REVIEW ARTICLE


NMOSD and MOGAD
C O N T I N UU M A UD I O By Elia Sechi, MD
I NT E R V I E W A V AI L A B L E
ONLINE
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ABSTRACT
OBJECTIVE: This article reviews the clinical features, MRI characteristics,
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diagnosis, and treatment of aquaporin-4 antibody–positive neuromyelitis

optica spectrum disorder (AQP4-NMOSD) and myelin oligodendrocyte
glycoprotein antibody–associated disease (MOGAD). The main differences
between these disorders and multiple sclerosis (MS), the most common
demyelinating disease of the central nervous system (CNS), are also
highlighted.

LATEST DEVELOPMENTS: The past 20 years have seen important advances in

understanding rare demyelinating CNS disorders associated with AQP4 IgG
and myelin oligodendrocyte glycoprotein (MOG) IgG. The rapidly
expanding repertoire of immunosuppressive agents approved for the
treatment of AQP4-NMOSD and emerging as potentially beneficial in
CITE AS: MOGAD mandates prompt recognition of these diseases. Most of the
CONTINUUM (MINNEAP MINN)
2024;30(4, AUTOIMMUNE
recent literature has focused on the identification of clinical and MRI
NEUROLOGY):1052–1087. features that help distinguish these diseases from each other and MS,
simultaneously highlighting major diagnostic pitfalls that may lead to
Address correspondence to misdiagnosis. An awareness of the limitations of currently available assays
Dr Elia Sechi, Viale San Pietro 10,
07100 Sassari, Italy, for AQP4 IgG and MOG IgG detection is fundamental for identifying rare
eliasechi87@gmail.com. false antibody positivity and avoiding inappropriate treatments. For this
RELATIONSHIP DISCLOSURE:
purpose, diagnostic criteria have been created to help the clinician
Dr Sechi has received speaker interpret antibody testing results and recognize the clinical and MRI
honoraria and/or support for phenotypes associated with AQP4-NMOSD and MOGAD.
attending scientific meetings
from Alexion Pharmaceuticals
Inc, F. Hoffman-La Roche Ltd, ESSENTIAL POINTS:An awareness of the specific clinical and MRI features
Horizon Therapeutics plc, associated with AQP4-NMOSD and MOGAD and the limitations of currently
Novartis AG, and UCB S.A; serves
as an editorial board member for available antibody testing assays is crucial for a correct diagnosis and
BMC Neurology and Frontiers in differentiation from MS. The growing availability of effective treatment
Neurology; and is a member of
options will lead to personalized therapies and improved outcomes.
the medical advisory board of
The MOG Project.

UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE: INTRODUCTION

T
Dr Sechi discusses multiple he detection of antibodies directed against the aquaporin-4 (AQP4)
therapies for the treatment and
water channel and myelin oligodendrocyte glycoprotein (MOG) in
prevention of myelin
oligodendrocyte glycoprotein patients with certain demyelinating syndromes of the central nervous
antibody–associated disease system (CNS) defines two distinct disease entities named AQP4
attacks, none of which are
approved by the US Food and
antibody–positive neuromyelitis optica spectrum disorder (AQP4-
Drug Administration (FDA). NMOSD) and MOG antibody–associated disease (MOGAD). Despite their
overall rarity, identifying these disorders in clinical practice is crucial since they
© 2024 American Academy differ substantially from multiple sclerosis (MS), the most common
of Neurology. demyelinating disease of the CNS, especially in treatment and outcomes. As these

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 autoimmune disorders are associated with antibodies targeting cell-surface KEY POINTS
proteins, they are typically characterized by a weak paraneoplastic association,
● Aquaporin-4 (AQP4) IgG is
wide range of affected ages, and favorable response to immunosuppressive considered to be directly
therapy. Other than being a useful diagnostic biomarker, AQP4 IgG is considered pathogenic and studies are
to be directly pathogenic, and studies are emerging to suggest that MOG IgG has emerging to suggest that
the potential to be pathogenic. These represent major differences from MS, myelin oligodendrocyte
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glycoprotein (MOG) IgG has

which lacks a specific antibody biomarker and has substantially different the potential to be
pathophysiologic mechanisms leading to CNS damage. The expanding repertoire pathogenic, which
of effective treatments available against AQP4 NMOSD and MOGAD warrants a represents a major
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deep understanding of their pathophysiology and clinical MRI manifestations to difference from multiple
sclerosis (MS), which lacks a
ensure prompt recognition and appropriate treatment. This article summarizes
specific antibody biomarker
the current understanding of AQP4-NMOSD and MOGAD, starting with their and has substantially
characteristic features, and discusses the most recent diagnostic criteria and different pathophysiologic
treatment advances. MS is frequently used as a comparator disease to better mechanisms leading to
central nervous system
appreciate the distinctive clinical and MRI characteristics of AQP4-NMOSD
(CNS) damage.
and MOGAD.
● Both AQP4 IgG and MOG
History and Definitions IgG are predominantly of the
The term neuro-myélite optique aiguë (“acute optic neuromyelitis”) was first used IgG1 subclass and thus able
to activate complement,
by the French neurologist Eugène Devic in 1894 to describe a novel syndrome although complement
characterized by the rapid development of severe optic neuropathy and myelopathy. activation seems
The new syndrome, named neuromyelitis optica (NMO), entered the neurologic significantly more efficient
lexicon after the description of MS by Jean-Martin Charcot in 1868, and for years was when induced by AQP4 IgG.
considered one of its more aggressive variants. In 2004, Vanda Lennon, Brian
Weinshenker, and colleagues1 from the Mayo Clinic published a seminal discovery
describing a novel serum antibody biomarker associated with NMO but not
detectable in patients with MS. The antibody, initially termed generically NMO IgG,
was then found to target the main CNS water channel AQP4 and was renamed AQP4
IgG. The discovery of AQP4 IgG allowed for the first clear dissection of the umbrella
term MS in distinct demyelinating CNS disorders, driving the transition from clinical
and MRI syndromes to etiologic diagnoses. It soon became clear that the spectrum of
clinical and MRI manifestations associated with AQP4 IgG was not limited to the
“pure” NMO phenotype, but many patients presented with partial forms of the
disease (eg, isolated or recurrent myelitis or optic neuritis). Brain involvement was
also found to occur, and area postrema syndrome (characterized by intractable
nausea, vomiting, or hiccups) was recognized as the third most common
manifestation of the disease. In 2015, diagnostic criteria for NMOSD were released to
formalize all of the possible clinical and MRI manifestations associated with AQP4
IgG.2 The criteria also introduced the possibility of a “seronegative NMOSD” to
facilitate diagnosis in patients with unknown AQP4 IgG serostatus, if strict clinical
and MRI requirements are met. However, the new seronegative NMOSD syndrome
was not specific and other antibodies were found to share the same clinical and MRI
phenotype, particularly MOG IgG, which was detectable in 25% to 50% of patients
with seronegative NMOSD.3
The scientific interest in the MOG protein began in the mid-1980s when it was
first highlighted as a major antibody target in experimental autoimmune
encephalomyelitis. In 2007, O’Connor and colleagues4 showed that assays
expressing MOG in its natural conformation delineated a strong association
between MOG IgG and non-MS demyelinating CNS syndromes, particularly
acute disseminated encephalomyelitis (ADEM). Other studies confirmed the

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 NMOSD AND MOGAD

association of MOG IgG with ADEM and other non-MS demyelinating CNS
syndromes testing negative for AQP4 IgG, including isolated myelitis, optic
neuritis, brain and brainstem syndromes, or combinations thereof. The spectrum
of clinical and MRI manifestations associated with MOG IgG is now known as
MOGAD and extends far beyond the seronegative NMOSD phenotype.5
However, after the discovery of AQP4 IgG and MOG IgG, a proportion of
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non-MS demyelinating CNS syndromes remain seronegative for both antibodies

despite sharing similar clinical MRI features, suggesting that other antibodies
associated with CNS demyelination might be identified in the future.
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PATHOPHYSIOLOGY
Both AQP4 IgG and MOG IgG are predominantly of the IgG1 subclass and thus
able to activate complement, although complement activation seems
significantly more efficient when induced by AQP4 IgG.6 Antibody production is
mainly mediated by T helper 17 (Th17) lymphocytes and interleukin 6 (IL-6),
which represent a major therapeutic target in both diseases.7 The AQP4 water
channel is mostly expressed on astrocytic end feet where it plays a key role in
regulating water homeostasis and preventing glutamate accumulation at neuronal
excitatory synapses. It is expressed in the CNS in two isoforms, M1 and M23, which
randomly assemble in tetramers. The tetramers with greater representation of the
M23 isoform tend to aggregate in supramolecular structures called orthogonal
arrays of particles, which represent a favorable substrate for AQP4 IgG binding
and complement activation because of the high AQP4 density. Orthogonal arrays
of particles seem to be more represented in optic nerves and the spinal cord, which
are preferential target sites in the disease. AQP4 IgG–mediated complement
activation results in both direct cytotoxicity via the formation of the membrane
attack complex and abundant recruitment of inflammatory cells (mostly
neutrophils and eosinophils). This inflammatory infiltrate contributes to tissue
damage via antibody-dependent cytotoxicity, which also affects surrounding
neurons and oligodendrocytes. Astrocytic dysfunction further enhances neuronal
loss indirectly through glutamate excitotoxicity. This pathophysiologic sequence is
in line with the large necrotic lesions that can be observed in patients with AQP4-
NMOSD. Findings in 2022 also suggest that silent water accumulation due to
AQP4 dysfunction can be detected on MRI before clinical attacks.8
MOG is selectively expressed in the CNS on the outermost myelin layers and
oligodendrocytes, where it represents approximately 0.05% of total myelin
proteins. The exact mechanisms through which MOG IgG exerts its pathogenic
effect remain unclear, but MOGAD lesions are characterized by confluent white
matter and intracortical demyelination, prominent CD4+ T-cell and granulocytic
inflammation, partial axonal preservation, complement deposition, and reactive
gliosis.9,10 These lesions are less destructive when compared with those related to
AQP4 IgG, where astrocytic and axonal loss is more pronounced. A detailed
description of the pathophysiology of the two diseases has been summarized
elsewhere.11,12

