Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis

INTRODUCTION — Neuromyelitis optica spectrum disorder (NMOSD; previously known as Devic disease or neuromyelitis optica [NMO]) is an inflammatory disorder of the central nervous system characterized by severe, immune-mediated demyelination and axonal damage predominantly targeting optic nerves and the spinal cord.

The epidemiology, pathogenesis, clinical manifestations, and diagnosis of NMOSD will be reviewed here. Treatment and prognosis are reviewed separately. (See "Neuromyelitis optica spectrum disorder (NMOSD): Treatment and prognosis".)

HISTORY — The first clinical descriptions of NMOSD 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 NMOSD made its distinction from multiple sclerosis less clear [3-8].

It was previously believed that NMOSD and multiple sclerosis represented one disease entity with variable phenotypes and expression. However, the discovery of a disease-specific serum NMO-immunoglobulin G (IgG) antibody that selectively binds aquaporin-4 (AQP4) has led to increased understanding that NMOSD is distinct from classic relapsing-remitting multiple sclerosis with respect to pathogenesis, imaging features, biomarkers, neuropathology, and treatment.

PATHOGENESIS

●Neuropathology – In NMOSD, florid demyelination and inflammation involve multiple spinal cord segments and the optic nerves with associated astrocyte death, 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 NMOSD at autopsy are those of a much more severe necrotic lesion of the cord rather than incomplete demyelination. This may be a consequence of the distribution of aquaporin-4 (AQP4) receptors, which predominate in astrocytes rather than oligodendrocytes.

●Autoimmune pathogenesis - The pathophysiology of NMOSD is thought to be primarily mediated by the humoral immune system [9-12]. Several lines of evidence support an autoimmune pathogenesis for NMOSD. The most important of these was the identification of a NMOSD disease-specific autoantibody, initially termed the NMO-immunoglobulin G (IgG) antibody, and now referred to as the 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 immunotherapy, and remain low during remissions, though they are typically not used as an index of therapeutic efficacy during treatment [14-16].

●Astrocytopathy – The inflammatory processes in NMOSD primarily target astrocytes, leading to immune-mediated inflammation and secondary demyelination [17-21]. The area postrema appears to be a preferential target of AQP4-IgG antibodies that bind to astrocyte AQP4 water channels, leading to astrocyte dysfunction and the clinical manifestations of nausea and vomiting [22,23]. (See 'Brain and brainstem syndromes' below.)

●AQP4 water channel protein – AQP4, the target antigen of NMO-IgG, is a water channel protein that is abundant in the astrocytic foot processes at the blood-brain barrier and highly concentrated in spinal cord gray matter, periaqueductal, and periventricular regions [24,25]. AQP4-IgG autoantibodies play a direct role in the pathogenesis of NMOSD [26-28]. In multiple sclerosis (MS) lesions, the distribution of AQP4 protein expression depends upon the stage of demyelination, while in NMOSD lesions, there is a loss of AQP4 expression that is unrelated to the stage of demyelination [29]. In addition, intrathecal anti-AQP4 antibodies have been identified in a patient with NMOSD at disease onset; monoclonal recombinant antibodies generated from this patient induced NMO-specific immunopathology in rats, demonstrating a direct pathogenic role of AQP4 antibodies [26].

●Other evidence of an autoimmune etiology – Additional data supporting an autoimmune pathogenesis for NMOSD include the following observations:

•Histopathologic examination of NMOSD lesions shows immunoglobulin and complement deposits in a characteristic vasculocentric rim and rosette pattern around hyalinized blood vessels [11,29].

•NMOSD is frequently associated with systemic autoimmune disorders, particularly some that are also thought to be mediated by abnormal antibodies; these include organ-specific disorders such as hypothyroidism, pernicious anemia, ulcerative colitis, myasthenia gravis, and idiopathic thrombocytopenic purpura; and nonorgan-specific disorders such as systemic lupus erythematosus, antiphospholipid syndrome, and Sjögren's disease [26,30,31]. In addition, some cases of NMOSD may be associated with neoplasms [32].

