FranaganNMO-MOGAD (1)

Updates in NMOSD and
MOGAD Diagnosis and

Tre a t m e n t
A Tale of Two Central Nervous System
Autoimmune Inflammatory Disorders
a a,b,
Laura Cacciaguerra, MD, PhD , Eoin P. Flanagan, MB, BCh *
KEYWORDS
AQP4-IgG MOG-IgG Diagnosis Treatment
myelin oligodendrocyte glycoprotein MOG aquaporin-4
neuromyelitis optica spectrum disorder
KEY POINTS
The recognition of aquaporin-4-IgG positive neuromyelitis optica spectrum disorder
(AQP41NMOSD) and myelin-oligodendrocyte glycoprotein antibody-associated disease
(MOGAD) as distinct disorders led to separate diagnostic criteria for each.
AQP4-IgG is highly specific for NMOSD diagnosis at any titer. In contrast, caution is
needed with low-titer myelin-oligodendrocyte glycoprotein-IgG (MOG-IgG), which can
be encountered with other diseases.
Recognition of the MRI features of AQP41NMOSD and MOGAD is helpful because there
are important discriminators between each other and multiple sclerosis.
Maintenance treatment should be started after the first attack in AQP41NMOSD but is
generally not started until the second attack in MOGAD given the latter can have a mono-
phasic course in more than half of cases.
Studies elucidating the pathophysiology of AQP41NMOSD led to the development of
proven targeted treatments in AQP41NMOSD, and similar analyses in MOGAD are under-
way in an attempt to develop attack-prevention treatments in that disease.
INTRODUCTION
Aquaporin-4-IgG positive neuromyelitis optica spectrum disorder (AQP41NMOSD)

and myelin-oligodendrocytes glycoprotein antibody-associated disease (MOGAD)
a
Department of Neurology, Mayo Clinic Center for Multiple Sclerosis and Autoimmune
Neurology, Mayo Clinic, Rochester, MN, USA; b Laboratory Medicine and Pathology, Mayo
Clinic, Rochester, MN, USA
* Corresponding author. Department of Neurology, 200 1st street SW, 55905, Rochester, MN,
USA
E-mail address: Flanagan.Eoin@mayo.edu
Neurol Clin 42 (2024) 77–114

https://doi.org/10.1016/j.ncl.2023.06.009 neurologic.theclinics.com
0733-8619/24/ª 2023 The Authors. Published by Elsevier Inc. This is an open access article under
the CC BY license (http://creativecommons.org/licenses/by/4.0/).
78 Cacciaguerra & Flanagan
are recently identified antibody-mediated autoimmune disorders of the central ner-

vous system (CNS).1,2
Biomarkers of these diseases are antibodies targeting the aquaporin-4 (AQP4) wa-
ter channel on the astrocyte end-feet in AQP41NMOSD3 and myelin-oligodendrocyte
glycoprotein (MOG) on the outermost myelin sheath layer in MOGAD.4
For a long time, the clinical and radiological overlaps have hampered the recognition
of these two diseases as separate entities. Initially, these disorders were considered
variants of multiple sclerosis (MS), given their similar predilection for the optic nerve
and spinal cord. Later, after the discovery of the AQP4-IgG, it was recognized that
some patients with an NMOSD phenotype were negative for AQP4-IgG. After the dis-
covery of MOG-IgG, it became apparent that some of these AQP4-IgG seronegative
NMOSD cases were positive for MOG-IgG. However, the phenotype of MOGAD is
much broader than that of NMOSD and only a minority of patients with MOGAD ful-
filled NMOSD criteria.5 Moreover, recent investigations have highlighted substantial
prognostic differences in terms of relapse-risk and disability accrual during the dis-
ease course, supporting a separate pathophysiology for each. There are also impor-
tant differences in demographic, clinical, radiologic, and pathologic features that
resulted in the need for separate criteria for MOGAD from NMOSD. This ultimately
led to the publication of separate diagnostic criteria for MOGAD in 2023 to capture
these patients and no longer label them as seronegative NMOSD.1
Epidemiology of AQP41NMOSD and MOGAD

AQP41NMOSD and MOGAD are rare disorders. The estimated annual incidence of
AQP41NMOSD is 0.4 to 7.3/million people6,7; it is largely unknown in MOGAD,
although a few European studies estimated it at 1.6 to 3.4/million people.8,9 AQP41N-
MOSD mainly affects middle-aged women (40–60 years, 9:1 female to male ratio)6,7
with a predilection for Afro-Caribbean or Asian individuals.6,7 MOGAD incidence has
a biphasic behavior, with a peak of incidence in children (reported up to 3 times
higher)9 and later in young adults (20–30 years).10–12 No clear sex preference or
high-risk ethnicities have been identified in MOGAD thus far.