EPIDEMIOLOGY
Epidemiologic studies of AQP4-NMOSD and MOGAD are still scarce and have
mostly been conducted on predominantly White populations in Europe and the
United States. Overall, AQP4-NMOSD has a higher prevalence in females
compared with males (9:1 ratio)13 and different prevalence across racial and

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 ethnic groups,13-15 although the reason for this difference, such as the effects of KEY POINT
differential access to diagnosis or the effect of social determinants of health, is
● AQP4 antibody–positive
currently unknown. The reported annual incidence of MOGAD ranges between neuromyelitis optica
1 to 4.8 per million people and seems twice as common compared with AQP4- spectrum disorder (AQP4-
NMOSD among White people. AQP4-NMOSD is rare before age 18 years in NMOSD) has a higher
predominantly White populations (<5% of total AQP4-NMOSD cases), although prevalence in females
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compared with males (9:1

the frequency of pediatric cases increases to up to 21% in other ethnic ratio) and different
populations. On the contrary, children represent approximately 25% to 50% of prevalence across racial and
total incident cases of MOGAD. Prior studies reported a higher mortality rate ethnic groups, although the
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among Black patients with AQP4-NMOSD, potentially attributable to a more reason for this difference,
such as the effects of
severe disease course, a younger age of symptom onset, or unequal access and
differential access to
utilization of healthcare facilities and treatments.16 diagnosis or the effect of
social determinants of
CLINICAL AND MRI CHARACTERISTICS health, is currently
unknown.
The clinical and MRI manifestations of AQP4-NMOSD and MOGAD are
heterogeneous, and their relative frequency and type differ with age and
according to the phase of the disease (eg, acute attacks versus remission). Clinical
attacks in AQP4-NMOSD and MOGAD typically develop subacutely over days to
a few weeks, although acute onset within 24 hours is possible. Symptoms are
generally severe and accompanied by large demyelinating lesions on MRI that are
rarely seen in MS and allow an initial distinction, although overlap may rarely
occur. The predominant involvement of optic nerves (often in a recurrent or
bilateral fashion) and the spinal cord (with myelitis lesions typically extending
for greater than three contiguous vertebral body segments) represents a hallmark
of AQP4-NMOSD and MOGAD.17 TABLE 4-1 compares the main clinical,
laboratory, and MRI features in AQP4-NMOSD, MOGAD, and MS, and
FIGURES 4-1, 4-2, 4-3, 4-4, and 4-5
18 19,20
show examples of the typical distribution
and characteristics of MRI abnormalities in the optic nerves, brain, and spinal
cord in the three disorders.

Disease Attacks in AQP4-NMOSD

Unlike the original description by Devic and Gault, only a minority of patients
with AQP4-NMOSD develop simultaneous or rapidly sequential involvement of
the spinal cord and optic nerves (NMO phenotype). Patients generally present
with isolated myelitis or optic neuritis, whereas onset with isolated area postrema
syndrome, other brain and brainstem syndromes, or combinations of the above-
mentioned manifestations is only seen in less than 30% of cases.

OPTIC NEURITIS. Optic neuritis in AQP4-NMOSD can be unilateral or bilateral.

MRI frequently shows selective involvement of the posterior optic pathway
including the chiasm and optic tracts (FIGURE 4-1A and 4-1B), which often
translates into normal fundoscopy and less frequent orbital pain compared with
MOGAD and MS.21,22 Patients generally report severe visual loss or blindness in
one or both eyes, but bitemporal or homonymous hemianopia is also possible
with chiasmal involvement.22

MYELITIS. The myelitis related to AQP4 IgG represents the most common cause of
isolated or recurrent longitudinally extensive myelitis of acute or subacute onset
in clinical practice.23,24 Paraplegia or tetraplegia are not infrequent at nadir,
although milder forms are possible. On MRI, it is typically accompanied by a

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 NMOSD AND MOGAD

TABLE 4-1 Comparison of the Demographic, Clinical, Laboratory, and MRI

Characteristics of AQP4-NMOSD, MOGAD, and Multiple Sclerosis

AQP4-NMOSD MOGAD Multiple sclerosis

Demographics
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Most common age at 30-50 0-40 20-40

onset (years)
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Onset age < 18 years Rare Common Infrequent

Sex (F:M) 9:1 1:1 3:1

Clinical features

Antecedent infection Infrequent Common Infrequent

or immunization

Disease course Generally relapsing (>90%); a Relapsing (50%) or monophasic Relapsing, secondary
progressive course is rare (50%); a progressive course is progressive or primary
rare progressive

Optic neuritis Common (unilateral or bilateral) Common (often bilateral) Common (often unilateral)

Myelitis Common Common Common

Area postrema Common Rare Rare

syndrome

Encephalopathy Rare Common (especially in Rare

children)

Seizures Rare Common with ADEM or Rare

cortical encephalitis
phenotype

CSF findings

Oligoclonal bands <20% (transient) <20% (transient) >85% (persistent)

White cell count 13% to 35% 35% Rare

>50/μl

MRI of acute attacks

Optic neuritis Mainly posterior segments Long lesions (>50%), mainly Short lesions, mainly along the
including chiasm anterior segments, perineural intraorbital tract
enhancement

Myelitis Longitudinally extensive (85%) Longitudinally extensive (60% Multiple short lesions;
single lesion; bright spotty to 80%), often coexisting with periphery of cord; ring or
lesions of T2 hyperintensity; short lesions; conus nodular enhancement
elongated ring or patchy frequently involved; H-sign
enhancement in most cases axially; acute enhancement in
50% of patients

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 CONTINUED FROM PAGE 1056

AQP4-NMOSD MOGAD Multiple sclerosis

Brain or brainstem Often nonspecific; Large “fluffy” lesions affecting Small ovoid periventricular,
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periventricular regions more both white and gray matter; infratentorial, or juxtacortical
affected, mostly area cortical hyperintensity may T2 lesions; central vein sign is
postrema; extensive white occur; enhancement in 50% of specific; ring or nodular
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matter lesions may sometimes cases and is typically enhancement

occur nonspecific; ring
enhancement is rare

Initially normal brain Possible (approximately 10% of Possible (up to 10% of brain or Rare
and spine MRI brain or myelitis attacks) myelitis attacks)

Postattack MRI

T2 lesion resolution Rare 50% to 80% Rare

New asymptomatic T2 Rare Rare Commona

lesion accumulation

Residual T1 Rare Infrequent Common

hypointensity

Persistent acute Rare Rare Rare

gadolinium
enhancement
>6 months

Clinical recovery

Optic neuritis Risk for poor recovery Generally good Generally good

Myelitis Risk for poor recovery Good motor recovery but risk Generally good but spinal cord
of residual sphincter or lesions and attacks increase
erectile deficit the risk of disease progression

Brain or brainstem Good recovery from area Generally good; risk of residual Generally good
attacks postrema attacks; risk of worse cognitive deficit in patients
recovery from attacks in other with recurrent encephalitis
brain regions

ADEM = acute disseminated encephalomyelitis; AQP4-NMOSD = aquaporin-4 antibody–positive neuromyelitis optica spectrum disorder;
MOGAD = myelin oligodendrocyte glycoprotein antibody–associated disease.
a
The accumulation of new asymptomatic T2 lesions on MRI over time is part of the natural history of the disease, but the probability of detecting
these lesions is very low in patients treated with highly effective treatments for MS (and similar to that of AQP4-NMOSD and MOGAD).

single, longitudinally extensive T2 lesion over the cervical spinal cord, upper
thoracic spinal cord, or both, whereas the involvement of the conus is
uncommon.25 Short myelitis lesions related to AQP4 IgG can be observed in 14%
of cases, mostly when the spine is imaged during lesion growth or resolution, and
may represent a diagnostic challenge.26
T2 lesions in these patients generally affect the entire cross-sectional area of
the spinal cord on axial images, sometimes resulting in marked parenchymal
swelling that can mimic a neoplasm (FIGURE 4-3A). Intralesional spots of higher
T2 hyperintensity similar to that of the surrounding CSF (“bright spotty lesions”)
can be detected in approximately 50% of cases and are highly suggestive of

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FIGURE 4-1
Representative examples of optic nerve abnormalities on MRI in aquaporin-4 antibody–
positive neuromyelitis optica spectrum disorder (AQP4-NMOSD), myelin oligodendrocyte
glycoprotein antibody–associated disease (MOGAD), and multiple sclerosis (MS). Orbital MRI
findings on T2-weighted images (first column) and post-gadolinium T1-weighted images
(second column) are compared among the three diseases. The typical distribution of
gadolinium enhancement in each type of optic neuritis is also schematically shown in the
corresponding diagrams (third column). In particular, optic neuritis in patients with AQP4-
NMOSD typically affects the posterior optic pathway with frequent T2 hyperintensity of the
chiasm (A), which enhances after gadolinium administration (B, arrow). In patients with
MOGAD, the optic neuritis is generally bilateral at onset with optic nerve T2 hyperintensity (C)
and abnormalities extending for greater than 50% of the nerve length (C), and prominent
enhancement of the optic nerve sheath (D) that extends to the perineural tissue. Lastly, optic
neuritis T2 lesions in MS are typically short (E) and sometimes accompanied by homogeneous
enhancement of the affected optic nerve segment (F, arrow).
MRI images reprinted with permission from Sechi, et al., Front Neurol.3 © 2022 Frontiers Media S.A.
Illustrations courtesy of Laura Cacciaguerra, MD, PhD, and Eoin P. Flanagan, MBBCh, FAAN.

AQP4 IgG–related myelitis (FIGURE 4-3B).27 Gadolinium enhancement is seen in

more than 90% of patients acutely, often at the lesion periphery with a ring or
elongated ring pattern (FIGURE 4-3C and 4-3D).28 Patients with AQP4 IgG–
related myelitis develop painful tonic spasms in up to 25% of cases, sometimes
after the acute phase of the myelitis. These are defined as paroxysmal,
stereotyped painful tonic postures of the limbs lasting 1 to 3 minutes, and usually
respond very well to carbamazepine 300 mg/d to 400 mg/d.29 Respiratory failure
may rarely occur in patients with severe cervical myelitis.30

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 KEY POINTS

● Short myelitis lesions

related to AQP4 IgG can be
observed in 14% of cases,
mostly when the spine is
imaged during lesion
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growth or resolution, and

may represent a diagnostic
challenge.
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● Area postrema syndrome

is the most common brain
manifestation in AQP4-
NMOSD and is defined by
intractable nausea,
vomiting, or hiccups.