•Antinuclear autoantibodies are common in patients with NMOSD who lack evidence of a systemic disorder. In one cohort of 78 patients with NMOSD, seropositivity for antinuclear antibodies (ANA) and Sjögren's disease A/Sjögren's disease B (SSA/SSB) was found in 53 and 17 percent, respectively [33].

•Among Japanese patients, Asian optic-spinal multiple sclerosis, now considered part of the spectrum of NMOSD, is associated with the HLA-DPB1-0501 allele of the major histocompatibility complex [34], while conventional MS is associated with the HLA-DRB1-1501 allele. Anti-AQP4 antibody-positive patients are more likely to bear the HLA-DPB1 allele [35].

•Clinical experience and evidence from randomized trials suggest that therapeutic plasma exchange and immunosuppressive therapies targeted to the production of antibodies are beneficial for treatment and prevention of acute NMOSD attacks. (See "Neuromyelitis optica spectrum disorder (NMOSD): Treatment and prognosis".)

EPIDEMIOLOGY

●Prevalence and incidence – The prevalence of NMOSD in adults in various studies ranges from 0.37 to 10 per 100,000 [36]. Ethnic, geographic, and sex-based disparities are recognized [36,37]. The reported incidence of AQP4-antibody seropositive NMOSD in females is up to 10 times higher than in males [36,38,39], whereas the female-to-male incidence with multiple sclerosis (MS) is approximately 2:1. (See "Pathogenesis and epidemiology of multiple sclerosis", section on 'Epidemiology and risk factors'.)

●Age of onset – The median age of onset for NMOSD is 32 to 41 years, but cases are described in children and older adults [16,40-43]. Comparatively, the median age of onset for MS is 24 years.

●Geographic distribution – NMOSD may be overrepresented in some non-European populations worldwide, including African, East Asian, and Latin American populations, among whom conventional MS is somewhat less common [16,36,44]. In a study that determined anti-aquaporin-4 (AQP4)-immunoglobulin G (IgG) seroprevalence, the incidence and prevalence of NMOSD and AQP4 autoimmunity were substantially higher among Black compared with White patients who had inflammatory demyelinating central nervous system disease [45]. As an example, the study found that overall prevalence of NMOSD in the Caribbean island of Martinique (predominantly Black participants) compared with Olmsted County, Minnesota (predominantly White participants) was 10/100,000 versus 3.9/100,000, respectively. However, the ethnic predilection of NMOSD was not supported by some earlier studies [46,47], suggesting it could represent the relative rarity of MS among these groups rather than a true excess of NMOSD [48]. One retrospective report of patients from six centers (Denmark, Germany, South Korea, the United Kingdom, the United States, and Thailand) who were seropositive for AQP4 antibodies found that Asian patients and Black patients had a younger mean age of onset and a higher prevalence of brain and brainstem involvement compared with White patients from these countries [37].

In Japan, optic-spinal multiple sclerosis (OSMS), clinically and immunologically similar to NMOSD, represents approximately 15 to 40 percent of MS cases and has been historically identified as a separate disorder, though on a spectrum with conventional Western MS [49]. Whether NMOSD and Asian OSMS are the same entity remains uncertain [49,50]. Nevertheless, Asian OSMS is now considered as part of the NMOSD. (See 'Other symptoms' below.)

●Risk factors – NMOSD is usually sporadic, though a few familial cases have been reported [48]. Limited data suggest that genetic variants in the major histocompatibility region are associated with NMOSD [51]. Patients with autoimmune conditions including systemic lupus erythematosus, Sjögren's disease, and myasthenia gravis may have an increased risk for developing NMOSD [52,53].

CLINICAL FEATURES

Spectrum of symptoms — Hallmark features of NMOSD 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 [1,2,9,40,41,54]. Attacks most often occur over days, with variable degrees of recovery over weeks to months [55].

Central nervous system involvement outside of the optic nerves and spinal cord is recognized in patients with NMOSD. Other suggestive symptoms include episodes of intractable nausea, vomiting, hiccups, excessive daytime somnolence or narcolepsy, reversible posterior encephalopathy syndrome (PRES), neuroendocrine disorders, and (in children) seizures [56-61]. While no clinical features are disease-specific, some are highly characteristic [56].

