Neuromyelitis Optica Spectrum Disorders

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Neuromyelitis optica spectrum disorders

Author: Christopher C Glisson, DO, MS, FAAN
Section Editor: Francisco González-Scarano, MD
Deputy Editor: John F Dashe, MD, PhD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2019. | This topic last updated: Aug 22, 2019.
INTRODUCTION
Neuromyelitis optica spectrum disorders (NMOSD, previously known as Devic disease or

neuromyelitis optica [NMO]) are inflammatory disorders of the central nervous system
characterized by severe, immune-mediated demyelination and axonal damage predominantly
targeting optic nerves and spinal cord.
The epidemiology, pathogenesis, clinical manifestations, diagnosis, treatment, and prognosis of

NMOSD will be reviewed here.
BACKGROUND
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. Mounting evidence indicates that NMOSD is
https://www.uptodate.com/contents/neuromyelitis-optica-spectrum-disorders/print 1/28
distinct from classic relapsing-remitting multiple sclerosis with respect to pathogenesis, imaging
features, biomarkers, neuropathology, and treatment.
PATHOGENESIS
Traditionally considered a variant of multiple sclerosis, NMOSD is now recognized as a distinct

clinical entity based on unique immunologic features. The discovery of a disease-specific serum
NMO-immunoglobulin G (IgG) antibody that selectively binds aquaporin-4 (AQP4) has led to
increased understanding of a diverse spectrum of disorders. This spectrum includes a potential
subset of patients with a phenotype of NMOSD who have anti-myelin oligodendrocyte glycoprotein
(MOG). (See 'MOG autoantibody' below.)
In NMOSD, 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 NMOSD 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 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 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].
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 NMOSD [19-21]. In 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 [22]. 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 [19]. The inflammatory processes
in NMOSD primarily targets astrocytes [23-25]; 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 [26,27]. (See 'Brainstem
syndromes' below.)
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 [11,22].
● 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 syndrome [19,28,29]. In
addition, some cases of NMOSD may be associated with neoplasms [30].
● 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 syndrome A/Sjögren 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
NMOSD, 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-DPB1 allele [33].
● Clinical experience suggests that therapeutic plasma exchange and immunosuppressive

therapies targeted to the production of antibodies are beneficial for treatment and prevention
of acute NMOSD attacks. (See 'Treatment' below.)
EPIDEMIOLOGY
The prevalence of NMOSD in various studies ranges from 0.5 to 10 per 100,000 [34-40]. Ethnic,
geographic, and gender disparities are recognized [41,42]. The reported incidence of NMOSD in
women is up to 10 times higher than in men [43-45]. In monophasic NMOSD (1 to 10 percent of
patients) men and women are affected equally, but in typical recurrent NMOSD, women
predominate over men by 5:1 to 10:1 [44]. The median age of onset is 32 to 41 years, but cases
are described in children and older adults [16,34,43,45,46]. 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'.)
NMOSD may be overrepresented in some non-European populations worldwide, including

Africans, East Asians, and Latin Americans, among whom conventional multiple sclerosis is less
common [16,47]. In a study that determined 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 [38]. As an example, the study found that overall
prevalence of 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 NMOSD was not supported by some earlier
studies [35,48], suggesting it could represent the relative rarity of multiple sclerosis among these
groups rather than a true excess of NMOSD [49]. One retrospective report found that Asian and
Afro-American/Afro-European patients seropositive for AQP4 had a younger mean age of onset
and a higher prevalence of brain and brainstem involvement than Caucasian patients [42].
In Japan, optic-spinal multiple sclerosis (OSMS), clinically and immunologically similar to NMOSD,
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 [50]. Whether NMOSD and Asian OSMS are the same entity remains uncertain [50,51].
Nevertheless, Asian OSMS is now considered as part of the NMOSD. (See 'Additional syndromes'
below.)
NMOSD is usually sporadic, though a few familial cases have been reported [49].
CLINICAL FEATURES
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 [1,2,9,43,45,52]. Attacks most often
occur over days, with variable degrees of recovery over weeks to months [53].
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
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 NMOSD are indistinguishable from isolated syndromes of optic
neuritis or those related to multiple sclerosis, though visual loss is generally more severe in
NMOSD [8,16,47,52,54]. While the majority of optic neuritis attacks in NMOSD are unilateral,
sequential optic neuritis in rapid succession or bilateral simultaneous optic neuritis is highly
suggestive of NMOSD [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 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 [16,52]. Accompanying symptoms may include paroxysmal tonic spams of
the trunk or extremities, radicular pain, or Lhermitte sign [52,55]. In contrast, myelitis in multiple
sclerosis tends to be incomplete and asymmetric. Patients with NMOSD typically have a longer
extent of spinal cord demyelination than patients with multiple sclerosis [43,52], 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 [56]. However, a minority of patients with NMOSD
present with a shorter extent of spinal cord involvement [57]. (See 'Additional syndromes' 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 [56,58,59]. Brainstem involvement may lead to acute
neurogenic respiratory failure and death [52].
Additional syndromes — The spectrum of NMOSD disorders is distinguished by clinical,