FIGURE 4-2
Schematic representation of typical spinal cord MRI abnormalities in patients with
aquaporin-4 antibody–positive neuromyelitis optica spectrum disorder (AQP4-NMOSD),
myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD), and multiple
sclerosis (MS). The illustrations schematically show the typical characteristics and
distribution of demyelinating spinal cord abnormalities for each disorder on T2-weighted
(both sagittal and axial) and postgadolinium T1-weighted images (sagittal only). Patients with
AQP4-NMOSD myelitis typically show a single, longitudinally extensive T2 lesion affecting the
cervical spinal cord, upper thoracic spinal cord, or both. The lesion generally affects the
entire cross-section of the spinal cord axially. After gadolinium administration, lesion
enhancement is typically peripheral, often with an elongated ring pattern on sagittal images.
In MOGAD myelitis, spinal cord lesions often appear fainter and predominantly affect the
central gray matter on axial images (H-sign). Although most lesions are longitudinally
extensive, shorter lesions often coexist, with frequent involvement of the conus medullaris.
Gadolinium enhancement is observed in only 50% of cases and is generally nonspecific.
Lastly, in MS myelitis a single or multiple short lesions, typically localized on the periphery of
the spinal cord, are characteristic. Gadolinium enhancement is generally nodular or ring-like.
Illustrations courtesy of Laura Cacciaguerra, MD, PhD, and Eoin P. Flanagan, MBBCh, FAAN.

AREA POSTREMA SYNDROME. Area postrema syndrome is the most common brain
manifestation in AQP4-NMOSD and is defined by intractable nausea, vomiting,
or hiccups.31 It can be the initial manifestation of the disease in approximately
12% of patients (often leading to inconclusive gastroenterological evaluations)
and ultimately occurs in up to 40% of patients during the disease course.
Symptoms typically last for 48 hours or longer and are accompanied by T2
hyperintensity or enhancement in the region of the area postrema in the dorsal
medulla (FIGURE 4-5A), although brain MRI can be normal in a minority of
patients.

OTHER SYMPTOMS OF BRAIN AND BRAINSTEM DYSFUNCTION. Other symptoms

of brain and brainstem dysfunction may rarely occur in patients with

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FIGURE 4-3
Representative examples of spinal cord abnormalities on MRI in patients with aquaporin-4
antibody–positive neuromyelitis optica spectrum disorder (AQP4-NMOSD), myelin
oligodendrocyte glycoprotein antibody–associated disease (MOGAD), and multiple sclerosis
(MS). For each disorder, T2-weighted and postgadolinium T1-weighted MRI images of the
spinal cord are shown in both the sagittal (top row) and axial (bottom row) planes. The
myelitis related to AQP4 IgG is typically longitudinally extensive and can be accompanied by
marked swelling of the spinal cord (A). Areas of higher T2 hyperintensity similar to that of the
surrounding CSF are frequently seen within the myelitis lesion (“bright spotty lesions”) on
both sagittal (A) and axial (B) images. Gadolinium enhancement typically localizes at the
lesion periphery with a ring or elongated ring pattern (C, D). MOGAD myelitis T2 lesions are
typically fainter and more commonly involve the conus medullaris (E). The preferential
involvement of the central gray matter may resemble an H on axial images (“H-sign,” F).
Although gadolinium enhancement of lesions is observed in only one-half of cases, a subtle
leptomeningeal enhancement is sometimes seen, especially in younger patients (G and H).
Lastly, in MS, T2 lesions are generally short (I) and located at the periphery of the spinal cord
on axial image (J). Gadolinium enhancement is nodular (K, L) or ringlike.
Reprinted with permission from Sechi E and Flanagan EP, Semin Neurol.18 © 2021 Georg Thieme Verlag KG.

AQP4-NMOSD. Brain lesions typically affect the periependymal regions around

the ventricles, where AQP4 expression is higher, or the corticospinal tracts.
Patients may variably show symptoms of brainstem dysfunction (eg,
ophthalmoparesis) or thalamic or hypothalamic dysfunction (eg, narcolepsy,
hypotension, syndrome of inappropriate antidiuretic hormone secretion
[SIADH]). Encephalopathy has been reported in patients with extensive white

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 KEY POINTS

● Optic neuritis associated

with MOGAD is typically
bilateral at onset and can
lead to blindness over
hours to a few days. Most
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patients describe intense

orbital or frontal pain in the
days before the onset of
visual symptoms.
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● MRI can initially be

normal in up to 10% of
patients with MOGAD
despite severe brain
dysfunction, spinal cord
dysfunction, or both.

● Cerebral cortical
encephalitis in patients
with MOGAD is
characterized by the
FIGURE 4-4 subacute onset of seizures
Schematic representation of typical brain MRI abnormalities in patients with aquaporin-4 accompanied by other signs
antibody–positive neuromyelitis optica spectrum disorder (AQP4-NMOSD), myelin and symptoms of cerebral
oligodendrocyte glycoprotein antibody–associated disease (MOGAD), and multiple sclerosis irritation (eg, headache,
(MS). The illustrations schematically show the typical characteristics and distribution of encephalopathy, focal
demyelinating brain abnormalities on fluid-attenuated inversion recovery (FLAIR) sequences neurologic deficits) and
in the three disorders at different levels: medulla (first column), pons (second column), deep fluid-attenuated inversion
gray matter (third column), and lateral ventricles (fourth column). The fifth column shows recovery (FLAIR)
typical patterns of gadolinium enhancement on post-gadolinium T1-weighted sequences. In hyperintensity of the
AQP4-NMOSD, T2 lesions tend to localize near the ventricle surface, starting from the area cortex.
postrema in the dorsal medulla. The corticospinal tract can also be affected, frequently at
the internal capsule level, whereas nonspecific T2 abnormalities scattered throughout the ● After the presenting
hemispheric white matter are common. Areas of linear gadolinium enhancement around the attack, the disease course
ventricles can also be observed, whereas lesion enhancement is often irregular and less is typically relapsing in
characteristic. In MOGAD, T2 abnormalities are typically large with poorly demarcated AQP4-NMOSD, whereas
margins and affect both white and gray matter, including deep gray nuclei and cortex. approximately one-half of
Gadolinium enhancement is generally nonspecific and can be absent in one-half of patients. patients with MOGAD
In patients with cerebral cortical encephalitis, T2 hyperintensity and swelling of the cortex maintain a monophasic
are noted and may be accompanied by enhancement of the meninges overlying the affected course without additional
cortical area. Lastly, in MS, T2 lesions are typically small and ovoid shaped, often abutting the relapses.
surface of the brainstem or ventricles. Gadolinium enhancement often follows a closed or
open ring pattern. ● On MRI, MOGAD lesions
Illustrations courtesy of Laura Cacciaguerra, MD, PhD, and Eoin P. Flanagan, MBBCh, FAAN. resolve completely in 50%
to 70% of cases, whereas
the more destructive
matter abnormalities on MRI (FIGURE 4-5C), sometimes resembling ADEM or attacks related to AQP4 IgG
typically culminate in
posterior reversible encephalopathy syndrome (PRES).32 Gadolinium
residual T2 hyperintensity
enhancement is generally nonspecific, whereas a more characteristic pattern of and atrophy of the
pencil-thin enhancement of the periependymal region around the ventricles is surrounding parenchyma.
sometimes seen (FIGURE 4-5E) and is a useful radiologic discriminator between
MS and MOGAD.33,34 Seizures are uncommon in AQP4-NMOSD.

Disease Attacks in MOGAD

The spectrum of attack phenotypes in MOGAD is broader than in AQP4-
NMOSD, although, as discussed, overlap is not uncommon and differentiation
between the two diseases can sometimes be challenging before receiving

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 NMOSD AND MOGAD

AQP4 IgG and MOG IgG testing results. Children commonly present with
multifocal CNS involvement or ADEM, whereas the frequency of more limited
forms (eg, isolated optic neuritis or myelitis) increases with age. However,
asymptomatic lesions in other CNS regions are common in patients presenting
with clinically isolated optic neuritis or myelitis. Unlike AQP4-NMOSD, the
onset of neurologic symptoms in MOGAD is often preceded by fever, infections,
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or immunizations, and patients may develop a steroid-dependent course (ie,

cluster of rapid exacerbations of clinical MRI disease activity with waning or
withdrawal of corticosteroids). The initial MRI can be unrevealing in up to 10%
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of patients with brain or spinal cord attacks or both, despite severe neurologic
deficit.35,36

OPTIC NEURITIS IN MOGAD. The optic neuritis in MOGAD is typically bilateral at

onset and can lead to blindness over hours to a few days. Most patients describe
an intense orbital or frontal pain in the days before the onset of visual symptoms
(often misreported as headache).37 The anterior optic pathway is predominantly
affected and fundoscopy often reveals optic disc edema, sometimes accompanied
by retinal hemorrhages. On MRI, optic nerves are typically affected for more
than 50% of their length, often showing a characteristic perineural enhancement
that may extend to the surrounding orbital tissue (FIGURE 4-1C and 4-1D).21,38
The optic chiasm can also be affected but typically in association with extensive
involvement of the optic nerves.39 Sometimes patients with optic neuritis
develop a steroid-dependent course meeting the definition of chronic recurrent
inflammatory optic neuritis.

MYELITIS IN MOGAD. The myelitis in MOGAD is longitudinally extensive in

approximately 70% to 80% of cases, but shorter lesions often coexist on MRI,
which is different from the single myelitis lesion typically encountered in AQP4-
NMOSD (FIGURE 4-2). The conus medullaris is frequently affected, often
accompanied by sphincter or sexual dysfunction.40 Spinal cord T2 lesions are
often faint with poorly demarcated margins. The central gray matter is
predominantly affected, resembling the shape of an H (H-sign) axially and
forming a ventral sagittal line of T2 hyperintensity on sagittal images (FIGURE 4-3E
and 4-3F).25 Although highly suggestive of MOGAD, similar lesions can be seen
in patients with acute flaccid paralysis, viral myelitis, or other inflammatory
myelopathies. Unlike AQP4-NMOSD, gadolinium enhancement of myelitis
lesions is only seen in 50% of MOGAD patients acutely and is generally faint and
nonspecific, whereas some patients (more commonly children) may show a
subtle leptomeningeal or nerve root enhancement (FIGURE 4-3G and 4-3H).41-43
MRI can initially be normal in up to 10% of patients with MOGAD despite severe
brain dysfunction, spinal cord dysfunction, or both.35 In these patients,
somatosensory evoked potentials may help confirm the myelopathy, and repeat
MRI after a few days may reveal spinal cord abnormalities.