Over time, the range of NMOSD has expanded to include patients with aquaporin-4 (AQP4) antibody positivity who have single or recurrent attacks of optic neuritis, myelitis, or brain or brainstem syndromes, often indistinguishable from multiple sclerosis (MS) [41,56,62-65].

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 is almost always associated with eye pain that worsens with movement of the eye.

Individual optic neuritis attacks in NMOSD may be similar to isolated syndromes of optic neuritis or those related to MS, though visual loss is generally more severe in NMOSD [8,16,44,54,66]. Involvement of the optic chiasm and tracts is characteristic of NMOSD. While most optic neuritis attacks in NMOSD are unilateral, sequential optic neuritis in rapid succession or bilateral simultaneous optic neuritis is highly suggestive of NMOSD [16]. Papilledema may suggest a diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease [67]. (See "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis", section on 'Optic neuritis'.)

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: Etiology, clinical features, and diagnosis".)

●Manifestations – Spinal cord involvement in NMOSD typically presents with transverse myelitis, characterized by symmetric paraparesis or quadriparesis, bladder dysfunction, and sensory loss below the level of the spinal cord lesion [16,54]. Accompanying symptoms may include paroxysmal tonic spasms of the trunk or extremities, radicular pain, or Lhermitte sign [54,68]. By contrast, myelitis in MS tends to be incomplete and asymmetric.

●Longitudinally extensive transverse myelitis – Patients with NMOSD typically have a longer extent of spinal cord demyelination than patients with MS [40,54], generally involving three or more vertebral segments on magnetic resonance imaging (MRI), a condition termed longitudinally extensive transverse myelitis (LETM). LETM represents an inaugural or limited form of NMOSD in a high proportion of patients [69]. However, a minority of patients with NMOSD present with a shorter extent of spinal cord involvement [63]. (See 'Other symptoms' below.)

Brain and brainstem syndromes — In addition to optic neuritis and transverse myelitis, other manifestations that can develop with NMOSD include encephalopathy, fulminant cerebral demyelination, hypothalamic dysfunction, area postrema syndrome, and PRES [16,23,70,71]. In rare cases, severe diffuse cerebral edema and demyelination can lead to brain herniation and death [71].

●Area postrema syndrome – 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 [56,69,72]. Brainstem involvement may lead to acute neurogenic respiratory failure and death [54].

●Hypothalamic lesions – 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 [57,58].

●Hyponatremia – Hyponatremia secondary to the syndrome of inappropriate antidiuretic hormone secretion or to cerebral salt-wasting syndrome has been associated with seropositive AQP4 antibody NMOSD [73,74].

Other symptoms

●Muscle involvement – Beyond 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 NMOSD who had recurrent myalgias and evidence of an autoimmune myopathy with targeting of sarcolemmal AQP4 in skeletal muscle by complement-activating immunoglobulin G [75]. In addition, there are several reports of transiently elevated serum creatine kinase (ie, "hyper-CKemia") associated with attacks of NMOSD [65,76-79].

●Pain – Pain is a common symptom. In retrospective studies of NMOSD, 75 to 80 percent of patients report pain, most often involving the trunk and legs [80-82].

Children — Although firm conclusions are limited by small numbers of patients, the available data suggest that a substantial minority of children with NMOSD have brain involvement at presentation associated with clinical features of encephalopathy, seizures, and/or lesions on brain MRI resembling those typically seen with MS or acute disseminated encephalomyelitis [59,83-88].

Relapsing clinical course — NMOSD has a relapsing course in 90 percent or more of cases [40,42,54]. 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 [54].

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 [54,89,90]. Unlike MS, a secondary progressive phase of the disease is rare, and disability is associated with specific attacks. Patients with cerebral presentations may have continued brain attacks without involvement of the optic nerves or spinal cord [91]. (See "Neuromyelitis optica spectrum disorder (NMOSD): Treatment and prognosis", section on 'Prognosis'.)