imaging, and antibody findings. This spectrum includes the following [16,45,57,59-62]:
● Limited or partial forms:
• 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 NMOSD (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 NMOSD who had
recurrent myalgias and evidence of an autoimmune myopathy with targeting of sarcolemmal
aquaporin-4 (AQP4) in skeletal muscle by complement-activating IgG [63]. In addition, there are
several reports of transiently elevated serum creatine kinase (ie, "hyper-CKemia") associated with
attacks of NMOSD [62,64-67].
Over time, the range of NMOSD 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 [61].
Other manifestations that can develop with NMOSD include encephalopathy, fulminant cerebral
demyelination, hypothalamic dysfunction, and posterior reversible leukoencephalopathy
[16,27,68,69]. 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 [70,71]. In rare cases, fulminant diffuse vasogenic
edema can lead to brain herniation and death [69].
Pain is a common symptom. In retrospective studies of NMOSD, 80 percent or more of patients

report pain, most often involving the trunk and legs [72,73].
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 multiple sclerosis or acute disseminated encephalomyelitis
[74-80].
Disease patterns — NMOSD has a relapsing course in 90 percent or more of cases [34,43,52]. 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 [52]. 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 [52,81,82]. 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 [83].
EVALUATION AND DIAGNOSIS
Clinical presentations that should raise suspicion for NMOSD include the following [59]:
● 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 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
[59]. In some patients, anti-myelin oligodendrocyte glycoprotein (MOG) antibodies are associated
with similar syndromes.
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 brain and spinal cord
neuroimaging with MRI, determination of AQP4-IgG serum antibody and MOG serum antibody
status, and often cerebrospinal fluid (CSF) analysis. 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 magnetic
resonance imaging (MRI) neuroimaging features (table 3) [59]. 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 2) requires the following [59]:
● 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 with negative or unknown AQP4-IgG antibody status are more
exacting (table 2) and require [59]:
● 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 applicable
● Negative tests for AQP4-IgG (NMO-IgG) using best available detection method, or,
alternatively, 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 2) [59].
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)
[52,84,85]. 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 [86]. Occasionally,
the spinal cord inflammation and swelling have been so severe that the lesion can mimic a tumor
[87-89]. 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 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 [90-93]. 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 multiple sclerosis diagnostic criteria for dissemination in space. (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'.)
Similar to the way that spinal cord lesions of NMOSD are longitudinally extensive, lesions of the
optic nerve tend to be longitudinally extensive [94]. 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 (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 [95].
AQP4 autoantibody — The AQP4-IgG serum autoantibody, also known as NMO-IgG based on its
original name, is a specific biomarker for NMOSD [59,62]. The aquaporin-4 receptor is the target
antigen of NMO-IgG, which has a direct role in the pathogenesis of NMOSD (see 'Pathogenesis'
above). Therefore, patients suspected of having NMOSD should be tested for serum AQP4-IgG
antibodies [59,62]. Ideally, testing for AQP4 antibody status should be performed during attacks
and before immunosuppressive therapy, since conversion to seronegative status may occur with
immunosuppression [96]. 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 multiple
sclerosis (58 and 100 percent, respectively) [13,97]. 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 (CBA) and enzyme-linked
immunosorbent assay (ELISA) against AQP4 [98].
Even using the most sensitive assays, 12 percent of patients with a clinical diagnosis of NMOSD
are seronegative for AQP4-IgG [96]. 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 [96,99].
MOG autoantibody — A minority of AQP4-seronegative patients with a phenotype of NMOSD

