The n e w e ng l a n d j o u r na l of m e dic i n e

Review Article

Allan H. Ropper, M.D., Editor

Neuromyelitis Optica Spectrum Disorder

Dean M. Wingerchuk, M.D., and Claudia F. Lucchinetti, M.D.​​

N
euromyelitis optica spectrum disorder (NMOSD) is a rare auto- From the Department of Neurology,
immune disease. It causes multifocal central nervous system (CNS) in- Mayo Clinic, Scottsdale, AZ (D.M.W.);
and the Department of Neurology, Mayo
flammation that primarily affects the optic nerves and spinal cord, and it Clinic, Rochester, MN (C.F.L.). Dr. Wing-
typically results in attacks of visual loss and paralysis. Associations between optic erchuk can be contacted at ­wingerchuk
nerve and spinal cord disease were noted in the 19th century, especially after De- ​.­dean@​­mayo​.­edu or at the Department
of Neurology, Mayo Clinic, 13400 E. Shea
vic’s description of “neuro-myélite optique aiguë” (acute neuromyelitis optica).1 In Blvd., Scottsdale, AZ 85259.
the 20th century, “Devic’s disease” was considered a severe, monophasic optic and
N Engl J Med 2022;387:631-9.
spinal variant of multiple sclerosis that spared the brain.2 However, the discovery DOI: 10.1056/NEJMra1904655
of IgG-class antibodies that bind to the water channel aquaporin-4 (AQP4-IgG) in Copyright © 2022 Massachusetts Medical Society.

serum from patients with Devic’s disease, but not from those with typical multiple
sclerosis, established neuromyelitis optica as a distinct entity with a chronic, re- CME
lapsing course.3-5 Studies of patients who are AQP4-IgG–seropositive have led to the at NEJM.org
recognition that many additional clinical and neuroimaging findings occur, in-
cluding brain involvement, which are captured by the term neuromyelitis optica
spectrum disorder.6,7 The AQP4-IgG autoantibody is detectable in more than 80%
of patients with NMOSD and is pathogenic, initiating the inflammatory CNS lesions
and clinical manifestations of the disease.8,9

Epidemiol o gy
NMOSD accounts for 1 to 2% of all cases of CNS inflammatory demyelinating
disease in the United States and Europe, with multiple sclerosis being much more
common, but NMOSD accounts for one third or more of cases of CNS inflamma-
tion in Asian and other non-White populations. Incidence and prevalence estimates
have ranged from 0.037 to 0.73 cases per 100,000 person-years and 0.7 to 10.0 cases
per 100,000 persons, respectively, but these estimates vary widely among studies,
with the highest rates among Africans and in the Afro-Caribbean region and the
lowest rates among Whites and persons in Australasia, probably reflecting genetic
and environmental influences and differences in ascertainment methods.10 A
population-based study in the United States showed a higher prevalence for Blacks
(13.0 cases per 100,000 persons) than for Whites (4.0 per 100,000).11
The median age at onset of the disorder is 40 years, but the disorder can affect
people at any age, and up to 20% of cases are in children or in adults over the age
of 65 years. Seropositive disease has a female preponderance that approaches 90%,
whereas seronegative cases have an equal sex distribution.10,12 Up to 3% of cases
are familial.13 Whole-genome sequencing has shown that AQP4-IgG is associated
with major-histocompatibility-complex region variants, and there is a causal relation-
ship between known risk variants and systemic lupus erythematosus, which may
coexist with antibody-positive NMOSD.14 It has been suggested that environmental
factors may play a role in the genesis of the disorder, but none have been identified.
In pediatric NMOSD, unlike in multiple sclerosis, exposures to common herpes
viruses, including Epstein–Barr virus, are not implicated.15