ADEM OR ADEM-LIKE PHENOTYPE. An ADEM or ADEM-like phenotype is

characterized by clinical MRI evidence of multifocal CNS involvement with or
without encephalopathy. ADEM is a common MOGAD phenotype in children,
although only 50% of pediatric patients with ADEM test positive for MOG IgG.
Patients with MOG IgG–associated ADEM may require ventilatory support at
the nadir due to profound encephalopathy, seizures, or both.30 Autonomic

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FIGURE 4-5
Representative examples of brain abnormalities on MRI in patients with aquaporin-4
antibody–positive neuromyelitis optica spectrum disorder (AQP4-NMOSD), myelin
oligodendrocyte glycoprotein antibody–associated disease (MOGAD), and multiple
sclerosis (MS). Axial fluid-attenuated inversion recovery (FLAIR) (first four columns) and
postgadolinium T1-weighted (fifth column) images of the brain are compared in patients with
AQP4-NMOSD, MOGAD, and MS. The images mostly follow the anatomical distribution
shown in FIGURE 4-4. In patients with AQP4-NMOSD, brain lesions are frequently localized
around the fourth ventricle (A, B), often in the dorsal medulla (area postrema; A, arrowhead ),
but extensive white matter lesions can also be encountered, sometimes involving the
splenium of the corpus callosum (“arch bridge sign,” C). Focal areas of increased T2
hyperintensity along the surface of the lateral ventricles are also common (D, arrow) and can
be accompanied by linear gadolinium enhancement (E, arrow). In patients with MOGAD, T2
lesions are usually large with poorly demarcated margins. Brainstem involvement is common
(F, G), often with diffuse involvement of one or both middle cerebellar peduncles (G), which
is quite characteristic. A faint T2 hyperintensity of the deep gray nuclei is also frequent and is
often asymmetric (H); cortical FLAIR hyperintensity is seen in patients with cerebral cortical
encephalitis (I, bracket), often accompanied by enhancement of the overlying meninges
(J, bracket). Lastly, MS lesions are smaller and typically ovoid shaped, localizing
infratentorially on the brainstem surface or cerebellar hemispheres (K, L) or around the
ventricles perpendicularly oriented compared with the main ventricle axis (M, N).
Juxtacortical lesions are also frequent, often with a characteristic S- or C-shape (N,
arrowhead). Gadolinium enhancement of lesions can be nodular, ringlike (O, arrowhead), or
open-ring shaped (O, arrow).
Panels A, C, and G reprinted with permission from Sechi E and Flanagan EP, in Piquet AL and Alvarez E, eds.,
Neuroimmunology.19 © 2021 Springer Nature.
Panel B reprinted with permission from Sechi, et al, Front Neurol.3 © 2022 Frontiers Media S.A.
Panels I and J reprinted with permission from Valencia-Sanchez C, et al, Ann Neurol.20
© 2023 John Wiley & Sons, Inc.

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 NMOSD AND MOGAD

instability (eg, bradycardia, hypertension) and fever may coexist. Brain MRI
usually shows multiple large, poorly demarcated lesions that can variably affect
white matter, deep gray nuclei, and cortex (FIGURE 4-5F through 4-5I). Solitary
brain lesions are uncommon in MOGAD.44 The corticospinal tracts can
sometimes be affected, often at the internal capsule level. Cases of multiple
confluent white matter lesions resembling a leukoencephalopathy have been
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reported in children.45 When present, acute gadolinium enhancement is

generally nonspecific, although leptomeningeal enhancement is more common
than in MS or AQP4-NMOSD, whereas the ring or open-ring enhancement
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typically seen in MS is very uncommon.34,44 In patients with MOGAD with

encephalitis, brain MRI may initially be normal, resembling other types
of autoimmune encephalitides associated with non-glial antibodies, like
N-methyl-D-aspartate receptor IgG (although coexistence of more antibodies has
been documented).46 The central vein sign, a typical accompaniment of MS
lesions, is generally absent in patients who test positive for AQP4 IgG or
MOG IgG.47
Brainstem or cerebellar dysfunction is common in MOGAD.48 The large
MOGAD T2 lesions often affect the medulla, pons, or midbrain for most of their
axial extent. Unilateral or bilateral involvement of the middle cerebellar peduncle
for its entire thickness is characteristic and rarely seen in AQP4-NMOSD or MS
(FIGURE 4-5G).48 Area postrema–like syndrome may rarely occur in the context
of ADEM but not in association with discrete area postrema lesions.49

CEREBRAL CORTICAL ENCEPHALITIS. Cerebral cortical encephalitis has been

recognized as a rare manifestation of MOGAD.20,50 It is characterized by the
subacute onset of seizures accompanied by other signs and symptoms of cerebral
irritation (eg, headache, encephalopathy, focal neurologic deficits) and fluid-
attenuated inversion recovery (FLAIR) hyperintensity of the cortex. Cortical
hyperintensity is generally unilateral and sometimes accompanied by
enhancement of the overlying meninges (FIGURE 4-5I and 4-5J).20 The acronym
FLAMES (unilateral cortical FLAIR-hyperintense lesions in anti–MOG-
associated encephalitis with seizures) has also been used in the literature to
describe this syndrome.51 The seizures may evolve into status epilepticus and
require ventilatory support.30 Fever and a marked CSF pleocytosis are common
accompaniments. Cerebral cortical encephalitis can occur in isolation or in the
context of other manifestations of the disease (eg, optic neuritis, ADEM).
Common MRI mimics of cerebral cortical encephalitis in MOGAD are infectious
encephalitis or meningitis and CNS vasculitis.

Cerebrospinal Fluid Findings

CSF analysis during attacks helps orient the diagnostic suspicion and exclude
alternative etiologies, particularly infections. Although an inflammatory CSF
(greater than five white blood cells) is common in different demyelinating CNS
disorders, a marked pleocytosis with greater than 50 white blood cells is
extremely rare in MS but can be seen in both AQP4-NMOSD (15% to 35% of
patients) and MOGAD (35% of patients).52,53 CSF white blood cells are typically
lymphocytes, but a proportion of neutrophils and eosinophils can be seen in both
AQP4-NMOSD and MOGAD, with eosinophils being a very uncommon CSF
finding in patients with MS.54 Notably, the frequency of CSF pleocytosis may
vary based on the associated clinical phenotype (eg, less common with isolated

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FIGURE 4-6
Comparison of T2-lesion evolution in the spinal cord between patients with aquaporin-4
antibody–positive neuromyelitis optica spectrum disorder (AQP4-NMOSD), myelin
oligodendrocyte glycoprotein antibody–associated disease (MOGAD), and multiple sclerosis
(MS). Sagittal (top row) and axial (bottom row) T2-weighted images of spinal cord MRI
obtained during acute myelitis attacks and more than 6 months after the acute attack. White
arrows indicate a transition from the initial image to the follow-up image. Note that acute T2
abnormalities related to AQP4 IgG (A and B) show reduction in size at follow-up (C, D, blue
arrows) with atrophy of the surrounding parenchyma. On the contrary, in MOGAD, the
extensive T2 abnormalities seen during the myelitis attack (E and F) typically resolve
completely at follow-up without associated atrophy (G and H). Lastly, the small T2 lesions
associated with MS myelitis (I and J) only show minimal reduction in size at follow-up (K and L)
and persist over time.
Reprinted with permission from Sechi E, et al., Neurology.38 © 2021 American Academy of Neurology.

optic neuritis, more common in patients with extensive CNS inflammation).

Oligoclonal bands are seen in less than 20% of patients with either disease and are
often transient, in contrast with MS in which they are found in approximately
85% of patients and persist over time.

Postattack Recovery, Disease Course, and Disability Accumulation

After the presenting attack, the disease course is typically relapsing in AQP4-
NMOSD, whereas approximately one-half of patients with MOGAD maintain a
monophasic course without additional relapses. Determining which patients
with MOGAD will face a relapsing course with certainty is not possible at

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 NMOSD AND MOGAD
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FIGURE 4-7
Comparison of T2-lesion evolution in the brain between patients with aquaporin-4 antibody–
positive neuromyelitis optica spectrum disorder (AQP4-NMOSD), myelin oligodendrocyte
glycoprotein antibody–associated disease (MOGAD), and multiple sclerosis (MS). The panels
show representative axial fluid-attenuated inversion recovery (FLAIR) images obtained during
different attacks and more than 6 months after the attacks. Arrows indicate a transition from
the initial image to the follow-up image. Attacks involving the infratentorial brain regions are
shown on the left half of the figure, whereas evolution of supratentorial T2 abnormalities is
shown on the right half. In AQP4-NMOSD, two different attacks involving the area postrema
(A, B) and diencephalic region (C, D), respectively, evolve to minimal residual T2 scarring
sometimes accompanied by focal atrophy (B, D, red circles). In MOGAD, extensive T2
abnormalities involving the left cerebellar peduncle (E, F) and cerebral hemispheres
multifocally (G, H) resolve to undetectable at follow-up, or sometimes with some tiny,
nonspecific residual T2 hyperintensity (H, black circle). Lastly, in MS, the small T2
abnormalities detected during acute brain attacks persist over time with only partial
reduction in size at follow-up (I, J [red circle] and K, L [red circle]).
Reprinted with permission from Sechi E, et al., Neurology.38 © 2021 American Academy of Neurology.

present, but the persistence of MOG IgG seropositivity over time seems to
increase the probability of future relapses.55 However, there is still not a
universally accepted definition of “persistent” seropositivity, and the optimal
timing to retest remains unclear in clinical practice.5 Alternative predictors of
relapsing disease course are under study.56 Although clinical attacks are similarly