has serum antibodies against MOG [100-103]. MOG autoantibodies may define an overlapping
and possibly distinct clinical syndrome that often meets the clinical criteria for NMOSD but has
some differences in features compared with AQP4 antibody-associated NMOSD or seronegative
NMOSD, including [101,104-108]:
● More likely to involve the optic nerve than the spinal cord
● More likely to present with simultaneous bilateral optic neuritis
● 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 may be wider and include acute disseminated encephalomyelitis
(ADEM), particularly in children
● The male-to-female ratio is close to 1:1, unlike the predominance of women in NMOSD with
AQP4-IgG antibodies
Proposed diagnostic criteria for MOG antibody-associated disorders require serum positivity for
MOG-IgG by cell-based assay and 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 [109]. In the
absence of serum, positivity for MOG-IgG in the CSF allows fulfillment of the criteria. In a series of
51 patients, transient seropositivity favored a lower risk of relapse [109].
Cerebrospinal fluid — 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 [16,43,52]. Notably, oligoclonal bands are typically absent (70 to 85 percent of cases)
[16,43].
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 "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 multiple
sclerosis, reflecting more severe axonal insult [110,111]. Microcystic macular edema of the inner
nuclear layer appears to be common among patients with NMOSD and a history of optic neuritis
[112]. 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
NMOSD 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 [113-115].
Of note, 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 syndrome, neuro-Behçet disease, sarcoidosis, multiple sclerosis,
parainfectious disorders (eg, acute disseminated encephalomyelitis), and anti-N-methyl-D-
aspartate (NMDA) receptor encephalitis [115-117]. Additional etiologies of longitudinally extensive
spinal cord lesions 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).
Differentiating NMOSD from other demyelinating disorders is based upon important differences
with respect to clinical course, prognosis, and underlying pathophysiology (table 1) as well as
responsiveness to multiple sclerosis disease-modifying therapies [16,85]. 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 [90-92]. Findings on brain MRI that suggest
the diagnosis of multiple sclerosis rather than NMOSD include T2-weighted lesions in one or
more of the following locations [93]:
• 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 aquaporin-4 (AQP4)
antibodies [118].
● 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
multiple sclerosis, with less likelihood of recovery.
NMOSD syndromes may also be associated with anti-myelin oligodendrocyte glycoprotein (MOG)
antibody seropositivity. However, the spectrum of disease associated with anti-MOG is wider than
with anti-AQP4 antibodies, and cases that are clinically consistent with NMOSD may be less
severe than with AQP4 seropositivity.
TREATMENT
The rationale for treatment of acute and recurrent attacks in NMOSD is based upon evidence that
humoral autoimmunity plays a role in the pathogenesis of NMOSD, and is driven by the high
attack-related disability, poor prognosis, and overall high risk of mortality in untreated patients
[16,119].
Acute attacks — All patients with suspected NMOSD 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 [16,120,121]. (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 rescue treatment [16,120,121]. Exchanges are carried out every other
day up to a total of seven exchanges.
Limited retrospective and uncontrolled data suggest that patients with severe attacks of NMOSD
do better if plasma exchange is started early as adjunctive therapy with glucocorticoids. One
report of patients with severe attacks (defined by an Expanded Disability Status Scale (table 4)
score ≥4 and/or visual acuity ≤20/200) found that initial treatment with intravenous glucocorticoids
plus early therapeutic plasma exchange was associated with improved outcomes compared with
delayed initiation of plasma exchange following glucocorticoid treatment [122].
Seronegative NMOSD is managed in the same way as seropositive NMOSD.
Intravenous immune globulin has not been specifically evaluated for acute attacks of NMOSD and
is rarely used in this setting.
Attack prevention — Because the natural history of NMOSD is one of stepwise deterioration due
recurrent attacks and accumulated disability, long-term immunosuppression treatment is indicated
for the prevention of attacks as soon as the diagnosis of NMOSD is made [16,121,123]. For
patients with NMOSD who are seropositive for aquaporin-4 (AQP4) IgG antibodies, we suggest
treatment with eculizumab rather than another immunosuppressive agent. However, the optimal
drug regimen and treatment duration are yet to be determined.
● Eculizumab – Limited high-quality data support the effectiveness of eculizumab, a

humanized antibody that binds to the complement component C5 and inhibits the formation of
C5b-induced membrane attack complex. In a randomized controlled trial of 143 patients with
NMOSD who were seropositive for aquaporin-4 (AQP4) IgG antibodies, treatment with
eculizumab reduced the risk of relapse; the annualized relapse rates for the eculizumab and
placebo groups were 0.02 and 0.35 (rate ratio 0.04, 95% CI 0.01-0.15) [124]. Most patients in
the trial were also taking concomitant immunosuppressive therapy (eg, azathioprine,
glucocorticoids, mycophenolate mofetil) but not rituximab, which was excluded because its
mechanism of action is incompatible with eculizumab.
Eculizumab is administered intravenously at 900 mg weekly for the first four doses, followed
by maintenance dosing of 1200 mg every two weeks beginning at week five.
Note that eculizumab treatment is associated with an increased risk of infection with Neisseria
meningitidis; patients should be immunized with meningococcal vaccines and receive daily
antimicrobial prophylaxis, as described separately. In the United States, eculizumab is
available only through a restricted program under a Risk Evaluation and Mitigation Strategy
(REMS). (See "Treatment and prevention of meningococcal infection", section on 'Patients
receiving C5 inhibitors'.)
Otherwise, eculizumab infusions are generally well tolerated. Commonly reported adverse
events in clinical trials included headache, upper respiratory tract infections, back pain, and
nausea.
● Other immunosuppressive agents – The evidence of efficacy for systemic