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 The n e w e ng l a n d j o u r na l
Acute attacks of NMOSD, including the initial
episode, usually occur in the absence of an iden-
tified inciting event, but approximately one third
of cases are preceded by an infection, which is
often viral, and in rare cases, an acute attack fol-
lows vaccination.2 However, no specific infection
or vaccine has been strongly implicated as a trig-
ger of disease activity. The initial attack of NMOSD
with AQP4-IgG has been associated with the use
of immune checkpoint inhibitor therapies.16,17
Cl inic a l Ch a r ac ter is t ic s
Six core clinical syndromes have been identified
in NMOSD. They are classified by their location:
optic nerve, spinal cord, area postrema of the
dorsal medulla, other brain-stem regions, dien-
cephalon, or cerebrum. These syndromes are
manifested as acute attacks and relapses of neu-
rologic dysfunction, with symptoms that typically
evolve over a period of days.7 The most common
syndromes are optic neuritis and transverse my-
elitis, as well as area postrema syndrome, which
causes intractable or repetitive vomiting and hic-
cups. Multifocal lesions may result in a simulta-
neous or rapidly sequential combination of syn-
dromes (e.g., optic neuritis and myelitis). Attacks
are identified on the basis of new clinical symp-
toms and objective neurologic signs (except in the
case of isolated area postrema symptoms) and
by ruling out other causes, such as infection, that
can simulate an attack. Detection of new lesions
on magnetic resonance imaging (MRI) in the rel-
evant neuroanatomical region provides support-
ive evidence that a neurologic event is due to
NMOSD.
The sentinel attack involves the optic nerve or
spinal cord in more than 85% of affected adults.
Patients with optic neuritis present with unilat-
eral or bilateral visual loss or scotoma, dyschro-
matopsia, and ocular pain exacerbated by eye
movement that is not distinguishable from optic
neuritis in multiple sclerosis or from an idiopathic
form. Acute transverse myelitis causes limb weak-
ness, numbness, sensory loss or pain below the
lesion level, and bladder and bowel dysfunction.
Other myelitis symptoms include Lhermitte’s sign
(trunk or limb paresthesias), elicited by neck flex-
ion, and episodes of paroxysmal tonic spasms
lasting 15 to 60 seconds, with painful agonist
and antagonist muscle cocontraction, often mis-
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of m e dic i n e
taken for convulsions. Severe high cervical my-
elitis can cause neurogenic respiratory failure.2
Area postrema syndrome is the presenting
feature of NMOSD in 10% of patients and occurs
at some time during the disease in 15 to 40% of
patients.18,19 Vomiting lasts a median of 2 weeks
and, in up to two thirds of cases, presages an at-
tack of optic neuritis or myelitis.19 The syndrome
can accompany myelitis when a destructive cer-
vical lesion ascends into the brain stem, or it
may be isolated and caused by nondestructive
dorsal medullary lesions. When the syndrome is
isolated, especially as the inaugural presentation
of NMOSD, patients are typically evaluated by
internists or gastroenterologists for intractable
vomiting, and the diagnosis may be delayed un-
til there are subsequent neurologic symptoms.
The other NMOSD syndromes occur less fre-
quently, except that cerebral syndromes are com-
mon in children and cause generalized or focal
signs, including encephalopathy, hemiparesis,
hemianopia, or seizures.7,20 Brain-stem lesions may
cause oculomotor dysfunction, hearing loss, ver-
tigo, dysarthria, or other cranial-nerve symptoms;
as with optic neuritis, these features alone are not
initially distinguishable from similar syndromes
in multiple sclerosis. Lesions in diencephalic struc-
tures such as the thalamus and hypothalamus
have been reported to cause narcolepsy-like symp-
toms, endocrinopathies, temperature dysregula-
tion, eating disorders, and a syndrome of inap-
propriate antidiuretic hormone secretion.
Neuroim aging
Confirmation that an attack is due to NMOSD is
greatly aided by the detection on MRI of charac-
teristic lesions in the brain, optic nerve, optic chi-
asm, or spinal cord21 (Fig. 1). In the acute phase,
T2-weighted MRI sequences may show new or
enlarging inflammatory lesions, and T1-weighted
sequences obtained with gadolinium may show
enhancement of actively inflamed lesions. Abnor-
malities on orbital MRI have a predilection for the
optic chiasm or the adjacent posterior optic nerve
but may occupy the full length of the nerve. MRI
of the spinal cord typically shows longitudinally
extensive transverse myelitis (Fig. 1A), defined as
a lesion that is at least three contiguous vertebral
