, Lensch E. Treating neuromyelitis optica with the interleukin-6 receptor antagonist tocilizumab. BMJ Case Rep 2014; 2014.
  132. Araki M, Matsuoka T, Miyamoto K, et al. Efficacy of the anti-IL-6 receptor antibody tocilizumab in neuromyelitis optica: a pilot study. Neurology 2014; 82:1302.
  133. Ayzenberg I, Kleiter I, Schröder A, et al. Interleukin 6 receptor blockade in patients with neuromyelitis optica nonresponsive to anti-CD20 therapy. JAMA Neurol 2013; 70:394.
  134. Ringelstein M, Ayzenberg I, Harmel J, et al. Long-term Therapy With Interleukin 6 Receptor Blockade in Highly Active Neuromyelitis Optica Spectrum Disorder. JAMA Neurol 2015; 72:756.
  135. Pittock SJ, Lennon VA, McKeon A, et al. Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study. Lancet Neurol 2013; 12:554.
  136. Papeix C, Vidal JS, de Seze J, et al. Immunosuppressive therapy is more effective than interferon in neuromyelitis optica. Mult Scler 2007; 13:256.
  137. Shimizu J, Hatanaka Y, Hasegawa M, et al. IFNβ-1b may severely exacerbate Japanese optic-spinal MS in neuromyelitis optica spectrum. Neurology 2010; 75:1423.
  138. Jacob A, Hutchinson M, Elsone L, et al. Does natalizumab therapy worsen neuromyelitis optica? Neurology 2012; 79:1065.
  139. Barnett MH, Prineas JW, Buckland ME, et al. Massive astrocyte destruction in neuromyelitis optica despite natalizumab therapy. Mult Scler 2012; 18:108.
  140. Juryńczyk M, Zaleski K, Selmaj K. Natalizumab and the development of extensive brain lesions in neuromyelitis optica. J Neurol 2013; 260:1919.
  141. Min JH, Kim BJ, Lee KH. Development of extensive brain lesions following fingolimod (FTY720) treatment in a patient with neuromyelitis optica spectrum disorder. Mult Scler 2012; 18:113.
  142. Wingerchuk DM, Weinshenker BG. Neuromyelitis optica: clinical predictors of a relapsing course and survival. Neurology 2003; 60:848.
  143. Kitley J, Leite MI, Nakashima I, et al. Prognostic factors and disease course in aquaporin-4 antibody-positive patients with neuromyelitis optica spectrum disorder from the United Kingdom and Japan. Brain 2012; 135:1834.
  144. Weinstock-Guttman B, Miller C, Yeh E, et al. Neuromyelitis optica immunoglobulins as a marker of disease activity and response to therapy in patients with neuromyelitis optica. Mult Scler 2008; 14:1061.
  145. Matiello M, Lennon VA, Jacob A, et al. NMO-IgG predicts the outcome of recurrent optic neuritis. Neurology 2008; 70:2197.
  146. Weinshenker BG, Wingerchuk DM, Vukusic S, et al. Neuromyelitis optica IgG predicts relapse after longitudinally extensive transverse myelitis. Ann Neurol 2006; 59:566.
  147. Nour MM, Nakashima I, Coutinho E, et al. Pregnancy outcomes in aquaporin-4-positive neuromyelitis optica spectrum disorder. Neurology 2016; 86:79.
  148. Bourre B, Marignier R, Zéphir H, et al. Neuromyelitis optica and pregnancy. Neurology 2012; 78:875.
  149. Kim W, Kim SH, Nakashima I, et al. Influence of pregnancy on neuromyelitis optica spectrum disorder. Neurology 2012; 78:1264.
Topic 14089 Version 14.0

All topics are updated as new information becomes available. Our peer review process typically takes one to six weeks depending on the issue.