Pathophysiology of AQP41NMOSD and MOGAD

Similar to most autoimmune disorders, the first step of the pathophysiological
cascade is represented by an unknown mechanism of loss of self-tolerance, which oc-
curs in the periphery. B cells differentiate into antibody-producing plasmablasts that
secrete the pathological autoantibodies that eventually enter the CNS.13,14 Antibody
production and entry into the CNS may be facilitated by high levels of a proinflamma-
tory cytokine called interleukin-6 (IL-6), which increases blood–brain barrier perme-
ability and promotes differentiation of B cells into plasmablasts to enhance
antibody-production.15 Alternatively, CNS regions free of the blood–brain barrier,
such as the area postrema, may be another route of entry, especially in AQP41N-
MOSD. However, intrathecal MOG-IgG production is reported in MOGAD but not
AQP41NMOSD.16–20
Other major differences in pathophysiology emerge once the respective antibodies
reach the CNS. AQP4-IgGs bind to the water channel on astrocytes at the blood–brain
barrier.3 The binding between the antibody and its target activates the classical
pathway of the complement cascade, with primary damage to the astrocytes through
the formation of the membrane attack complex and antibody-dependent cellular
cytotoxicity.13 Meanwhile, secondary products of complement activation, such as
the C5a anaphylatoxin, act as a chemoattractant for granulocytes, which are locally
NMOSD and MOGAD Diagnosis and Treatment 79
recruited and cause secondary axonal loss and eventually demyelination in bystander
tissue.13
This pathogenesis is supported by pathology findings in AQP41NMOSD showing:
(1) antibody and complement deposition, (2) astrocyte damage or loss (even outside of
lesioned tissue) with reduced AQP4 expression, (3) granulocyte infiltration, and (4)
secondary demyelination and axonal loss in the white matter and gray matter.21
The mechanism of CNS damage has yet to be fully elucidated in MOGAD. One
reason is that human MOG-IgG do not usually cross-react with rodent MOG, making
studies of animal models more challenging. The selective loss of MOG is also incon-
sistent in human pathology samples,22,23 raising doubts on the pathogenicity of MOG-
IgG. However, MOG-IgG pathogenicity was supported by using the small proportion
of MOG-IgG that does cross-react to MOG rodent epitopes, showing that intrathecal
MOG-IgG induces a similar disease to humans in murine models.24
According to the most recent hypothesis, in the CNS the binding between MOG-IgG
and myelin may lead to increased local production of IL-6 and B-cell activating factor
(BAFF), with recruitment of CD41 T cells and macrophages that will ultimately damage
neurons and oligodendrocytes.14 Complement may also contribute to MOGAD patho-
physiology, as supported by preclinical models,25 evidence of complement deposition
with antibody-dependent cellular phagocytosis on pathology samples22,23,26 and
higher activation of both the classic and alternative complement pathways in patients
than healthy individuals.27 However, complement activation seems less effective with
MOG-IgG than AQP4-IgG, possibly because most patients have bivalent binding
MOG-IgG, which are known to be less effective in complement activation.28 In addition,
MOG-IgGs were able to induce demyelination also by activating the neonatal Fc-
receptor pathway, which enhanced the activation and tissue infiltration by T cells in an-
imal models.29 The involvement of CD41 T cells represents one of the main differences
with MS, where CD81 T cells are usually predominant on pathology samples.22
Cytokine profiling is similar in AQP41NMOSD and MOGAD but different to MS,
showing upregulation of T helper 17-related and some T helper 1-related molecules.30
Differences and similarities in AQP41NMOSD and MOGAD pathophysiology are
summarized in Table 1 and graphically shown in Fig. 1.
AQP4DNMOSD AND MOGAD DIAGNOSIS

Summary of Core Clinical Manifestations
AQP41NMOSD and MOGAD share several core clinical features, namely the pres-
ence of optic neuritis and myelitis, and are discussed below:
Optic neuritis is associated with variable degrees of visual loss, eye pain wors-
ened by eye movements, and dyschromatopsia. At disease onset, it is the
most common presentation in adult MOGAD (50%–65%)14 and relatively com-
mon in AQP41NMOSD (35%).31 It can occur in isolation, in association with
myelitis, or in the context of acute disseminated encephalomyelitis (ADEM).1,2
In contrast to MS, bilateral simultaneous involvement of the optic nerves is com-
mon in both AQP41NMOSD (17%–82%)32,33 and MOGAD (50%–84%).33,34 Vi-
sual loss at nadir is usually severe with a median visual acuity of hand
movement in AQP41NMOSD and between hand movements and count fingers
in MOGAD.35,36 Clues suggesting a diagnosis of MOGAD may be the presence of
eye pain before the onset of visual loss (often mistaken for headache, especially
in children)37 and evidence of optic disc edema at fundoscopy (86%–90%)11,36
that is often moderate to severe and sometimes accompanied by peripapillary
hemorrhages.36 At follow-up, recovery is usually complete or almost complete
Table 1
Differences and similarities in AQP4DNMOSD and MOGAD pathophysiology
AQP4DNMOSD MOGAD
Targets
Antigen AQP4 MOG
Cell Astrocyte Oligodendrocyte
Site of antibody production
Periphery Yes Yes
CNS No Yes
Cytokines
IL-6 Yes Yes
IL-10 Yes Yes
IL-17a Yes Yes
G-CSF Yes Yes
TNF-alfa Yes Yes
BAFF/APRIL Yes Yes
Effectors of damage
Complement Yes Yes, but less prominent
Cell infiltrates Granulocytes CD41T cells, macrophages/microglia
Outcomes
Neuronal loss Yes Yes, but less severe
Astrocytic damage Yes No
Oligodendrocyte Not prominent Yes
damage
Demyelination Yes Yes
Damage Biomarkers
Neurofilament High (during attacks) High (during attacks)
light chain
GFAP High Normal
Myelin basic protein Normal High
Abbreviations: APRIL, a proliferation-inducing ligand; AQP4, aquaporin-4; AQP41NMOSD,

aquaporin-4-IgG positive neuromyelitis optica spectrum disorder; BAFF, B-cell activating factor;
CD4, cluster of differentiation 4; G-CSF, granulocytes colony-stimulating factor; GFAP, glial fibrillary
acidic protein; IL, interleukin; MOG, myelin oligodendrocyte glycoprotein; MOGAD, myelin oligo-
dendrocyte glycoprotein antibody-associated disease; TNF-alfa, tumor necrosis factor-alfa.
in MOGAD (visual acuity of 20/30 or 20/25),35,36 whereas recovery can be partial

or absent in AQP41NMOSD (median visual acuity of count fingers).35 Residual
permanent blindness in at least one eye (ie, visual acuity of 20/200) is rare in
MOGAD (6%–12%)35,36 and relatively common in AQP41NMOSD (60%–
69%).32,35 However, a proportion of patients with MOGAD (16%)36 may develop
a steroid-dependent chronic form of optic neuropathy, which relapses at steroid-
withdrawal or tapering (chronic relapsing inflammatory optic neuropathy).