immunosuppression comes mainly from observational studies of agents including
azathioprine [125,126], mycophenolate mofetil [127,128], rituximab [129], methotrexate
[130,131], mitoxantrone [132], and oral glucocorticoids [133]. Among these, the agents most
often considered as effective treatments for NMOSD are azathioprine, rituximab, and
mycophenolate mofetil [120,134,135].
Comparative data for NMOSD treatments are scant.
• In an open-label randomized trial of 86 patients who had NMOSD with or without AQP4
antibodies, the reduction in the annualized relapse rate at 12 months was significantly
greater for patients assigned to rituximab compared with those assigned to azathioprine
[136].
• A retrospective, nonrandomized study from two tertiary centers in the United States
analyzed relapses among patients with NMOSD who were treated with azathioprine and
concomitant prednisone (n = 32) for at least six months, or with 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 [137]. Treatment with these agents was associated
with significant reductions in annualized relapse rates in the range of 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, defined as the development of any new central nervous system
inflammatory event, varied from 33 to 53 percent.
Treatment with tocilizumab (an IL-6 receptor antagonist) has been associated with clinical
stabilization or improvement in a small number of patients with refractory NMOSD who failed
one or more of the "standard" treatments discussed above [138-142]. In an observational
study of five Chinese patients with highly active NMOSD that was poorly responsive to
"standard" immunosuppressive agents, treatment with bortezomib (a proteosome inhibitor
that depletes plasma cells) was associated with relapse-free status in four and clinical
stabilization in all five [143].
Limited observational evidence suggests that treatment of NMOSD with interferon beta,
natalizumab, or fingolimod is not effective and may be harmful [144-149]. There is no
published evidence regarding the treatment of NMOSD with ocrelizumab.
● Duration of therapy – Immunosuppression is usually continued for at least five years for
patients who are seropositive for AQP4 antibodies, including those presenting with a single
attack, because they are at high risk for relapse or conversion to NMOSD [150]. However,
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.
PROGNOSIS
The natural history of NMOSD 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 [43,52,151,152]. These
prognostic factors need to be confirmed in larger independent prospective studies.
Mortality rates are high in NMOSD, 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 NMOSD

[47,82,151]. These studies may be biased towards more severe cases. Progress in the diagnosis
and treatment of NMOSD is expected to decrease mortality rates.
The aquaporin-4 (AQP4) autoantibody (NMO-immunoglobulin G [IgG]) may be a marker for