EVALUATION AND DIAGNOSIS

When to suspect NMOSD — Clinical presentations that should raise suspicion for NMOSD include the following [56]:

●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 anti-aquaporin-4 (AQP4)-immunoglobulin G (IgG) antibodies are not detected and, conversely, the continuum of NMOSD can be wider, based upon the presence of AQP4-IgG antibodies in milder spinal cord syndromes [56]. In some patients, anti-myelin oligodendrocyte glycoprotein (MOG) antibodies are associated with similar syndromes. (See "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis".)

Other clinical and imaging manifestations are considered "red flags" (table 1) 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.

Investigations — The evaluation of suspected NMOSD entails the following investigations:

●MRI, with and without contrast, of the brain and spinal cord. In some cases, spinal arteriography may be needed to confirm the diagnosis of vascular pathologies that can present as acute myelopathies, such as dural arteriovenous fistula.

●Serum for AQP4-IgG antibody and MOG-IgG antibody testing, using a cell-based assay.

●Cerebrospinal fluid (CSF) analysis is not strictly required for the diagnosis of NMOSD but is used to distinguish from other entities such as multiple sclerosis, since for example oligoclonal bands are not usually present in NMOSD, unlike multiple sclerosis.

●Most clinicians also obtain assays for other autoimmune conditions such as systemic lupus erythematosus and Sjögren's disease, as well as antibodies against HIV as part of the workup.

The detection of AQP4-IgG antibodies is specific for confirming the diagnosis (table 2) in appropriate clinical settings.

Diagnostic criteria — Revised consensus criteria published in 2015 (table 2) base the diagnosis of NMOSD on the presence of core clinical characteristics, AQP4 antibody status, and MRI neuroimaging features (table 3) [56].

●Core clinical features of NMOSD – 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

●Diagnosis with AQP4-IgG – The diagnosis of NMOSD with AQP4-IgG antibodies (table 2) requires the following [56]:

•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

●Diagnosis without AQP4-IgG – The diagnostic criteria for NMOSD with negative or unknown AQP4-IgG antibody status are more exacting (table 2) and require [56]:

•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 2) as determined by the clinical presentation

•Negative tests for AQP4-IgG (NMO-IgG) using cell-based methods (this criterion is waived if testing is 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 NMOSD (table 3 and image 1 and image 2) [54,92,93]. 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 [94]. Occasionally, the spinal cord inflammation and swelling have been so severe that the lesion can mimic a tumor [95-97]. Gadolinium enhancement disappears with treatment, and spinal cord lesions diminish during remissions [16]. Over time, there may be significant spinal cord atrophy (image 1).

MRI of the brain and orbits — At presentation, MRI of the brain is normal in 55 to 84 percent of patients with NMOSD, 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 NMOSD [98-101]. 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 3 and image 4). These lesions in patients with NMOSD occasionally fulfill MS diagnostic criteria for dissemination in space. Lesions of the corticospinal tract also suggest NMO [91]. Ring-enhancing lesions, either open or closed, are characteristic of MS, not NMO. (See "Evaluation and diagnosis of multiple sclerosis in adults", section on 'Magnetic resonance imaging' and "Evaluation and diagnosis of multiple sclerosis in adults", section on 'McDonald diagnostic criteria'.)

Like the longitudinally extensive spinal cord lesions of NMOSD, lesions of the optic nerve tend to be extensive [102]. Inflammation in the optic nerves extends more posteriorly than in MS, 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 (image 5) was observed in some patients diagnosed with NMOSD but was not found in patients diagnosed with multiple sclerosis, suggesting it is a reliable differentiator between the two conditions [103].

AQP4 autoantibody — Patients suspected of having NMOSD should be tested for serum AQP4-IgG antibodies [56,65]. Ideally, testing for AQP4 antibody status should be performed during attacks and before immunotherapy, since conversion to seronegative status may occur with immunotherapy [104]. In addition, patients who are initially seronegative for AQP4 antibody should be retested if there is suspicion for NMOSD.