Myelitis: these episodes are characterized by acute/subacute onset of motor,
sensory, and autonomic symptoms indicating an involvement of the spinal
cord, including but not limited to para/tetraparesis or plegia, sensory level across
the trunk, Lhermitte’s phenomenon, sphincteric urgency or retention, and sexual
dysfunction. Myelitis is the most common presentation in patients with
Fig. 1. AQP4DNMOSD and MOGAD pathogenesis. AQP41NMOSD: 1. IL-6 promotes the dif-
ferentiation of B cells into AQP4-IgG secreting plasmablasts; 2. AQP4-IgGs reach the blood
stream and cross the blood–brain barrier; 3. AQP4-IgGs bind to AQP4 on astrocytes and acti-
vate the complement cascade through the classical pathway leading to astrocyte damage; 4.
The release of anaphylatoxins after complement activation recruit granulocytes, which will
ultimately damage neurons and eventually, although not primarily, oligodendrocytes (5).
MOGAD: 1. IL-6 promotes the differentiation of B cells into MOG-IgG secreting plasmablasts;
2. MOG-IgGs reach the blood stream and cross the blood–brain barrier but recent evidence
suggest they might also be produced intrathecally; 3. MOG-IgGs bind to MOG on oligoden-
drocytes and activate the complement cascade through the classical pathway leading to oly-
godendrocyte damage; 4. Local inflammation recruits T cells and monocytes/macrophages;
and 5. MOG-IgGs recycling in the blood stream seems to contribute to the persistence of
the mechanism of damage. Figure created with Biorender.com. Abbreviations: AQP4,
aquaporin-4; AQP41NMOSD, aquaporin-4-IgG positive neuromyelitis optica spectrum disor-
der; IL-6, interleukin-6; MOG, myelin oligodendrocyte glycoprotein; MOGAD, myelin oligo-
dendrocyte glycoprotein antibody-associated disease.
AQP41NMOSD (50%)31 but also occurs in 20% to 40% of adult and 15% to 20%
of pediatric MOGAD.14 Similar to optic neuritis, attacks are usually moderate or
severe at nadir, with a median expanded disability status scale (EDSS) of 7.0 in
AQP41NMOSD and 5.5 in MOGAD.38 More than 30% of patients are wheelchair
dependent at nadir in both diseases,39 and there is a potential need for admission
to the intensive care unit for mechanic ventilation due to respiratory failure, espe-
cially in AQP41NMOSD (2%–7%).40,41 In the long term, only 6% to 7% of MO-
GAD compared with 37% to 44% of AQP41NMOSD will need a gait aid.38,39 In
MOGAD, residual sphincteric dysfunction may persist over time in more than
50% of patients with history of myelitis with many requiring ongoing intermittent
urinary catheterization.38 The presence of an accompanying itch,42 or the devel-
opment of painful paroxysmal tonic spasms43 should prompt AQP4-IgG testing
because they are more typical of AQP41NMOSD. In contrast, the presence of
acute flaccid weakness with areflexia may suggest MOGAD and could reflect
the involvement of the anterior gray matter. This presentation may mimic the
acute flaccid myelitis that has been reported to follow enterovirus infection.39
Besides the clinical involvement of the optic nerve and the spinal cord, patients with
AQP41NMOSD and MOGAD can also manifest with symptoms related to infratento-
rial or cerebral involvement:
(Acute) brainstem/cerebellar syndromes: signs or symptoms referable to infra-
tentorial involvement can be observed in both AQP41NMOSD and MOGAD. In
AQP41NMOSD, the area postrema syndrome, characterized by intractable
vomiting or hiccups for days to several weeks, is the most frequent manifestation
of brainstem involvement (16%–60% of patients).1,44 It is usually associated with
a lesion in the area postrema, sometimes representing the extension of a cervical
spinal cord lesion.45 In MOGAD, brainstem or cerebellar symptoms usually occur
in the context of polyfocal cerebral involvement or ADEM, and are mainly repre-
sented by ataxia (45%) or diplopia (26%).44 Attacks of isolated facial numbness
and diplopia and trigeminal neuralgia are all much more common in MS than
AQP41NMOSD or MOGAD.
Cerebral manifestations: The frequency and manifestations of cerebral involve-
ment are very different between AQP41NMOSD and MOGAD.