segments in length.2,22 Although this pattern is
characteristic of NMOSD, about 15% of sentinel
 Neuromyelitis Optica Spectrum Disorder
myelitis attacks are associated with a shorter le-
sion that simulates multiple sclerosis.23 Detection
of a dorsal medullary lesion with the use of MRI
is confirmatory of area postrema syndrome, but
the lesion is small and visible for only a few days.7
Seen on MRI scans, focal lesions in the brain stem,
diencephalon, or cerebrum, even those that are
asymptomatic, may also be indicative of NMOSD.7
Di agnosis
International consensus–based criteria for the di-
agnosis of NMOSD (Table 1)7 require the manifes-
tation of one or more of the six typical syndromes
and emphasize that clinical–radiologic correla-
tions and a positive serologic test for AQP4-IgG
distinguish NMOSD from multiple sclerosis and
other disorders. About 80% of cases are seroposi-
tive, but current criteria allow for the diagnosis
of NMOSD if AQP4-IgG testing is negative or not
available, which may be the case in some low-
income regions of the world. However, according
to the international consensus criteria, the diag-
nosis of NMOSD is almost ensured if there is a
characteristic first attack and AQP4-IgG antibodies
are present.7
The standard serum AQP4-IgG reference test
is a live cell–based flow-cytometric assay with
more than 80% sensitivity and more than 99%
specificity.24,25 False positive low-titer results
may occur with the use of enzyme-linked im-
munosorbent assays and, in an atypical case,
should prompt reconsideration of the diagnosis
and confirmation with a cell-based assay. False
negative AQP4-IgG results can occur if serum is
sampled during immunosuppressive drug treat-
ment or after plasma exchange. Retesting at an
interval after discontinuation of treatment or dur-
ing a relapse is recommended in such cases.7 Test-
ing for cerebrospinal fluid AQP4-IgG is relatively
insensitive.
The categorization of NMOSD with negative
or unknown AQP4-IgG status requires stringent
clinical and MRI criteria and a search for other
causes of the CNS symptoms.7 The most common
alternative diagnosis is a CNS demyelinating dis-
order associated with serum antibodies to myelin
oligodendrocyte glycoprotein (MOG-IgG). This
disorder overlaps with both AQP4-IgG–seroposi-
tive NMOSD and multiple sclerosis, both of which
also can cause optic neuritis or myelitis.26 Pa-
tients with NMOSD clinical syndromes generally
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undergo testing for both antibodies; however,
AQP4-IgG and MOG-IgG antibodies rarely coex-
ist. Patients who test negative for both antibodies
may be described as having “double seronegative”
NMOSD, a category that could be narrowed with
the discovery of new autoantibodies.
Dise a se C our se
Attacks of NMOSD usually reach peak severity in
several days, plateau, and then spontaneously sub-
side, frequently leaving moderate-to-severe and
permanent functional deficits.27 In more than
90% of cases, the disease has a relapsing course,
similar to that of multiple sclerosis, with a period
of months or years between attacks. Neurologic
impairment is stable or may diminish during
remission, but relapses lead to stepwise accrual
of disability. The type, frequency, and severity of
relapses are influenced by age, sex, and ethnic
group.28,29 Data regarding these factors have been
obtained from retrospective series. Among women
with seropositive NMOSD, relapse rates have been
higher during the first 3 months post partum
than in the period before or during pregnancy,
and the risk of miscarriage has been increased.30
Five years after the onset of disease, nearly
one quarter of untreated AQP4-IgG–seropositive
patients require gait assistance, more than 40%
are blind in at least one eye, and mortality ap-
proaches 10%.28,31 Hospitalization rates and use
of health resources are substantial.32 In con-
trast to relapsing multiple sclerosis, in which
late neurodegeneration and progressive function-
al deterioration may dominate the clinical pic-
ture, NMOSD rarely has a secondary progressive
course.33
A sso ci at ions w i th O ther
Disor der s
Up to half of patients with NMOSD and AQP4-IgG
have other detectable serum autoantibodies
(e.g., thyroperoxidase, antinuclear, and Ro/SS-A
antibodies), and one third have an autoimmune
disease, most commonly thyroiditis, systemic
lupus erythematosus, or Sjögren’s syndrome.2 It
is advisable to perform AQP4-IgG testing before
making a diagnosis of “lupus myelitis” or other
CNS complications of rheumatologic disease, be-
cause AQP4-IgG seropositivity usually indicates
the coexistence of one of these diseases and
633
 The n e w e ng l a n d j o u r na l of m e dic i n e