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 severe in AQP4-NMOSD and MOGAD, recovery from attacks is often different. KEY POINTS
In particular, whereas the risk of incomplete postattack recovery is substantial
● A primary or secondary
with AQP4 IgG, most patients with MOGAD show complete or nearly complete progressive disease course
recovery from attacks and lower disability accumulation over time.57 This is also is extremely rare in AQP4-
reflected by the different evolution of MRI T2 lesions over time. In fact, MOGAD NMOSD and MOGAD, unlike
lesions resolve completely in 50% to 70% of cases, whereas the more destructive MS in which disease
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progression is part of the

attacks related to AQP4 IgG typically culminate in residual T2 hyperintensity and natural history of the
atrophy of the surrounding parenchyma.42,58 Nevertheless, 7% to 10% of patients disease.
with MOGAD will show a poor outcome at their last follow-up, which is not
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predictable at disease onset and highlights the importance of attack prevention in ● An accurate diagnosis of
AQP4-NMOSD and MOGAD
both diseases.57 Representative examples of T2-lesion evolution over time in
requires the demonstration
AQP4-NMOSD, MOGAD, and MS are shown in FIGURE 4-6 and FIGURE 4-7. of AQP4 IgG or MOG IgG
A primary or secondary progressive disease course is extremely rare in positivity with a reliable
AQP4-NMOSD and MOGAD, unlike in MS in which disease progression is part assay in the presence of a
of the natural history of the disease despite less severe disease relapses.57,59 compatible clinical MRI
phenotype.
This contrast is in line with the different pathophysiology of MS in which
silent CNS inflammation may persist chronically between attacks, leading to ● Because isolated CSF
important structural and functional alterations that are not expected in positivity may rarely occur
AQP4-NMOSD and MOGAD.60 The accumulation of new asymptomatic MRI with MOG IgG, CSF testing
should be considered in
lesions over time, a main characteristic of MS that is commonly monitored to patients who are
seronegative with strong
diagnostic suspicion.

● AQP4 IgG testing by

cell-based assay is usually
very reliable, with a
reported specificity of
approximately 100% for
both fixed and live cell-
based assays, and has a
minimal risk of false-
positive results even when
the pretest probability is
low.

● Indiscriminate MOG IgG

testing in populations with
low pretest probability in
which the disease is poorly
represented is not
recommended because it
inevitably increases the risk
of false-positive results.

● False MOG IgG positivity

is typically low titer and can
occur in both serum and
CSF, whereas high-titer
FIGURE 4-8 MOG IgG positivity is highly
Schematic comparison of the different disease courses and patterns of disability predictive of MOGAD.
accumulation in patients with aquaporin-4 antibody–positive neuromyelitis optica spectrum
disorder (AQP4-NMOSD), myelin oligodendrocyte glycoprotein antibody–associated disease
(MOGAD), and multiple sclerosis (MS). The four panels schematically show the different
disease courses typically observed in the three diseases and the change in Expanded
Disability Status Scale (EDSS) score over time.
PPMS = primary progressive multiple sclerosis; RRMS = relapsing-remitting multiple sclerosis; SPMS =
secondary progressive multiple sclerosis.

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 NMOSD AND MOGAD

evaluate disease activity and treatment efficacy in this disease, is uncommon in

AQP4-NMOSD and MOGAD.61 The different disease courses and patterns of
disability accumulation in AQP4-NMOSD, MOGAD, and MS are compared in
FIGURE 4-8.

DIAGNOSIS
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A correct diagnosis of AQP4-NMOSD and MOGAD requires demonstration of

AQP4 IgG or MOG IgG positivity with a reliable assay, in the presence of a
compatible clinical and MRI phenotype. For this purpose, an awareness of the
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available testing assays and potential pitfalls that can be encountered during the
diagnostic workup is fundamental to avoid misdiagnosis.

Antibody Testing
Cell-based assays represent the methodology of choice for both AQP4 IgG and
MOG IgG detection. These assays use cell lines transfected with plasmids
encoding the AQP4 and MOG proteins, which are subsequently expressed on the
cell membrane. The target antigens are recognized by antibodies in the serum or
CSF of patients, marked with a secondary fluorescent antibody. The degree of
fluorescence can then be assessed visually with a fluorescence microscope or by
flow cytometry to determine antibody positivity. Cell-based assays using live
cells are the most accurate as they express the antigens in their natural
conformation, although the availability of these assays is usually limited to
specialized laboratories. Commercial cell-based assays are more widely available
but use fixed transfected cells in which the natural conformation of the target
proteins can be altered by the fixation process, hampering antigen recognition by
the antibodies with slight reduction in sensitivity and specificity. Alternative
assays using denatured target proteins (eg, ELISA) are significantly less accurate
because antigen fragmentation may result in false antibody-epitope bindings that
would not naturally occur or the loss of conformational binding sites that are no
longer recognized by the antibody. These assays bear an unacceptable risk of
false-positive and false-negative results and should be avoided in clinical
practice. Serum testing is generally preferred for both AQP4 IgG and MOG IgG
because of the higher sensitivity, although some exceptions exist.62,63 In patients
evaluated for a new-onset demyelinating CNS disorder, serum and CSF samples
should be ideally obtained and stored (if possible) before treatment is initiated,
because it can alter antibody test results. In patients with a strong diagnostic
suspicion and a negative test result, repeat testing in specialized laboratories on
stored samples obtained acutely is reasonable. Repeat testing over time (eg, after
1 to 2 years) may also be considered in highly suspected cases as seroconversion
to positivity after an initially negative test result may occur in both diseases in a
minority of patients.64 Serum positivity for AQP4 IgG usually persists over time
with minimal titer fluctuations,64 which facilitates the diagnosis in patients
evaluated years after disease onset. Conversely, patients with MOG IgG may
become seronegative over time, which may limit the diagnosis outside of the
acute setting.55 Most patients with MOGAD show MOG IgG positivity in both
serum and CSF, but isolated CSF positivity occurs in approximately 10% of
patients with MOGAD.65-68 Hence, CSF testing should be considered in
seronegative patients with strong diagnostic suspicion, as illustrated in CASE 4-1.
Moreover, findings in 2023 suggest that patients with MOG IgG seropositivity
might have more severe clinical syndromes with worse outcomes in the setting of

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 concomitant CSF positivity (compared with patients with isolated serum
positivity), which might justify combined serum and CSF testing at baseline.65
CSF testing is not recommended with AQP4 IgG as isolated CSF positivity is not
expected to occur in patients with AQP4-NMOSD.

Antibody False Positives and Risk of Misdiagnosis

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False or clinically irrelevant antibody positivity may rarely occur if the test is
performed in low-probability situations or when suboptimal testing assays are
used. AQP4 IgG testing by cell-based assay is usually very reliable, with a
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reported specificity of approximately 100% for both fixed and live cell-based
assay and a minimal risk of false-positive results even when the pretest
probability is low.69 Despite similar specificity, live cell-based assays have higher
sensitivity than fixed cell-based assays, with a lower risk of falsely negative
results. The risk of false AQP4 IgG positivity and AQP4-NMOSD misdiagnosis
becomes meaningful when non–cell-based assays are used (eg, ELISA).70 The
reported specificity of live and fixed cell-based assays for MOG IgG detection is
99% and 97% to 98%, respectively.62,71 Despite the high specificity, false MOG
IgG positivity may occur if the test is performed indiscriminately in large
unselected populations.71 This is because of the rarity of the disease in the
population, particularly when compared with other demyelinating CNS
disorders (eg, MS is 50 to 80 times more common than AQP4-NMOSD and
MOGAD among White people). For instance, the frequency of MOG IgG
positivity among patients with MS ranges from 0.3% to 2.5%, making this a low-
risk population with a low pretest probability.5 On the contrary, MOG IgG
frequency in children with ADEM is approximately 50%, which translates into a
high pretest probability. Indiscriminate MOG IgG testing in populations with low
pretest probability in which the disease is poorly represented is not
recommended because it inevitably increases the risk of false-positive results.71
MS is generally the most common alternative diagnosis in patients with false
MOG IgG positivity.71,72 This observation reflects the common misstep of
ordering antibody testing in all patients with new-onset demyelinating CNS
diseases, in which MS is highly represented, in an attempt to rule out AQP4-
NMOSD and MOGAD. In reality, MOG IgG testing should only be requested for
patients with compatible clinical MRI characteristics and when more common
alternative etiologies have been ruled out to minimize the risk of misdiagnosis.73
False MOG IgG positivity is typically low titer and can occur in both serum and
CSF, whereas high-titer MOG IgG positivity is highly predictive of MOGAD.66,71
However, a low-titer positivity does not necessarily imply that the result is false
because it may occur in patients with MOGAD, especially if the test is performed
after treatments that can reduce antibody titer (eg, corticosteroids, plasma
exchange).
CSF testing may also help identify false-positive results because isolated serum
positivity (with negative CSF test) is significantly more common in patients with
false MOG IgG positivity and only occurs in a minority of patients with
MOGAD.68 The pathophysiologic significance of false MOG IgG positivity
remains unclear. Possible explanations include epitope spreading in the context
of other neurologic disorders (MOG IgG is typically not found in patients
without known neurologic disorders) or fluctuations of MOG IgG titer across the
positivity threshold. Despite these assay challenges, AQP4 IgG and MOG IgG are
excellent diagnostic biomarkers and extremely useful in clinical practice.

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 NMOSD AND MOGAD

CASE 4-1 A 27-year-old woman developed subacute left facial palsy in a nuclear
pattern and was treated at home with dexamethasone 8 mg/d for 5 days
with no improvement. She had a 6-year history of relapsing-remitting
multiple sclerosis with recurrent short myelitis, sometimes severe
(Expanded Disability Status Scale [EDSS] score of 6 reported in one of her
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previous evaluations), despite treatment with interferon beta and

glatiramer acetate. Her last spinal cord MRI documented the resolution
of some of the previously detected spinal cord lesions. A prior CSF
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analysis reported the absence of oligoclonal bands. Her EDSS score at

her last neurologic follow-up was 4.
One week later, she developed left hypoacusis, gait instability, and
right optic neuritis (could count fingers only at nadir). She was treated
with IV methylprednisolone (1 g/d for 5 days) with improvement. One
week after that, she developed contralateral optic neuritis and severe
tetraparesis for which she was admitted to the hospital. MRI revealed
extensive T2 hyperintensities in the pons, left middle cerebellar
peduncle, and left midbrain (FIGURE 4-9A and 4-9B) with patchy gadolinium
enhancement (FIGURE 4-9C), and multiple longitudinally extensive
spinal cord lesions (FIGURE 4-9D and 4-9E). She was treated with IV
methylprednisolone and plasma exchange with improvement but
relapsed several times during the subsequent 2 months with a steroid-
dependent course. Aquaporin-4 (AQP4) IgG and myelin oligodendrocyte
glycoprotein (MOG) IgG were absent in serum (live cell-based assay). CSF
testing for MOG IgG was positive, and she was diagnosed with MOG
antibody–associated disease (MOGAD). Rituximab was initiated with
clinical MRI stabilization. At her last follow-up 4 years later, the patient
continued to use a wheelchair and required bladder catheterization due
to residual myelopathy and spinal cord atrophy (FIGURE 4-9F and 4-9G).