disease course and prognosis [153-155], though the available data are inconsistent [96]. In
patients with recurrent optic neuritis, retrospective evidence suggests that AQP4-IgG seropositivity
is associated with poor visual outcome and development of NMOSD [154]. A prospective study of
29 patients presenting with longitudinally extensive spinal cord lesions found 55 percent of the
patients seropositive for AQP4-IgG relapsed within one year or converted to NMOSD, while none
of seronegative patients relapsed [155]. In contrast, a subsequent report noted that seronegative
and seropositive NMOSD were similar in terms of relapse rate, severity, and long-term outcomes
[96]. The discrepancy in these results may be due in part to small numbers of patients with
seronegative NMOSD 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 [156], and that the
annualized relapse rate of NMOSD is increased in the first three to six months of the postpartum
period [157,158].
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
● Neuromyelitis optica 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. NMOSD can be distinguished from multiple sclerosis 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 '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. NMOSD 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 magnetic resonance imaging (MRI) (table 3),
determination of AQP4 antibody status, and often cerebrospinal fluid analysis. 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-
immunoglobulin G (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). (See
'Evaluation and diagnosis' above.)
● NMOSD 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
syndrome, neuro-Behçet disease, acute disseminated encephalomyelitis, and intrathecal
spinal cord tumors. NMOSD may also be associated with anti-myelin oligodendrocyte
glycoprotein (MOG) antibody seropositivity. However, the spectrum of disease associated with
MOG autoantibodies is wider than with AQP4 autoantibodies. (See 'Differential diagnosis'
above.)
● For patients with acute or recurrent attacks of NMOSD, we suggest initial treatment with high-
dose intravenous methylprednisolone (1 gram daily for three to five consecutive days) (Grade
2C). For patients with severe symptoms, unresponsive to glucocorticoids, we suggest
treatment with plasma exchange (Grade 2C). Plasma exchange may be more effective if
started early as adjunctive therapy with glucocorticoids. (See 'Acute attacks' above.)
● Because the natural history of NMOSD is one of stepwise deterioration due recurrent attacks
and accumulated disability, long-term immunosuppression is indicated to reduce the risk of
relapse as soon as the diagnosis of NMOSD is made. For patients with NMOSD who are
seropositive for aquaporin-4 (AQP4) IgG antibodies, we suggest treatment with eculizumab
rather than another immunosuppressive agent (Grade 2C); eculizumab was highly effective
for reducing the relapse rate compared with placebo in a randomized trial. For patients who
meet diagnostic criteria for NMOSD without AQP4-IgG or who meet criteria with unknown
AQP4-IgG status, alternative agents include rituximab, azathioprine, or mycophenolate. (See
'Attack prevention' above.)
Immunosuppression is usually continued for at least five years for patients who are
seropositive for AQP4-IgG, including those presenting with a single attack, because they are
at high risk for relapse. However, the optimal drug regimen and treatment duration for
NMOSD, with or without AQP4 seropositivity, are yet to be determined. (See 'Attack
prevention' above.)
● The natural history of NMOSD is one of stepwise deterioration due to accumulating visual,
motor, sensory, and bladder deficits from recurrent attacks. Long-term disability and mortality
rates are high. (See 'Prognosis' above.)
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Topic 14089 Version 29.0
Contributor Disclosures
Christopher C Glisson, DO, MS, FAAN Nothing to disclose Francisco González-Scarano,
MD Consultant/Advisory Boards: DeLoitte [Physician Leadership Academy]. Equity Ownership/Stock
Options: Multiple, but traded by advisors without personal input [Pharmaceutical]. John F Dashe, MD,
PhD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
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Neuromyelitis optica spectrum disorders (NMOSD, previously known as Devic disease or

The epidemiology, pathogenesis, clinical manifestations, diagnosis, treatment, and prognosis of

Traditionally considered a variant of multiple sclerosis, NMOSD is now recognized as a distinct

Whereas multiple sclerosis is mostly a cell-mediated disorder, the pathophysiology of NMOSD is

● Histopathologic examination of NMOSD lesions shows immunoglobulin and complement

● Clinical experience suggests that therapeutic plasma exchange and immunosuppressive

NMOSD may be overrepresented in some non-European populations worldwide, including

Additional syndromes — The spectrum of NMOSD disorders is distinguished by clinical,

● Limited or partial forms:

• Single or recurrent unilateral or simultaneous bilateral optic neuritis

• Optic neuritis or transverse myelitis in isolation

● Asian optic-spinal multiple sclerosis

Pain is a common symptom. In retrospective studies of NMOSD, 80 percent or more of patients

EVALUATION AND DIAGNOSIS

● At least one core clinical characteristic

● Exclusion of alternative diagnoses

• Dissemination in space (two or more different core clinical characteristics)

• Fulfillment of additional MRI requirements (table 2) as applicable

● Exclusion of alternative diagnoses

MOG autoantibody — A minority of AQP4-seronegative patients with a phenotype of NMOSD

Optical coherence tomography — Optical coherence tomography studies in NMOSD report

• Lesions adjacent to lateral ventricle

For patients with severe symptoms, unresponsive to glucocorticoids, therapeutic plasma

Seronegative NMOSD is managed in the same way as seropositive NMOSD.

● Eculizumab – Limited high-quality data support the effectiveness of eculizumab, a

● Other immunosuppressive agents – The evidence of efficacy for systemic

Comparative data for NMOSD treatments are scant.

reported mortality rates of 32 percent, 50 percent, and 25 percent, respectively in NMOSD

The aquaporin-4 (AQP4) autoantibody (NMO-immunoglobulin G [IgG]) may be a marker for

SOCIETY GUIDELINE LINKS

SUMMARY AND RECOMMENDATIONS

● Hallmark features of NMOSD include acute attacks characterized by bilateral or rapidly

● In addition to a comprehensive history and examination, the evaluation of suspected NMOSD

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