A B C D

E F G

H I J

NMOSD, with NMOSD usually accounting for Pathol o gic a l Fe at ur e s

the CNS syndrome.34 Up to 5% of antibody-pos-
itive NMOSD cases are paraneoplastic, and a
search for an occult malignant process may be
considered in patients with risk factors for can-
cer, particularly patients in whom NMOSD de-
velops at a late age.
a nd Patho gene sis
AQP4 is an integral membrane water channel
protein expressed by many cell types, including
gastrointestinal, lung, retinal, renal, and muscle
cells. In the CNS, AQP4 is expressed on astro-

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 Neuromyelitis Optica Spectrum Disorder
Figure 1 (facing page). MRI Patterns in Neuromyelitis
Optica Spectrum Disorder (NMOSD).
A sagittal T2-weighted scan shows a longitudinally ex-
tensive cervical spinal cord lesion that extends into the
medulla and has been considered relatively characteris-
tic of NMOSD (Panel A); the lesion is associated with
an area of ringlike contrast enhancement on T1-weight-
ed imaging (Panel B). Axial T1-weighted sequences
with contrast material show increased signal along the
length of the left optic nerve (Panel C) and optic chi-
asm (Panel D). A sagittal fluid-attenuated inversion re-
covery (FLAIR) sequence shows increased signal in the
dorsal medulla (Panel E), which is associated with area
postrema syndrome. A pair of small foci of contrast en-
hancement on T1-weighted sequences confirms a re-
lapse of acute area postrema syndrome (Panel F). An
axial FLAIR sequence shows diencephalic lesions in-
volving the hypothalamus (Panel G). Characteristic
brain lesions include large, confluent white-matter le-
sions, seen on an axial FLAIR sequence (Panel H), with
cloudlike contrast enhancement on an axial T1-weight-
ed, contrast-enhanced sequence (Panel I), and lesions
involving the long axis of the corpus callosum, seen on
a sagittal FLAIR sequence (Panel J). The arrows in the
panels point to lesions. Additional images are shown in
Figure S1 in the Supplementary Appendix, available
with the full text of this article at NEJM.org.
cytic end-feet that abut endothelial cells, which
form the glia limitans component of the blood–
brain barrier. When the barrier is breached, or
in regions such as the area postrema where it is
lacking, circulating AQP4-IgG gains access and
binds to its target antigen, initiating inflamma-
tory responses that generate NMOSD lesions. The
pathological hallmark of NMOSD with AQP4-IgG
is a focal inflammatory CNS lesion with marked
or complete loss of AQP4.35,36 Human immuno-
pathological findings support the concept that
NMOSD is an autoimmune astrocytopathy9 and
that AQP4-specific autoantibodies initiate lytic
and sublytic astrocyte disease with variable po-
tential for reversibility.35,37,38 Animal and tissue-
based models that use patient-derived monoclo-
nal antibodies can reproduce some characteristics
of NMOSD, further supporting the pathogenic
role of AQP4-IgG.39
The current concept of NMOSD immunopatho-
genesis is outlined in Figure S2 in the Supplemen-
tary Appendix, available with the full text of this
article at NEJM.org.40 The putative steps in the
pathogenesis begin with immune tolerance check-
point defects that allow the development of a set
of autoreactive B cells from which pathogenic
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Table 1. Core Clinical Characteristics and Diagnostic Criteria for
Neuromyelitis Optica Spectrum Disorder (NMOSD).*
Core clinical characteristics
The six core clinical characteristics are optic neuritis, acute myelitis, area
postrema syndrome, acute brain-stem syndrome (with associated
periependymal brain-stem lesions on MRI in AQP4-IgG–negative
patients), symptomatic narcolepsy or acute diencephalic clinical
syndrome with diencephalic lesions on MRI that are characteristic
of NMOSD, and symptomatic cerebral syndrome with brain lesions
that are characteristic of NMOSD
Criteria for NMOSD with AQP4-IgG
One or more of the six core clinical characteristics
Positive serum test for AQP4-IgG with the use of the best available detection
method (cell-based assay strongly recommended)
No alternative diagnoses
Criteria for NMOSD without AQP4-IgG or with unknown antibody status
Two or more of the six core clinical characteristics resulting from one or
more clinical attacks; must include at least one of the following three
core clinical characteristics:
Acute optic neuritis with either no abnormalities or only nonspecific
white-matter lesions in the brain on MRI, or with orbital MRI show-
ing a lesion extending over more than half the optic-nerve length or
involving the optic chiasm
Acute myelitis with a longitudinally extensive cord lesion on MRI
Area postrema syndrome with a dorsal medullary lesion on MRI
Negative test (or tests) for AQP4-IgG with use of best available detection
method or testing unavailable
No alternative diagnoses
* Diagnostic criteria are from Wingerchuk et al.7 AQP4-IgG denotes IgG-class
antibodies against aquaporin-4.
AQP4-IgG can originate.41 Cross-reactivity with
bacterial antigens resembling AQP4 or, in para-
neoplastic cases, initiation of an antibody-medi-
ated response to tumor-cell expression of AQP4
may be the originating mechanism. Complement
activation is an immediate consequence of the
selective binding of AQP4-IgG to its antigen. Ac-
tivated complement, together with interleukin-6,
increases the permeability of the blood–brain bar-
rier and is a chemoattractant, signaling eosino-
phils and neutrophils to enter the evolving lesion
and degranulate. Astrocyte injury occurs from
the effects of C5 and membrane attack complex
components of complement. Demyelination oc-
curs as a secondary consequence of myelinolysis
and oligodendrocyte injury.42
Despite widespread tissue expression of
AQP4, extra-CNS clinical disease such as myosi-
tis is rare.43 One potential explanation for selec-
tive CNS vulnerability is that the CNS lacks
635
 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 2. Treatment for Prevention of NMOSD Relapse.*