COMMENT This is a rare case of isolated CSF positivity for MOG IgG. The patient’s
history of MS with recurrent short myelitis was initially not clearly
suggestive of MOGAD, although the reported severity of certain myelitis
attacks, absence of CSF oligoclonal bands, and resolution of some of the
T2 lesions over time are in retrospect compatible with the disease. The
patient eventually developed a severe, steroid-dependent cluster of
demyelinating attacks involving the central nervous system multifocally
that was strongly suggestive of MOGAD and prompted MOG IgG testing in
the CSF. Unfortunately, clinical recovery was poor due to severe spinal
cord atrophy, consistent with recent findings suggesting that isolated CSF
positivity for MOG IgG may be associated with worse outcomes.

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FIGURE 4-9
Imaging of the patient in CASE 4-1. Arrows indicate a transition from the initial image to the
follow-up image. Axial brain MRI revealing extensive T2 hyperintensities in the pons and left
middle cerebellar peduncle (A and B) with patchy gadolinium enhancement (C). Sagittal spinal
cord MRI revealing multiple longitudinally extensive T2 lesions (D and E). Follow-up MRI
images after the attack show residual T2 hyperintensity at lesion levels (F and G),
accompanied by marked spinal cord atrophy in the thoracic cord (yellow bracket).

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 NMOSD AND MOGAD

Diagnostic Criteria
Diagnostic criteria have been published that can guide the clinician through the
interpretation of diagnostic test results and clinical and MRI phenotypes.2,5 The
diagnostic criteria for AQP4-NMOSD and MOGAD are summarized in
TABLE 4-2 and TABLE 4-3, respectively. Diagnostic criteria for seronegative
NMOSD are not discussed in this article.
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DIAGNOSIS OF AQP4-NMOSD. The diagnosis of AQP4-NMOSD requires a

demonstration of serum positivity for AQP4 IgG, using the best available assay,
CX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 09/22/2024

in patients with at least one of the six core clinical manifestations of the disease:
(1) optic neuritis, (2) myelitis, (3) area postrema syndrome, (4) other brainstem
syndromes, (5) narcolepsy or other diencephalic syndromes associated with
typical AQP4-NMOSD lesions on brain MRI, and (6) cerebral syndromes
associated with typical AQP4-NMOSD lesions on brain MRI. The criteria also
emphasize the need to exclude alternative diagnoses that could better explain the
clinical MRI manifestations, which is especially relevant when AQP4 IgG
positivity is demonstrated by using suboptimal testing assays (eg, ELISA).

DIAGNOSIS OF MOGAD. A correct diagnosis of MOGAD requires demonstration

of a clear MOG IgG positivity by cell-based assay, in the presence of at least one
of the six core clinical manifestations of the disease: (1) optic neuritis, (2)
myelitis, (3) ADEM, (4) cerebral monofocal or polyfocal deficit without

TABLE 4-2 Diagnostic Criteria for AQP4-NMOSDa

The diagnosis of AQP4-NMOSD requires the fulfillment of criteria A, B, and C

A At least one of the following core clinical manifestations of the disease
1 Acute or subacute optic neuritis
2 Acute or subacute myelitis
3 Area postrema syndrome, defined as an otherwise unexplained episode of hiccups, nausea,
or vomiting lasting for ≥48 hours and that do not recede with symptomatic medications
4 Acute or subacute brainstem syndrome
5 Symptomatic narcolepsy or acute diencephalic clinical syndrome with diencephalic MRI
lesions typical of AQP4-NMOSD around the third ventricle
6 Symptomatic cerebral syndrome with brain MRI lesions typical of AQP4-NMOSD
(extensive white matter lesions around the lateral ventricles)
B AQP4 IgG positivity: demonstration of AQP4 IgG positivity in serum with the best available
assay; cell-based assays (live cell-based assays are preferred over fixed cell-based
assays) are highly recommended because of the unacceptably high risk of false-positive
results with other techniques; CSF antibody testing is not routinely recommended unless
serum testing is not available or might have been altered by specific treatments (eg,
rituximab) and should be interpreted with caution
C Exclusion of alternative diagnoses: see TABLE 4-4 for red flags commonly associated with
misdiagnosis

AQP4-NMOSD = aquaporin-4 antibody–positive neuromyelitis optica spectrum disorder.

a
Modified with permission from Wingerchuk DM, et al., Neurology.2 © 2015 American Academy of Neurology.

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 encephalopathy, (5) brainstem or cerebellar syndromes, and (6) cerebral cortical
encephalitis. Note that, given the risk of false antibody positivity, the MOGAD
criteria request a demonstration of MOG IgG positivity exclusively by cell-based
assay (ie, other assays are not accepted). A clear MOG IgG positivity is defined
by an antibody titer of at least two doubling dilutions above the specific assay
positivity cutoff for live cell-based assays, or a titer of 1:100 or greater with fixed
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cell-based assays. In case of weaker evidence of MOG IgG positivity (ie, lower
antibody titer, titer not available, or isolated CSF positivity), the criteria require
the presence of at least one supporting clinical or MRI feature and a negative test
CX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 09/22/2024

for AQP4 IgG (TABLE 4-3). Like the AQP4-NMOSD criteria, a final diagnosis of
MOGAD mandates the exclusion of more convincing alternative diagnoses.
TABLE 4-4 lists common red flags that help distinguish alternative etiologies in
patients with suspected AQP4-NMOSD or MOGAD. It must be noted that both
sets of diagnostic criteria strongly rely on the correct interpretation of different
clinical and MRI findings by the clinician, acknowledging the risk of
interobserver variability. As an example, the distinction between typical MS
lesions and lesions related to AQP4-NMOSD or MOGAD may not always be
straightforward, and the degree of expertise of the individual clinician becomes
fundamental. For this reason, consultation with experts in demyelinating CNS
disorders is advised if there is doubt when interpreting the diagnostic criteria.

MANAGEMENT
FIGURE 4-10 shows a schematic algorithm summarizing the recommended
diagnostic and therapeutic approach to patients with new-onset demyelinating
CNS disorder, with a focus on AQP4-NMOSD and MOGAD.

Treatment of Acute Attacks

Prompt acute-treatment initiation for disease attacks is fundamental in AQP4-
NMOSD and MOGAD because treatment delay has been associated with poorer
recovery and worse outcomes. The following treatment options are valid in both
diseases unless otherwise specified.

HIGH-DOSE CORTICOSTEROIDS. High-dose corticosteroids are the mainstay for the

treatment of any type of CNS demyelinating attack. Patients are generally treated
with IV methylprednisolone 1 g daily for 5 to 7 days, which can be followed by 1 g
weekly for 6 to 12 weeks, based on symptom recovery. Although generally well
tolerated, relatively common complications of corticosteroid treatment include
disturbances of blood glucose levels or blood pressure and steroid-induced
psychosis (more common in older individuals). A taper with oral corticosteroids
can be considered after the acute treatment of MOGAD attacks to avoid
symptom recrudescence that can occur with steroid waning or withdrawal in this
disease.74 After the 5- to 7-day cycle of IV methylprednisolone, patients are
started on oral prednisone (1 mg/kg/d or 50 mg/d to 75 mg/d) and the full dosage
can be maintained for a few weeks to up to 12 weeks, followed by a slow taper
(eg, 5 mg every 2 weeks until withdrawal). However, some may consider no oral
steroid taper as most patients will not have an early relapse, and corticosteroid
use beyond a few weeks has significant morbidity, particularly in children.75
Further studies are needed to better determine the best approach to steroid
tapering after attacks. The initiation of a long-term immunosuppressant can be
considered in the meantime.

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 NMOSD AND MOGAD

PLASMA EXCHANGE. Plasma exchange has increasingly gained popularity for the
treatment of AQP4-NMOSD and MOGAD over the past decade.76 Plasma
exchange sessions are typically planned on alternate days, for a total of five to
seven sessions, and can be done in association with corticosteroids, preferably
scheduling the corticosteroid infusion soon after the plasma exchange session.
Several studies have shown the benefit of early plasma exchange initiation within
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days in both AQP4-NMOSD and MOGAD.76,77 However, in clinical practice,

AQP4 IgG and MOG IgG serostatuses are often unknown or not readily available
for many patients at disease presentation, which may lead the clinician to wait for
CX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 09/22/2024

antibody test results before starting plasma exchange. In reality, the efficacy of
plasma exchange for treating severe attacks of CNS demyelination was proven in
a pivotal randomized, sham-controlled, double-masked clinical trial in 1999,
before the discovery of AQP4 and MOG antibodies.78 Thus, in patients
presenting with severe disability from an acute attack of CNS demyelination,
plasma exchange should be considered early (eg, day 3 or 4 after IV

TABLE 4-3 Diagnostic Criteria for MOGADa

The diagnosis of MOGAD requires fulfillment of A, B, and C

A) At least one of the following 1 Acute or subacute optic neuritis

core clinical manifestations of
the disease 2 Acute or subacute myelitis

3 ADEM, defined as acute or subacute polyfocal neurologic deficits with encephalopathy

accompanied by multifocal T2 lesions on MRI

4 Cerebral monofocal or polyfocal deficits without encephalopathy

5 Acute or subacute brainstem or cerebellar deficits

6 Cerebral cortical encephalitis with seizures, defined as MRI evidence of FLAIR cortical
hyperintensity often with enhancement of the overlying meninges, accompanied by
cerebral irritability (eg, encephalopathy, headache, focal neurologic deficit) in addition
to seizures

B) MOG IgG positivity by cell- Clear serum MOG IgG positivity, No additional supporting features
based assay defined as: 1) at least two doubling required
dilutions above the assay-specific cutoff,
titer cutoff, or flow cytometry ratio cutoff by
live cell-based assay; or 2) titers of ≥1:100
by fixed cell-based assay