The original NMO-IgG serum assay demonstrated moderate sensitivity and high specificity for the detection of NMOSD (73 and 91 percent, respectively) in addition to Asian optic-spinal MS (58 and 100 percent, respectively) [13,105]. Further-refined 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 NMOSD [14]. A blinded, multicenter trial confirmed a high specificity (100 percent) but only moderate sensitivity (72 percent) using combined commercial cell-based assay and enzyme-linked immunosorbent assay against AQP4 [106].

The AQP4-IgG serum autoantibody, also known as NMO-IgG based on its original name, is a specific biomarker for NMOSD [56,65]. The AQP4 receptor is the target antigen of NMO-IgG, which has a direct role in the pathogenesis of NMOSD. (See 'Pathogenesis' above.)

Even using the most sensitive cell-based assays, 12 percent of patients with a clinical diagnosis of NMOSD are seronegative for AQP4-IgG [104]. Limited data suggest that seronegative NMOSD may differ from seropositive NMOSD on certain features, including an equal male to female ratio and a greater likelihood of simultaneous optic neuritis and transverse myelitis at first presentation [104,107].

MOG autoantibody — A minority of AQP4-seronegative patients with a phenotype of NMOSD has serum antibodies against MOG [108-111]. MOG autoantibodies define an overlapping clinical syndrome known as myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) that often meets the clinical criteria for NMOSD but has some differences in features compared with AQP4 antibody-associated NMOSD, as summarized in the table (table 4), including [109,112-116]:

●More likely to involve the optic nerve than the spinal cord

●More likely to present with simultaneous bilateral optic neuritis with papilledema on funduscopic examination

●More likely to be monophasic or to have fewer relapses

●Less likely to be associated with other autoimmune disorders

●Proportionally more brainstem and cerebellar lesions, and fewer supratentorial lesions

●Spinal cord lesions mainly occur in the lower portion of the spinal cord

●The spectrum of disease includes acute disseminated encephalomyelitis (ADEM), particularly in children

●The male to female ratio is close to 1:1, unlike the predominance of females in NMOSD with AQP4-IgG antibodies

Proposed diagnostic criteria for MOGAD require serum positivity for MOG-IgG by cell-based assay, a clinical presentation consistent with central nervous system demyelination (ie, ADEM, optic neuritis, transverse myelitis, a brain or brainstem demyelinating syndrome, or any combination of these), and exclusion of an alternative diagnosis [117]. In the absence of serum positivity, CSF positivity for MOG-IgG allows fulfillment of the criteria. (See "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis", section on 'Diagnosis'.)

MOGAD is reviewed in detail separately. (See "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis" and "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Treatment and prognosis".)

Cerebrospinal fluid — A lumbar puncture is often unnecessary in patients with a typical presentation of NMOSD. However, it may be helpful to distinguish NMOSD from MS when the diagnosis is uncertain. During acute attacks of NMOSD, CSF abnormalities are common, including pleocytosis and elevated protein levels. Pleocytosis is detected in 14 to 79 percent of patients with NMOSD, 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 NMOSD; those with longitudinally extensive spinal cord lesions show a higher incidence than those with optic neuritis [16,40,54]. Notably, oligoclonal bands are typically absent (70 to 85 percent of cases) [16,40].

By contrast, a CSF pleocytosis >50 cells/mm³ is rare in MS, while oligoclonal bands are present in over 90 percent of patients. (See "Evaluation and diagnosis of multiple sclerosis in adults", section on 'CSF analysis and oligoclonal bands'.)

Optical coherence tomography — Optical coherence tomography studies in NMOSD report significantly greater retinal nerve fiber layer thinning in patients with NMOSD than MS, reflecting more severe axonal insult [118,119]. Microcystic macular edema of the inner nuclear layer appears to be common among patients with NMOSD and a history of optic neuritis [120]. In patients with NMOSD-related optic neuritis, other studies have reported retinal microvascular changes, as measured by radial peripapillary capillary density and macular superficial vessel density, and reduced thickness of the combined ganglion cell and inner plexiform layer [121,122]. 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 — The most common considerations in the differential diagnoses of aquaporin-4 (AQP4)-immunoglobulin G (IgG) antibody-positive NMOSD are multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). A comparison of these three disorders is summarized in the table (table 4). MRI discriminating features are illustrated in the figures for orbital and brain MRI (image 6) and for spine MRI (image 7).