Drug† Mechanism of Action
Prednisone Immunosuppression
Azathioprine T-cell and B-cell suppression
Mycophenolate T-cell and B-cell suppression
mofetil
Rituximab B-cell depletion; anti-CD20
monoclonal antibody
Eculizumab Complement inhibition; anti-
C5 monoclonal antibody
Inebilizumab B-cell depletion; anti-CD19
monoclonal antibody
Satralizumab Interleukin-6 inhibition;
anti–interleukin-6 receptor
monoclonal antibody
Route and Dose
Oral; initial dose: 40–80 mg
daily; maintenance dose:
5–30 mg daily
Oral; 2–3 mg/kg daily
Oral; 1–3 g daily
Intravenous; initial dose: 1 g,
repeated after 2 wk; main-
tenance dose: 0.5–2 g at
6-mo intervals
Intravenous; initial dose: Nausea, headache,
900 mg weekly for 4 wk and
1200 mg 1 wk later; main-
tenance dose: 1200 mg at
2-wk intervals
Intravenous; initial dose:
300 mg, repeated after
2 wk; maintenance dose:
300 mg at 6-mo intervals
Subcutaneous; initial dose: Injection-site reac-
120 mg at wk 0, 2, and 4;
maintenance dose: 120 mg
at 4-wk intervals
Side Effects Key Risks
Dose-related systemic Gastrointestinal bleeding
glucocorticoid
effects
Nausea, vomiting, Leukopenia, liver toxicity, infec-
fatigue tions, cancer
Nausea, diarrhea Leukopenia, hypertension, tera-
togenicity; REMS program
required for reproductive risks
Infusion reactions Infections, hepatitis B reactiva-
tion, immunoglobulin defi-
ciency with prolonged use,
reduced vaccine response
Meningococcal vaccine and
back pain REMS program required for
risk of meningococcal infec-
tion‡
Infusion reactions Infections, immunoglobulin
deficiency with prolonged
use, reduced vaccine re-
sponse‡
Infections, neutropenia, amino-
tions, nasophar- transferase and lipid abnor-
yngitis, headache, malities‡
arthralgia

* REMS denotes Risk Evaluation and Mitigation Strategy.