Low serum MOG IgG positivity, The following additional items are
defined as low-range positivity by live required:
cell-based assay or titers between
1:10 and 1:100 by fixed cell-based 1 Negative test for AQP4 IgG
assay 2 At least 1 supporting clinical or MRI
feature
Serum MOG IgG positivity with unknown
or not reported titer

Isolated MOG IgG positivity in CSF

CONTINUED ON PAGE 1075

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 methylprednisolone initiation) and regardless of antibody serostatus, possibly in
association with corticosteroids. Plasma exchange is usually safe, although it may
rarely induce hypotension, so caution is advised in patients with cardiac disease.
Neurologic worsening after the initiation of corticosteroid treatment or plasma
exchange is a major red flag and should prompt considering alternative diagnoses
while waiting for antibody testing results. Typical examples include a
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myelopathy due to dural arteriovenous fistulas, which can worsen after

corticosteroids, and rare infectious myelopathies (eg, intramedullary spinal cord
abscess). Spinal cord infarction can also potentially worsen in the case of plasma
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exchange–induced hypotension.70

INTRAVENOUS IMMUNOGLOBULIN. Intravenous immunoglobulin (IVIg) can be

considered mostly on an empiric basis because evidence to support its efficacy
for the treatment of acute attacks of CNS demyelination is scarce and
limited to retrospective studies.79 Patients are generally treated at a dosage

CONTINUED FROM PAGE 1074

The diagnosis of MOGAD requires fulfillment of A, B, and C

Supporting clinical and MRI Optic neuritis Bilateral simultaneous clinical

features involvement

Optic nerve involvement for >50% of the

nerve length on MRI

Perineural optic sheath enhancement on

MRI

Optic disc edema

Myelitis Longitudinally extensive spinal cord

lesion on MRI

Central cord lesion or H-sign

Conus lesion

Brain or brainstem syndrome Multiple ill-defined T2 hyperintense

lesions in supratentorial and often
infratentorial white matter

Deep grey matter involvement

Ill-defined T2 hyperintensity involving

pons, middle cerebellar peduncle, or
medulla

Cortical lesion with or without lesional

and overlying meningeal enhancement

C) Exclusion of alternative See Table 4-4 for red flags commonly associated with misdiagnosis
diagnoses including MS

ADEM = acute disseminated encephalomyelitis; AQP4 = aquaporin-4; FLAIR = fluid-attenuated inversion recovery; MOG = myelin oligodendrocyte
glycoprotein; MOGAD = myelin oligodendrocyte glycoprotein antibody–associated disease; MS = multiple sclerosis.
a
Modified with permission from Banwell B, et al, Lancet Neurol.5 © 2022 Elsevier Ltd.

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 NMOSD AND MOGAD

TABLE 4-4 Red Flags Suggestive of an Alternative Diagnosis in Patients With AQP4 IgG
or MOG IgG Positivity

Clinical features and disease course

◆ Progressive disease course, either from onset (primary progressive course) or after an
initial period of relapsing disease activity (secondary progressive course); consider MS,
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spinal cord sarcoidosis, or metabolic or genetic etiologies (eg, vitamin B12 deficiency,
adrenoleukodystrophy)
◆ Hyperacute presentation (<4 hours); consider stroke or ischemic damage (eg, spinal cord
CX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 09/22/2024

infarction, ischemic optic neuropathy)

◆ Concomitant peripheral neuropathy; can rarely be found in patients with AQP4-NMOSD
and MOGAD and its significance is unclear; consider other causes of myeloneuropathy or
encephalomyeloneuropathy (eg, other autoimmune or paraneoplastic neurologic
disorders, metabolic or genetic conditions)
◆ Comorbidities that can have similar manifestations, particularly sarcoidosis and cancer
(potential for both direct and indirect CNS involvement as paraneoplastic syndrome)
CSF findings
◆ CSF-restricted oligoclonal bands; consider MS or sarcoidosis
MRI
◆ Brain abnormalities typical of MS
◇ Ovoid periventricular lesions in the hemispheric white matter (perpendicularly oriented to
the main ventricle axis), brainstem, or cerebellar hemispheres
◇ Linear or S-shaped juxtacortical lesions
◇ Ring or open-ring enhancement
◆ Spinal cord abnormalities typical of MS
◇ Multiple, short (fewer than three contiguous vertebral body segments) lesions
peripherally located on axial images (commonly along the dorsal and lateral columns),
often accompanied by focal atrophy
◇ Ring or open-ring enhancement
◆ Development of new asymptomatic brain or spine lesions over time; consider MS
◆ Lack of lesion resolution over time (uncommon in MOGAD)
◆ Central vein sign; consider MS
◆ Persistence of gadolinium enhancement of lesions for >6 months; consider sarcoidosis,
neoplasms, or spondylotic myelopathy
Serology
◆ AQP4 IgG low positivity detected with ELISA
◆ Borderline or low MOG IgG titer; these should be interpreted based on the clinical MRI
phenotype (also see supportive diagnostic criteria); consider repeat testing, preferably
with a more accurate assay (eg, live versus fixed cell-based assay)
Other
◆ Lack of response to acute treatment with corticosteroids and plasma exchange
◆ Other clinical MRI findings suggestive of alternative diagnosis (eg, blood or
microhemorrhages on MRI, positive screening for infections in serum or CSF)

AQP4 = aquaporin-4; AQP4-NMOSD = aquaporin-4 antibody–positive neuromyelitis optica spectrum

disorder; CNS = central nervous system; ELISA = enzyme-linked immunosorbent assay; MOG = myelin
oligodendrocyte glycoprotein; MOGAD = myelin oligodendrocyte glycoprotein antibody–associated
disease; MS = multiple sclerosis.

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 of 0.4 g/kg/d for 5 consecutive days. Treatment with IVIg might be considered KEY POINTS
in cases of incomplete recovery after corticosteroids and plasma exchange,
● Given the risk of false
and then protracted as maintenance therapy in patients with MOGAD (see antibody positivity, the
the Maintenance Treatments for Attack Prevention section). IVIg is used in MOGAD criteria request the
practice more commonly in children. Common complications of IVIg demonstration of MOG IgG
administration include headache and increased blood pressure during positivity exclusively by
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cell-based assay (ie, other

infusions. assays are not accepted).

RESCUE THERAPIES. Rescue therapies may rarely be necessary in severe cases ● Prompt acute-treatment
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refractory to high-dose corticosteroids, plasma exchange, or IVIg. Reasonable initiation for disease attacks
is fundamental in AQP4-
options for both diseases with an expected rapid response include IL-6 receptor
NMOSD and MOGAD as
inhibitors (eg, tocilizumab) and cyclophosphamide,80 whereas complement treatment delay has been
inhibitors (eg, eculizumab) can also be considered in AQP4-NMOSD. B cell– associated with poorer
depleting agents (eg, rituximab) may require a longer amount of time to become recovery and worse
fully effective. Improvement after autologous hematopoietic stem cell outcomes.

transplantation in super-refractory cases has also been reported.81 ● A taper with oral
corticosteroids can be
Maintenance Treatments for Attack Prevention considered after the acute
Long-term treatment of the two diseases aims to prevent relapses and disability treatment of MOGAD
attacks to avoid symptom
accumulation. Although the need for relapse prevention is clear in patients with recrudescence that can
AQP4-NMOSD in whom the risk of relapses after the presenting attack is nearly occur with this disease.
universal, the same is not true for MOGAD. As previously mentioned, a relapsing
disease course is observed in only one-half of patients with MOGAD and most ● In patients presenting
with severe disability from
patients recover completely or nearly completely from attacks, making the
an acute attack of CNS
decision on whom and when to treat more challenging. Moreover, no drugs demyelination, plasma
have yet been approved for relapse prevention in MOGAD, although preliminary exchange should be
results from ongoing clinical trials are promising. A commonly used approach to considered early and
patients with MOGAD is to evaluate the degree of recovery from the presenting regardless of antibody
serostatus.
attack and, if complete, propose that the patient wait for a second attack before
starting long-term immunosuppression. In the meantime, periodic ● Periodic measurements
measurements of MOG IgG titer might be informative as conversion of MOG IgG titer can be
to a seronegative state reduces the risk of future relapses. On the contrary, informative because
conversion to a seronegative
if recovery from the presenting attack is incomplete, the early initiation of state reduces the risk of
long-term attack-prevention treatment may be preferred to prevent further future relapses.
disability. However, in this uncertain context, it becomes clear that an
adequate discussion with the patient on available treatment options becomes ● Worldwide, rituximab is a
commonly used treatment
fundamental.
for AQP4-NMOSD, with
For a full review of available treatment options for AQP4-NMOSD and effective relapse prevention
MOGAD, treatment dosing, treatment-related side effects, and treatment during in approximately 60% to 70%
pregnancy, refer to the article “Therapeutic Approach to Autoimmune of patients.
Neurologic Disorders” by Stacey L. Clardy, MD, PhD, FAAN and Tammy L.
● Intravenous
Smith, MD, PhD,82 in this issue of Continuum, in addition to dedicated articles on immunoglobulin (IVIg) can
this topic.3,11,83-86 Four types of drugs have been proven effective for relapse be a reasonable treatment
prevention in AQP4-NMOSD by randomized clinical trials: rituximab (anti- option for attack prevention
CD20),87 inebilizumab (anti-CD19),88 satralizumab and tocilizumab (anti-IL-6),89-91 in pediatric patients with
MOGAD or in patients with a
and eculizumab and ravulizumab (anti-C5).92,93 Of these treatments, higher risk of infections for
satralizumab, inebilizumab, and eculizumab are currently US Food and Drug whom avoiding
Administration (FDA) approved in the United States (CASE 4-2). In MOGAD, immunosuppression is
multiple drugs are under development (eg, Fc receptor inhibitors, IL-6 receptor preferable.
blockers) for the treatment of this disease given the different pathophysiology.

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 NMOSD AND MOGAD

The main available treatment options for relapse prevention in the two diseases
are summarized below.