Approximately 3% of patients with AQP41NMOSD may present with symptoms
of diencephalic involvement (eg, narcolepsy, inappropriate antidiuretic hormone
secretion syndrome, hyperphagia, thermic homeostasis dysregulation, and
dysfunction of the hypothalamus–hypophysis axis).46,47 Other cerebral manifes-
tations, including encephalopathy, ADEM, posterior-reversible encephalopathy,
and seizures have been reported as well but are rare.48,49
In MOGAD, ADEM represents the most common presenting manifestation in
pediatric patients (20%–60%), especially in those aged younger than 12 years.2,14
It is defined by the concomitant presence of polyfocal CNS symptoms, unex-
plained encephalopathy, and large poorly demarcated lesions in the gray and
white matter at MRI.50 Severe encephalopathy or status epilepticus can lead to
inability to protect the airway and the need for mechanical ventilation.41 Despite
the potential severity of the acute phase, recovery is usually good although def-
icits in cognition have been reported.51–53
Finally, patients with MOGAD may present with cerebral cortical encephalitis, a
recently described phenotype characterized by clinical manifestations (ie, head-
ache [79%], seizures [68%], encephalopathy [63%], and fever [42%])54 and
typical T2-FLAIR cortical hyperintensity with corresponding leptomeningeal or
cortical gadolinium enhancement.54,55 It is observed in almost 7% of all patients
but is more common in children (13.5%) than in adults (3.6%).54 Cerebral cortical
encephalitis often precedes other short-term MOGAD attacks. Radiological ab-
normalities resolve in more than 90% of patients54 and can occasionally improve
without acute immunotherapy.56
Major MRI Features

MRI is useful when it comes to differentiating between AQP41NMOSD and MOGAD.
Details are provided below:
Optic nerve imaging: It is essential to order orbital MRI with fat-saturated images
to have sufficient sensitivity to confirm optic neuritis but also to be able to
adequately identify discriminators because conventional MRI brain is inadequate
for the evaluation of the optic nerve. Optic neuritis is frequently bilateral and se-
vere in both AQP41NMOSD and MOGAD. In both cases long-segments of
inflammation (ie, T2-hyperintensity or gadolinium enhancement involving more
than half the distance from the orbit to the chiasm) are common.1,2,57 However,
lesions usually involve the anterior portion of the optic nerves in MOGAD (some-
times with optic nerve head swelling visible on MRI)2 and are commonly posteri-
orly located involving the chiasm and the optic tracts in AQP41NMOSD.1,33
Isolated optic chiasm involvement is more characteristic of AQP41NMOSD but
MOGAD optic nerve enhancement may extend to involve the chiasm relatively
frequently with MOGAD optic neuritis.58 Enhancement of the optic nerve sheath
(perioptic enhancement/optic perineuritis) and extension to the orbital fat can
also be observed in 50% of MOGAD-related optic neuritis36 and may help
discriminate from MS.59 In both disorders asymptomatic enhancement may be
observed at the site of prior optic neuritis in approximately 20% of patients,
possibly representing subclinical blood–brain barrier leakage or residual inflam-
mation.60,61 Chronic atrophy of the optic nerve or optic disc occurs in 12% to
83% of AQP41NMOSD,57,62 and can be clinically observed in MOGAD. Exam-
ples of acute and chronic MRI findings are shown in Fig. 2, with the corresponding
schematic representation in Fig. 3.
Spinal cord imaging: During acute myelitis, AQP41NMOSD and MOGAD involve
similar regions of the cord, although conus involvement favors MOGAD.39,63
Approximately 85% of patients with AQP41NMOSD and 70% of patients with
MOGAD with acute myelitis demonstrate longitudinally extensive spinal cord
T2-lesions,39 which by definition extend over at least 3 vertebral segments on
Fig. 2. MRI examples of optic neuritis in patients with MOGAD, AQP4DNMOSD, and MS.
Top row shows MRI findings during the acute phase (postcontrast T1-weighted images
with fat saturation), whereas follow-up imaging is displayed in the bottom row (precontrast
T1-weighted images without fat saturation). Unless otherwise specified, images are all
shown in axial view. MOGAD: Bilateral anterior optic neuritis (A, arrows) extending more
than 50% of optic nerve length on the right side (ie, long optic neuritis), and short on
the left side, with no or minimal residual optic nerve atrophy (B). AQP41NMOSD: Bilateral
optic neuritis (C, arrows) involving the chiasm (zoom-in picture, coronal detail) with mild re-
sidual atrophy (D). MS: Unilateral short left optic neuritis (E, arrow) with mild residual focal
atrophy (F). Abbreviations: AQP41NMOSD, aquaporin-4-IgG positive neuromyelitis optica
spectrum disorder; Gd, postcontrast T1-weighted images; MOGAD, myelin oligodendrocyte
glycoprotein antibody-associated disease; MS, multiple sclerosis; T1, precontrast T1-
weighted images.
Fig. 3. Optic neuritis in patients with MOGAD, AQP4DNMOSD, and MS. Top row shows
schematic representation of the optic nerve during the acute phase, while follow-up imag-
ing is displayed in the bottom row. All images are shown in axial view. MOGAD: Bilateral
anterior optic neuritis with accompanying optic disc edema extending more than 50% of
optic nerve length bilaterally with optic nerve sheaths and perioptic fat involvement (A)
and minimal residual optic nerve atrophy (B). AQP41NMOSD: Bilateral optic neuritis
involving the chiasm (C) with residual atrophy (D). MS: Unilateral short right optic neuritis
(E) with residual focal atrophy (F). (Used with permission of Mayo Foundation for Medical
Education and Research, all rights reserved.) Abbreviations: AQP41NMOSD, aquaporin-4-
IgG positive neuromyelitis optica spectrum disorder; Gd, postcontrast T1-weighted images;
MOGAD, myelin oligodendrocyte glycoprotein antibody-associated disease; MS, multiple
sclerosis.