† Eculizumab, inebilizumab, and satralizumab are approved by the Food and Drug Administration for relapse prevention in adults who have
NMOSD with AQP4-IgG. There are no approved therapies for NMOSD in the absence of AQP4-IgG.
‡ Eculizumab is contraindicated in patients with unresolved Neisseria meningitidis infection. Inebilizumab and satralizumab are contraindi-
cated in patients with active hepatitis B and those with active or latent tuberculosis.

protective complement regulatory proteins that Preventive Immunotherapy

are coexpressed with AQP4 in peripheral tissues The principal goal of NMOSD management is
such as the kidney.44 prevention of relapse, both for patients who are
AQP4-IgG–seropositive at the initial presentation,
who have more than a 70% risk of relapse in the
T r e atmen t
subsequent year, and for all patients, whether
Acute Relapses and Symptoms seropositive or seronegative for AQP4-IgG, who
Acute relapses are initially treated with intra- have an established relapsing course. Prevention
venous glucocorticoids, but one study has of relapse is expected to preserve long-term neuro-
shown short-term remission of symptoms in logic function because the accumulation of lesions
only 19% of patients treated with these drugs.27 with each attack would be averted; a secondary
Moderate-to-severe relapses, including those progressive course of NMOSD, independent of
that respond incompletely to glucocorticoids, relapses, is rare.
may be ameliorated with early administration Available preventive therapies are listed in
of plasma exchange.27 Management of residual Table 2. Until 2019, there were no approved drugs
effects of relapses such as gait impairment, for NMOSD, but observational data suggested
weakness and spasticity, neuropathic pain, low that immunosuppression reduces the frequency
vision, neurogenic bladder and bowel, and cog- of relapse among both AQP4-IgG–seropositive
nitive and mood disorders can improve the patients and AQP4-IgG–seronegative patients,45,46
quality of life. and one small, randomized, placebo-controlled