Acute disseminated encephalomyelitis and other autoimmune diseases such as systemic lupus erythematosus and Behçet disease may rarely have similar presentations as NMOSD [123-125].

●Distinguishing MOGAD from NMOSD – It is relatively easy to distinguish MOGAD from AQP4-IgG NMOSD, as both have reliable serum biomarkers, and dual positivity of MOG-IgG and AQP4-IgG is rare.

●Distinguishing multiple sclerosis from NMOSD – Multiple sclerosis is the most common disorder likely to cause central nervous system demyelination. Differentiating NMOSD from other demyelinating disorders is based upon important differences with respect to clinical course, prognosis, and underlying pathophysiology (table 1 and table 4) as well as responsiveness to MS disease-modifying therapies [16,93]. Several features appear to distinguish NMOSD from classic relapsing-remitting multiple sclerosis:

•Brain MRI is often normal in patients with NMOSD, 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 NMOSD [98-100]. Of note, ring-enhancing lesions, either open or closed, are typical of MS, not NMO. Additional findings on brain MRI that suggest the diagnosis of MS rather than NMOSD include T2-weighted lesions in one or more of the following locations [101]:

-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 NMOSD, as they can occur in patients with NMOSD who are seropositive for AQP4 antibodies [126].

•During acute attacks of NMOSD, the cerebrospinal fluid 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 NMOSD. (See 'AQP4 autoantibody' above.)

•The myelopathy and optic neuritis associated with NMOSD tends to be more severe than with MS, with less likelihood of recovery.

●Differential of longitudinally extensive spinal cord lesions – Longitudinally extensive spinal cord lesions are not specific for NMOSD. They have been described in patients with other autoimmune or inflammatory diseases, including systemic lupus erythematosus, Sjögren's disease, neuro-Behçet disease, sarcoidosis, MS, MOGAD, parainfectious disorders (eg, acute disseminated encephalomyelitis), and anti-N-methyl-D-aspartate receptor encephalitis [125,127,128].

●Acute myelopathies – Additional etiologies of acute myelopathy include intrathecal tumors, vascular abnormalities (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).

Spinal dural arteriovenous malformations should be considered and ruled out as appropriate with either MRI or arteriography.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multiple sclerosis and related disorders".)

SUMMARY AND RECOMMENDATIONS

●Pathogenesis – Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disorder 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. NMOSD can be distinguished from multiple sclerosis (MS) and other central nervous system inflammatory disorders by the presence of the disease-specific aquaporin-4 (AQP4) antibody, which plays a direct role in the pathogenesis of NMOSD. (See 'History' above and 'Pathogenesis' above.)

●Epidemiology – The incidence of NMOSD in females is up to 10 times higher than in males. The median age of onset is 32 to 41 years, but there are cases in children and older adults. (See 'Epidemiology' above.)

●Clinical features – 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. NMOSD has a relapsing course in 90 percent or more of cases. (See 'Clinical features' above.)

●Evaluation – 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-IgG and myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) antibody status, and often cerebrospinal fluid analysis.

●Diagnosis – Diagnostic criteria for NMOSD (table 2) 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 2). Red flags (ie, atypical findings) for the diagnosis of NMOSD are summarized in the table (table 1). (See 'Evaluation and diagnosis' above.)

●Differential diagnosis – NMOSD must be distinguished from MS, which is the most common disorder likely to cause central nervous system demyelination, and from myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). A comparison of these three disorders is summarized in the table (table 4). MRI discriminating features are illustrated in the figures for orbital and brain MRI (image 6) and for spine MRI (image 7).

Other conditions that should be considered in the differential diagnosis include systemic lupus erythematosus, Sjögren's disease, neuro-Behçet disease, acute disseminated encephalomyelitis, intrathecal spinal cord tumors, vascular abnormalities and infarctions, and neurosarcoidosis. (See 'Differential diagnosis' above.)