sagittal T2-weighted images.2,46 By contrast, longitudinally-extensive lesions in

MS myelitis occur in less than 1%, although occasionally coalescence of multiple
short lesions can artifactually appear longitudinally-extensive, and hazy longitu-
dinally-extensive T2-hyperintensity can be sometimes encountered in chronic
MS .64 T2-lesions are more likely to be solitary in AQP41NMOSD and multiple
in MOGAD.39 Acute gadolinium enhancement (elongated ring-like, patchy) is
almost invariably present in AQP41NMOSD but less frequent and more faint in
MOGAD39,65,66; leptomeningeal enhancement can be observed in both dis-
eases.65,67 To note, around 10% of acute myelitis in MOGAD initially have a
normal MRI, which will usually reveal spinal cord abnormalities after a median
delay of 6 days.68
T2-lesions on axial images are usually central and involve the gray and the white
matter,2,69 although T2-hyperintensity restricted to the gray matter in an H-shaped
fashion (H-sign) is more frequent in MOGAD than AQP41NMOSD.39 Marked central
canal T2-hyperintensity may occur with AQP41NMOSD and MOGAD but is rare in
MS and this signal change usually resolves in follow-up.70 It may reflect a potential
space from incomplete closure of the central canal that becomes apparent in the
setting of central spinal cord inflammation and swelling.70 Another transient radiolog-
ical sign helpful in differentiating AQP41NMOSD from MS and potentially MOGAD is
the evidence of spinal cord lesions with areas of T2-hyperintensity at least equal to the
cerebrospinal fluid (brighter spotty lesions), which tend to be more extensive than just
an enlarged central canal and are more common in AQP41NMOSD.71–73
The severity of chronic atrophy is proportional to the number of myelitis in AQP41N-
MOSD and MOGAD,74 is mainly lesional rather than diffuse, and long segments of at-
rophy can be a clue to AQP41NMOSD diagnosis.38,69
Examples of acute and chronic MRI findings are shown in Fig. 4, with the corre-
sponding schematic representation in Fig. 5.
Brain imaging: Brain lesions are observed in up to 80% of patients with AQP41N-
MOSD.75 MRI findings have been extensively analyzed and classified in 2015, with the
definition of typical and nonspecific lesions.46 Typical lesions are usually observed at
periependymal level,46 following regions of high AQP4 expression.76 Among them,
periependymal lesions along the lateral ventricles are the most common (12%–
40%),46 especially in the course of cerebral attacks.77 Corresponding pencil-thin linear
ependymal enhancement is typical of AQP41NMOSD and is neither found in MOGAD
nor found in MS.78
During the acute phase, lesions may demonstrate typical patterns of heterogeneous
appearance (marbled pattern) or homogeneous involvement of the splenium (arch
bridge pattern), which may help diagnosis.46 Of note, callosal lesions can also be
observed in patients with MOGAD at a similar frequency but their size rarely exceeds
2.5 cm (11%) and the extracallosal brain involvement is common (55%).77 Callosal le-
sions can resolve in the chronic phase, although with a higher rate in MOGAD than
AQP41NMOSD (56% vs 15%).77 The shape of callosal lesions may also help differen-
tiate MS, where lesions are usually focal ovoid, with sharp margins, and with the major
axis perpendicular to the lateral ventricles.79
Other periependymal lesions in AQP41NMOSD may surround the third ventricle
resulting in diencephalic involvement (ie, thalamus, hypothalamus, and anterior border
of the midbrain) that may be asymptomatic. Diencephalic lesions favor AQP41N-
MOSD over MS, although rarely encountered (6% of patients with AQP41NMOSD).75
Finally, periependymal lesions around the cerebral aqueduct and the fourth ventricle
are also relatively frequent (7%–46% of patients with AQP41NMOSD), and those in
the dorsal medulla can involve the area postrema causing the hallmark clinical syn-
drome with intractable nausea, vomiting and hiccups.46 Other brain lesions considered
typical of AQP41NMOSD are those in the cerebral peduncles and corticospinal tracts
and large hemispheric lesions in the white matter (ie, with maximum transverse diam-
eter of >3 cm, often spindle-like or with a radial shape). Similar lesions have also been
reported in patients with MOGAD.80 Tumefactive lesions (2 cm) are more frequent in
MOGAD than AQP41NMOSD (22% vs 5%).81
Small nonspecific lesions (ie, <3 mm) in the subcortical and deep white matter,
similar to those encountered in aging, small vessel disease or migraine, are the
most common type of brain lesions in patients with AQP41NMOSD (35%–84%).46
Other than the ependymal enhancement, also cloud-like, nodular, and leptomenin-
geal enhancement were considered typical of AQP41NMOSD. However, more recent
investigations suggest that cloud-like and nodular enhancement may be encountered
with a similar frequency also in MOGAD and MS,78,81 whereas the leptomeningeal
enhancement is much more common in MOGAD (46% of cerebral attacks) and can
actually help discriminate from AQP41NMOSD (7%) and MS (4%).78 Persistent
enhancement over 3 months is rare in all these disorders.78
Similar to the variety of cerebral manifestations, the radiological features of brain MRI
in MOGAD are heterogeneous. Brain lesions can be found in 42% to 53% of patients
with MOGAD,82 and include lesions in the deep gray matter, cortical lesions, subcortical
Fig. 4. MRI examples of myelitis in patients with MOGAD, AQP4DNMOSD, and MS. Top
row shows MRI findings during the acute phase (T2-weighted images and postcontrast
T1-weighted images), whereas follow-up imaging is displayed in the bottom row (T2-
weighted images). MOGAD: Longitudinally extensive myelitis (ie, T2-lesion extending over
at least 3 continuous vertebral segments) with a linear appearance involving the thoracic
or juxtacortical lesions, brainstem and cerebellar lesions, large hemispheric lesions,

and, rarely, leukodystrophy-like patterns.63,82,83 Among all these locations, lesions in
the deep gray matter63,82 and large lesions in the middle cerebellar peduncles44 are
the most characteristic and more common in MOGAD than in AQP41NMOSD. Diffuse
involvement of the pons and/or adjacent to the fourth ventricle (anterior location) may
also favor MOGAD over AQP41NMOSD, although not confirmed in all studies.44,82
Brain lesions in this disease are usually poorly demarcated (fluffy),84 in line with what
is observed in patients with ADEM,50 of which conversely 50% test positive for MOG-
IgG.85 Transient faint T1-hypointensity can occur in the acute phase of MOGAD but
chronic T1 hypointensities are rare and are much more suggestive of MS.81 Cortical
lesions in MOGAD usually occur during episodes of cerebral cortical encephalitis,
are visible on fluid-attenuated inversion recovery (FLAIR) images and involve large
cortical areas.54,55 This contrasts with MS, where the assessment of cortical lesions
may be less visible on conventional sequences and are better identified using
advanced sequences such as double inversion recovery, phase sensitive inversion re-
covery, or magnetization-prepared rapid gradient-echo.86,87 Furthermore, evidence of
cortical lesions also favors MOGAD over AQP41NMOSD, as in the latter cortical
involvement was absent75,88,89 or rarely90,91 found.