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 Neuromyelitis Optica Spectrum Disorder
trial showed a benefit of rituximab in seroposi-
tive patients.47 The most frequently used drugs
have been rituximab, mycophenolate mofetil, and
azathioprine. Many patients who do not have ac-
cess to recently approved drugs (discussed below)
continue to receive these therapies if they have
been in prolonged remission with one of these
treatments or if they have seronegative, relapsing
NMOSD; these drugs are also used in children.
Low-dose prednisone (or another glucocorticoid),
methotrexate, mitoxantrone, or cyclophosphamide
is used for relapse prevention in various regions
of the world.
Three approved monoclonal antibody therapies
for adults with NMOSD and AQP4-IgG autoanti-
bodies48 are eculizumab, inebilizumab, and sa-
tralizumab; each targets steps in the immuno-
pathogenesis of NMOSD and has been tested in
trials. In randomized, double-blind, placebo-
controlled trials, the time to the first adjudicated
relapse has been used as the primary outcome.
Differences in trial design have included enroll-
ment criteria (i.e., whether enrollment has been
restricted to AQP4-IgG–positive patients), attack
definition, and the use of placebo alone or pla-
cebo added to existing therapy as the comparator.
In one trial, eculizumab, which inhibits C5 and
presumably the formation of the membrane at-
tack complex mediated by C5b, reduced the risk
of relapse by 94% as compared with placebo in
AQP4-IgG–seropositive adults, some of whom
were receiving concomitant immunosuppressive
agents.49 No formal inferences regarding overall
disability or quality-of-life outcomes could be
made, because the period of follow-up after a
relapse was limited (6 weeks) and the between-
group difference in a measure of disability pro-
gression was not significant. Patients receiving
eculizumab as monotherapy accounted for 24% of
the trial participants, and the reduction in the
risk of relapse in this group was similar to the
reduction in the group of patients who received
eculizumab in addition to an established immu-
nosuppressive therapy. Upper respiratory tract
infections and headache were more common in
the eculizumab group. There were no infections
by encapsulated organisms such as Neisseria men-
ingitidis; infections are a known risk of comple-
ment inhibition. One death occurred from pulmo-
nary empyema.
Inebilizumab targets CD19; it depletes a broad-
er spectrum of the B-cell lineage, including anti-
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body-producing plasmablasts and plasma cells,
than anti-CD20 rituximab. In a phase 2–3 trial
that included AQP4-IgG–seropositive and AQP4-
IgG–seronegative patients and did not permit
concomitant treatment with immunosuppressive
drugs, the risk of relapse was reduced by 73%
overall and by 77% among seropositive patients.50
Inebilizumab reduced the rates of accumulating
disability, accumulating lesions on brain MRI,
and hospitalization. Two patients died, one from
a relapse of NMOSD and the other from an in-
determinate CNS cause.
Satralizumab targets the interleukin-6 recep-
tor and thereby inhibits the downstream effects
of interleukin-6; another drug targeting this re-
ceptor, tocilizumab, reduced the risk of relapse
as compared with azathioprine in an open-label,
randomized trial.51 Two trials of satralizumab for
the treatment of patients who have NMOSD with
or without AQP4-IgG have been completed, one
of which allowed concurrent immunosuppres-
sive therapy.52,53 Efficacy was achieved only in the
seropositive groups in the two studies, with a 74%
and a 79% reduction in relapse risk, and no deaths
or cancers occurred.
Considerations in selecting one of the recently
approved preventive therapies include efficacy,
problems with current treatment (side effects or
lack of a response), safety, frequency and route
of administration, potential for adherence, effect
on vaccine response, planning for conception,
drug access, and cost. Several drugs appear to be
relatively safe when taken during pregnancy, but
the data are limited.30 Aside from confirmation
of eligibility on the basis of AQP4-IgG–seroposi-
tive status, there are no biomarkers that facilitate
drug selection.
Extension studies for approved drugs have
not identified major additional safety concerns
and have shown low relapse rates, but inferences
about sustained efficacy and long-term risks are
limited because these studies were unblinded for
the participants and investigators, observations
have been uncontrolled, and the longest extension
study followed treated patients for a mean of 4 to
5 years.54,55 Monitoring of AQP4-IgG titers or le-
sions seen on MRI is not currently recommended
for therapeutic decision making, but serum bio-
markers such as glial fibrillary acidic protein are
being studied for confirming or predicting clin-
ical relapse.56 Breakthrough relapses usually
prompt changes in therapy, possibly a switch to
637
 The n e w e ng l a n d j o u r na l of m e dic i n e

a drug with a different mechanism of action, but Sum m a r y

a consensus definition of treatment failure and
more data are needed. Combination therapy, other
immunosuppressive agents, and autologous stem-
cell transplantation57 have been considered for
treatment-refractory disease. Indefinite treatment
is recommended for NMOSD with AQP4-IgG,
since retrospective data suggest that stopping pre-
ventive therapies leads to high relapse rates.58
Research on new treatments, guided by an
understanding of the pathobiologic features of
NMOSD, is focused on approaches to the resto-
ration of immune tolerance; inhibition of AQP4-
IgG binding or pathogenicity; targeting of the ef-
fects of complement, granulocytes, and microglia;
and neuroprotection.59,60
The canonical clinical features of neuromyelitis
optica have been supplemented by other charac-
teristic syndromes and the finding of pathogenic
AQP4-IgG autoantibodies. The expanded disease
spectrum, NMOSD, is treated with drugs that tar-
get the steps in pathogenesis. Promising approach-
es to predicting and preventing relapses, enhanc-
ing recovery from relapse, and achieving immune
tolerance are under investigation.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Mr. Seth Lambert and Mr. Bryce Bergene, Mayo
Clinic, for assistance with earlier versions of the figures.

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