RITUXIMAB. Worldwide, rituximab is a commonly used treatment for

AQP4-NMOSD, with effective relapse prevention in approximately 60% to 70%
of patients. It is an intravenously administered CD20 monoclonal antibody.
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The initial induction is with either two 1-g infusions 2 weeks apart or 375 mg/m2
of body surface area weekly for 4 consecutive weeks. Reinfusions at the
same dose or lower doses (eg, a single 1-g reinfusion; two consecutive reinfusions
CX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 09/22/2024

of 375 mg/m2 of body surface 1 week apart) can be offered at fixed 6-month
intervals or when the proportion of CD19+ or CD27+ cells exceeds the
threshold of 1% and 0.05% of total lymphocytes, respectively.94 The two
administration regimens are similarly effective with fixed preplanned infusions
ensuring better compliance, whereas retreating based on CD19+ or CD27+
percentage levels results in a lower total amount of infusions (patients
are typically retreated after a median of 10 months with this approach).
Prolonged B-cell depletion for years may rarely occur.95 In patients with
MOGAD, rituximab was initially shown to be less effective compared with
AQP4-NMOSD, although findings in 2023 suggest that the drug may be
similarly effective when patients with similar annualized relapse rates are
compared.96

ECULIZUMAB. Eculizumab is a monoclonal antibody directed against the C5

complement protein that acts by inhibiting the final steps of the complement
pathway. It is administered intravenously with an induction phase of 1 month
(900 mg weekly for 4 consecutive weeks); then, the dose is increased to 1200 mg
for the fifth week of treatment and then maintained at 1200 mg every 2 weeks.
Ravulizumab is another C5 inhibitor administered intravenously every 8 weeks
(the single doses are weight dependent). Although complement inhibitors have
been shown to be highly effective for relapse prevention in AQP4-NMOSD, these
drugs have not been studied in patients with MOGAD.

SATRALIZUMAB. Satralizumab is an IL-6 receptor monoclonal antibody

administered by subcutaneous injections of 120 mg. After an induction of 1 dose
every 2 weeks for the first 4 weeks (3 total doses in the first month), the drug is
reinjected every 4 weeks. Satralizumab has been proven effective for the
treatment of AQP4-NMOSD89,91 and is now being studied for relapse prevention
in patients with MOGAD.

TOCILIZUMAB. Tocilizumab is another IL-6 receptor inhibitor administered

intravenously at a dose of 8 mg/kg every 4 weeks, which was proven superior to
azathioprine in preventing AQP4-NMOSD relapses in a phase 2 trial.90
Tocilizumab appeared safe and potentially effective for relapse prevention in
MOGAD in a retrospective observational study, but prospective randomized,
placebo-controlled trial data is lacking.7

INEBILIZUMAB. Inebilizumab is an intravenously administered CD19 monoclonal

antibody. After an induction phase with 300 mg 2 weeks apart, the drug is
reinfused at fixed 6-month intervals. Unlike CD20 inhibitors (eg, rituximab),
inebilizumab acts on a broader spectrum of B cells, including antibody-

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FIGURE 4-10
Suggested diagnostic steps toward the diagnosis and treatment of patients with new-onset
demyelinating CNS disorders, with a focus on aquaporin-4 antibody–positive neuromyelitis
optica spectrum disorder (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein
antibody–associated disease (MOGAD). The flow chart shows the recommended steps to
follow during the evaluation of patients with new-onset demyelinating CNS disorders, with
particular attention to the diagnostic testing for AQP4 IgG and MOG IgG and the risk of
misdiagnosis. The most common acute and long-term treatment options are also shown.
AQP4 = aquaporin-4; CBA = cell-based assay; CIS = clinically isolated syndrome; CNS = central nervous
system; IL-6 = interleukin 6; IVIg = intravenous immunoglobulin; IVMP = intravenous methylprednisolone
infusions; MOG = myelin oligodendrocyte glycoprotein; MOGAD = myelin oligodendrocyte glycoprotein
antibody–associated disease; MRI = magnetic resonance imaging; MS = multiple sclerosis; NMOSD =
neuromyelitis optica spectrum disorder; PLEX = plasma exchange; RIS = radiologically isolated syndrome.
a
Consider repeat antibody testing with a better assay (if available) or after 3 months, if the diagnostic
suspicion is high.

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 NMOSD AND MOGAD

CASE 4-2 A 44-year-old woman was admitted to the hospital after the acute onset
of paraparesis, left arm paresthesia, and urinary retention. A T10 sensory
level was also present. Spinal cord MRI showed two short T2
hyperintense lesions at the C3 to C5 and T9 to T10 levels, respectively,
with associated ringlike gadolinium enhancement (FIGURE 4-11A and 4-11B).
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Brain MRI revealed a focal area of T2 hyperintensity around the posterior

horn of the right lateral ventricle with associated thin peripheral
enhancement (FIGURE 4-11C and 4-11D). CSF analysis was unremarkable,
CX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 09/22/2024

including the absence of oligoclonal bands. She was treated with IV

methylprednisolone (1 g/d for 5 days) with improvement. Testing for
aquaporin-4 (AQP4) IgG came back positive in serum (fixed cell-based
assay) and a diagnosis of AQP4 antibody–positive neuromyelitis optica
spectrum disorder (AQP4-NMOSD) was made. She was started on
rituximab with initial clinical MRI stability. After 16 months from rituximab
initiation, she developed painful tonic spasms, weakness of the left
upper and lower limbs, and severe gait instability (Expanded Disability
Status Scale [EDSS] score of 6). Spinal cord MRI showed a longitudinally
extensive spinal cord lesion (FIGURE 4-11E) with associated peripheral
gadolinium enhancement. She was treated with a new cycle of IV
methylprednisolone and plasma exchange (six total exchanges on
alternate days) with improvement. She was also started on
carbamazepine 400 mg/d with a resolution of painful tonic spasms. Given
the disease reactivation under rituximab, eculizumab was initiated after
meningococcal vaccination. There were no further clinical relapses or
disease activity. At her last follow-up 21 months later, her EDSS score was
3.5 and her spinal cord MRI showed some residual T2 hyperintensity in
the dorsal cervical spinal cord (FIGURE 4-11F).

COMMENT This case represents a rare presentation of AQP4-NMOSD with short myelitis
lesions, likely detected because of early acquisition of MRI images at the
beginning of T2 lesion formation. Short myelitis lesions are seen in 14% of
patients with AQP4-NMOSD myelitis and can represent a diagnostic challenge
when detected at disease onset because of their similarity with MS (including
the presence of ring enhancement). In this case, the characteristic MRI T2
abnormalities around the ventricular surface with thin linear gadolinium
enhancement, in the absence of other brain lesions suggestive of MS and
oligoclonal bands in the CSF, prompted testing for AQP4 IgG. The patient
eventually developed a more typical, longitudinally extensive myelitis
during the disease course. Acute attacks of AQP4-NMOSD are generally
treated with high-dose IV methylprednisolone (1 g/d for 5 to 7 days), but
plasma exchange should be started concomitantly if symptoms are severe,
as observed in this case for the second attack. Rituximab is a reasonable
first option for relapse prevention but may fail in approximately 30% of
cases, prompting a switch to a more effective agent with an alternative
mechanism of action (eg, eculizumab, ravulizumab, or satralizumab). Painful
tonic spasms are common with AQP4 IgG–associated myelitis and typically
respond well to carbamazepine 150 mg to 200 mg 2 times a day.

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Downloaded from http://journals.lww.com/continuum by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCyw
CX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 09/22/2024

FIGURE 4-11
Imaging of the patient in CASE 4-2. Sagittal spinal cord MRI revealing two short T2 hyperintense
lesions at the C3 to C5 (A) and T9 to T10 (not shown) levels with associated ringlike gadolinium
enhancement (B). Axial brain MRI revealing a focal area of T2 hyperintensity around the
posterior horn of the right lateral ventricle (C) with associated thin peripheral enhancement
(D [arrow]). Sagittal spinal cord MRI revealing a longitudinally extensive spinal cord lesion (E)
with associated peripheral gadolinium enhancement. Sagittal spinal cord MRI revealing
some residual T2 hyperintensity in the dorsal cervical spinal cord (F). Arrow from panel
E to panel F indicates the transition from acute to follow up MRI.

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 NMOSD AND MOGAD

producing plasmablasts and plasma cells. Inebilizumab has not been studied for
the treatment of MOGAD.

PERIODIC INTRAVENOUS IMMUNOGLOBULIN INFUSIONS. Periodic IVIg infusions have

shown promise for relapse prevention in MOGAD medications in retrospective
studies.97 After an initial loading dose of 0.4 g/kg/d for 5 days, IVIg is generally
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reinfused monthly with a variable dose that ranges from 0.4 g/kg to 2 g/kg. A
commonly used protocol is with reinfusions of 1 g/kg. IVIg can be a reasonable
treatment option for attack prevention in pediatric patients with MOGAD or
CX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 09/22/2024

patients with a higher risk of infections for whom avoiding immunosuppression

is preferable.

ORAL IMMUNOSUPPRESSANTS. Oral immunosuppressants such as azathioprine and

mycophenolate mofetil have shown promise as potentially moderately effective
medications in preventing relapses in both diseases and can be considered when
other more effective treatment options are unavailable. These drugs typically
require 3 to 6 months to become fully effective so concomitant treatment with
oral corticosteroids is usually prescribed.

OTHER DRUGS. Other drugs currently under clinical evaluation or development

include inhibitors of the neonatal Fc receptor in MOGAD (a trial with
rozanolixizumab is currently ongoing for relapse prevention) and aquaporumab
in AQP4-NMOSD. The latter is a humanized monoclonal antibody targeting the
AQP4 water channel but with a modification at the Fc fragment that does not
allow complement activation, making the antibody harmless but able to compete
with AQP4 IgG binding sites.

CONCLUSION
Our understanding of AQP4-NMOSD and MOGAD has rapidly increased over
the past decade. These rare antibody-mediated demyelinating disorders of the
CNS differ from MS in clinical and MRI characteristics, diagnostic-therapeutic
approaches, and outcomes. Published diagnostic criteria2,5 help clinicians
interpret clinical and MRI phenotypes and antibody testing results, although
subspecialty consultation is advisable when in doubt to avoid misdiagnosis and
inappropriate treatment. The number of available treatment options is
expanding with important differences between the two diseases, and according
to patient age and comorbidities, which highlights the need for a personalized
approach.

ACKNOWLEDGEMENT
The author would like to thank Dr Eoin Flanagan for being an extraordinary and
inspiring mentor.

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