Examples of acute and chronic MRI findings with the corresponding schematic rep-
resentation are shown in Figs. 6 and 7 (MOGAD), Figs. 8 and 9 (AQP41NMOSD), and
Figs. 10 and 11 (MS).
REMISSION MRI
Finally, although not specifically covered by the diagnostic criteria, remission MRI may
be relevant for the differentiation of AQP41NMOSD, MOGAD, and MS given their
different behavior in terms of T2-lesion resolution and accumulation of asymptomatic
lesions.
After the acute event, brain T2-lesion resolution is very common in MOGAD (60%–
79%),2,81,92–94 can occasionally be observed in AQP41NMOSD (14%–27%),44,81,93,95
and is very rare in MS (0%–17%).44,81,92,93 Similar findings are observed in the spinal
=
cord down to the conus (A, arrows, sagittal view). There is associated H-sign (ie, exclusive
involvement of the gray matter; C, axial view). Enhancement is absent, except for a mild lep-
tomeningeal enhancement of the conus (B, arrows, sagittal view). The T2-lesion completely
resolved on T2-weighted images at follow-up (J, sagittal view and K, axial view), with no
evident atrophy. AQP41NMOSD: Longitudinally extensive myelitis with a T2-lesion starting
from the area postrema and involving the cervical cord (D, arrows, sagittal view) with asso-
ciated swelling. Intralesional increased focal T2-hyperintensity similar to the cerebrospinal
fluid (CSF; ie, brighter spotty lesion) is also present (D, green arrow). The T2-lesion is cen-
trally located in both the gray and the white matter (F). Enhancement is inhomogeneous
(E, arrows, sagittal view). At follow-up, the T2-lesion reduced in size on T2-weighted images
(L, sagittal view and M, axial view) although still present. Residual atrophy of the cord is
particularly evident on axial view (M). MS: Multiple focal short spinal cord T2-lesions (G, ar-
rows, sagittal view) located in the peripheral white matter (I, axial view). All lesions
enhance, with the bottom lesion showing a ring-pattern of enhancement (H, arrows,
sagittal view). T2-lesions reduce in size and prominence of T2-hyperintensity persists on
follow-up T2-weighted images (N, arrows, sagittal view and O, axial view). The patient
also developed an interval T2-lesion (N, green arrow). Abbreviations: AQP41NMOSD,
aquaporin-4-IgG positive neuromyelitis optica spectrum disorder; Gd, postcontrast T1-
weighted images; MOGAD, myelin oligodendrocyte glycoprotein antibody-associated dis-
ease; MS, multiple sclerosis; T2, T2-weighted images.
Fig. 5. Myelitis in patients with MOGAD, AQP4DNMOSD, and MS. Top row shows spinal
cord findings during the acute phase (T2-weighted images and postcontrast T1-weighted
images), whereas follow-up imaging is displayed in the bottom row (T2-weighted images).
MOGAD: Longitudinally extensive myelitis with a linear T2-lesion appearance involving the
lower cervical and upper to middle thoracic cord and another lesion in the conus (A, sagittal
view). There is associated H-sign with the T2-lesion restricted to gray matter (C, axial view).
Minimum linear enhancement and leptomeningeal enhancement of the conus (B, sagittal
view). The T2-lesion completely resolved on T2-weighted images at follow-up (J, sagittal
view and L, axial view), with no evident atrophy. Gadolinium enhancement resolved (K).
AQP41NMOSD: Longitudinally extensive myelitis with a T2-lesion involving the cervical
and thoracic cord (D, sagittal view) with elongated ring enhancement (E). The T2-lesion is
centrally located in both the gray and the white matter (F, axial view). At follow-up, the
lesion is smaller on T2-weighted images (M, sagittal and O, axial view) although still present.
Gadolinium enhancement resolved (N). MS: Multiple focal short spinal cord T2-lesions (G,
sagittal view) located in the peripheral white matter (I, axial view). One lesion shows
cord, where 67% to 79% of lesions will ultimately resolve in MOGAD.92–94 T2-lesion
resolution in MOGAD occurs at approximately 3 months from appearance but can
be faster for small lesions.94 Steroid administration favors resolution of large lesions
(ie, 1 cm) but is not a necessary condition because spontaneous resolution is
observed in more than half T2-lesions not undergoing any acute treatment.94 In
contrast, concomitant T1-hypointensity during the acute phase reduces the likelihood
of lesions resolving over time.94 Altogether, these observations (ie, spontaneous res-
olution, steroid response, effect of T1-hypointensity, and timing of resolution) suggest
that this phenomenon is part of the natural history of MOGAD and relies on at least 3
factors: edema reabsorption, mild tissue damage, and postacute healing processes
such as, for instance, remyelination.94
Large reductions and progressive fragmentation is typical in AQP41NMOSD,
although complete resolution is rare,92,93,96 and persistence of T2-lesions is the rule
in MS.92,93
Surveillance MRI outside of attacks is standard of care in MS as new asymptomatic
lesions or enlarging T2-lesions are well recognized to occur particularly with low or
moderate efficacy medication and their presence may lead to treatment escalation.
However, new asymptomatic T2-lesions or enlarging T2-lesions are far less common
in MS when high-efficacy treatments are used. The presence of new or enlarging T2-
lesions has been commonly used in MS clinical trials as a surrogate end-point.97 In
AQP41NMOSD and MOGAD, the frequency of new or enlarging asymptomatic T2-
lesions is rare and estimated between 3% and 13%98–101 and between 3% and
14%,100–102 respectively. This has implications for clinical practice because surveil-
lance MRIs are generally not recommended in AQP41NMOSD or MOGAD. Moreover,
it has implications for upcoming clinical trials in these disorders because this will be a
less useful clinical trial endpoint.
Table 2 summarizes the main radiological features of AQP41NMOSD, MOGAD,
and MS.
AQP4-IgG and MOG-IgG Testing
Some basic knowledge of the antibody testing methodology, the optimal specimen
and technique, and potential pitfalls is crucial given their importance in diagnosis of
AQP41NMOSD and MOGAD. The cell-based assay (CBA) technique and analysis
in serum is generally recommended for AQP4-IgG and MOG-IgG, with live CBA
conferring some advantages over the fixed technique.2,103
AQP4-IgG testing: Live or fixed CBA with immunofluorescence or flow cytometry/
fluorescence-activated cell sorting (FACS)-based detection or quantification are rec-
ommended for AQP4-IgG testing because they demonstrated high sensitivity (69.7%–
100.0%) and the highest specificity (85.8%–100.0%) in independent cohorts.95,104,105
Older generation techniques using mouse tissue-based immunofluorescence have
lower sensitivity although reasonably high specificity.106 The enzyme-linked immuno-
sorbent assay has lower sensitivity and a false-positive rate 5-fold higher than CBA,
homogeneous nodular enhancement (H, sagittal view). T2-lesions reduce in size and persist
on follow-up T2-weighted images (P, sagittal view and R, axial view) with development of
focal left-sided spinal cord atrophy particularly evident on axial images (R). A new interval
T2-lesion is also present (P). Gadolinium enhancement resolved (Q). (Used with permission
of Mayo Foundation for Medical Education and Research, all rights reserved.) Abbreviations:
AQP41NMOSD, aquaporin-4-IgG positive neuromyelitis optica spectrum disorder; Gd, post-
contrast T1-weighted images; MOGAD, myelin oligodendrocyte glycoprotein antibody-
associated disease; MS, multiple sclerosis; T2, T2-weighted images.
Fig. 6. MRI examples of brain lesions in patients with MOGAD. Top row shows MRI findings
during the acute phase, whereas follow-up imaging is displayed in the bottom row. Images
are in axial view. Poorly defined (ie, fluffy) T2-lesions in the entire medulla and cerebellum
(A, arrows), completely resolving at follow-up imaging (E). Bilateral fluffy T2-lesions in the
middle cerebellar peduncles (B, arrows) with reduction in size but persistence at follow-up
(F, arrows) with accompanying fourth ventricle ex vacuo enlargement. Bilateral fluffy T2-
lesions of the thalami (C, arrows) in a patient with prominent leptomeningeal enhancement
(zoom-in picture, postcontrast T1-weighted sequence) undergoing complete resolution at
follow-up (G). Patient with cerebral cortical encephalitis showing an extensive cortical T2-
lesion (D, arrow) with focal enhancement (zoom-in picture, postcontrast T1-weighted
sequence), completely resolved at follow-up (H). Abbreviations: FLAIR, fluid-attenuated
inversion recovery; Gd, postcontrast T1-weighted images; MOGAD, myelin oligodendrocyte
glycoprotein antibody-associated disease.
particularly with low-positive results.104,105 False positives are usually low titers and
confirmatory testing with one or more different assays is recommended.1 However,
evidence of low-positive results in the context of live CBA assays can be considered
reliable because different live CBA assays demonstrated a strong agreement irrespec-
tive of antibody titer (100% concordance in high positive and 79% in low-positive
patients).107
False negatives may be also encountered (especially in patients receiving immunosup-
pressive treatments or when tested just after plasma exchange)1 and retesting in these
scenarios should be considered,1 although less than 1% of individuals initially testing
negative for AQP4-IgG will subsequently seroconvert to AQP4-IgG-positive.108
Finally, although AQP4-IgG can also be found in the CSF,16,109 antibody testing with
modern CBA or FACS on serum are more sensitive.16 The presence of CSF positivity
seems related to high AQP4-IgG titers in serum (higher likelihood of a CSF-positive
test in patients with AQP4-IgG titer in serum >1:100) and is more common during clin-
ical attacks.16 Therefore, serum testing is generally sufficient for AQP4-IgG testing,
although in highly suspicious cases CSF AQP4-IgG can be considered but isolated
CSF AQP4-IgG positives are exceedingly rare.16
MOG-IgG testing: In contrast to AQP4-IgG, MOG-IgG testing is more complex and
has historically represented a challenge. In fact, initial reports using Western Blot or
enzyme-linked immunosorbent assay (ELISA) targeting denatured MOG proteins,
yielded the presence of MOG-IgG in serum of many patients with MS and healthy
Fig. 7. Brain lesions in patients with MOGAD. Top row shows brain findings during the
acute phase, while follow-up imaging is displayed in the bottom row. Images are all shown
on axial view. T2-lesion involving the entire medulla (A), completely resolving at follow-up
(F). Bilateral fluffy T2-lesions in the middle cerebellar peduncles (B) resolved at follow-up
(G). Bilateral fluffy T2-lesions of the thalami and additional lesions in the white matter
(C) undergoing complete resolution at follow-up (H). Cerebral cortical encephalitis with
an extensive cortical T2-lesion (D) accompanied by leptomeningeal enhancement (E). Both
cortical lesion and enhancement completely resolved at follow-up (I, J). (Used with permis-
sion of Mayo Foundation for Medical Education and Research, all rights reserved.) Abbrevi-
ations: FLAIR, fluid-attenuated inversion recovery; Gd, postcontrast T1-weighted images;
MOGAD, myelin oligodendrocyte glycoprotein antibody-associated disease.
controls,110–112 leading to the misconception that these antibodies may represent an

epiphenomenon of demyelination. The association between MOG-IgG and specific
demyelinating phenotypes such as ADEM and optic neuritis (but not MS), was first
highlighted by using a laboratory assay expressing MOG in its native tridimensional
conformation4 and was subsequently confirmed by CBAs expressing full-length
human MOG.113,114 ELISA testing demonstrated a poor diagnostic performance and
reproducibility and is therefore not recommended or suitable for diagnosing
MOGAD.2,107
However, in contrast with AQP4-IgG testing,104,107 an excellent agreement between
different CBA assays was only reached with clear positive (82%) and clear negative
results (97.5%), with a slight improvement when only live CBA were considered.107
The agreement on borderline positives was poor (33%).107 Caution is needed with
low-positive CBA results given MOG-IgG can be found at low titer in 1% to 2% of dis-
ease controls.107,115,116 The positive predictive value of MOG-IgG increases when or-
dered in high probability situations and with higher antibody titers.115 MOG-IgG is still
a very useful test with high specificity (z98%–99%), and this is exemplified by a
recent study that showed no MOG-IgG positive among 703 pediatric healthy
controls.117
These observations highlight two fundamental principles that should be considered
when testing MOG-IgG: (1) CBA methodologies providing quantitative or semiquanti-
tative data can be useful and (2) testing should be reserved to patients with a high a
priori probability of having MOGAD. Universal testing of all patients with MS is not
recommend given the potential for 1% to 2% to have low-positive results that may
Fig. 8. MRI examples of brain lesions in patients with AQP4DNMOSD. Top row shows MRI
findings during the acute phase, whereas follow-up imaging is displayed in the bottom row.
Images are shown in axial view.T2-lesion in the area postrema (A, arrow) almost invisible but
still present at follow-up (F, zoom-in picture, arrow). T2-lesion involving the dorsal pons
abutting to the fourth ventricle (B, arrow) with complete resolution at follow-up (G). Peri-
ependymal T2-lesion (C, arrow) with corresponding linear ependymal enhancement (zoom-
in picture, postcontrast T1-weighted sequence), persisting at follow-up (H, arrow). T2-lesion
involving the splenium of the corpus callosum in another patient (D, arrow), significantly
reduced in size but still visible at follow-up (I, arrow). Multiple small nonspecific
T2-lesions in the subcortical white matter (E, arrows), persisting unchanged at follow-up
(J, arrows). Additional interval T2-lesions are observed as well (J, green arrows). Abbrevia-
tions: AQP41NMOSD, aquaporin-4-IgG positive neuromyelitis optica spectrum disorder;
FLAIR, fluid-attenuated inversion recovery; Gd, postcontrast T1-weighted images.
lead to confusion about the diagnosis. It is preferred to select those with features that
are suggestive of MOGAD and avoid testing in patients with classic features of MS.
Finally, recent investigations have highlighted a role for CSF testing in MOGAD. In
fact, although serum is overall more sensitive to MOG-IgG detection, concomitant
detection of MOG-IgG in serum and CSF occurs in 41% to 87% of patients.17–20,118–120
CSF positivity can be observed in isolation in 3% to 29%,17–20,118–120 and in suspicious
cases negative for MOG-IgG in serum, CSF MOG-IgG testing should be undertaken.
Patients with evidence of intrathecal synthesis of MOG-IgG or CSF MOG-IgG positivity
seem to have a worse clinical prognosis.19,20 Because false-positive MOG-IgG in CSF
can be rarely encountered in MS and other diseases,19,20 the result should always be
put into clinical context.
Additional CSF analysis and other laboratory features in MOGAD and AQP41N-
MOSD: Other than disease-specific antibody testing, additional laboratory analysis
can be helpful in the differential diagnosis process, although not included in the diag-
nostic criteria. CSF usually reveals pleocytosis in more than 50% of patients with
MOGAD (median 31–40 cells/mL)121,122 and AQP41NMOSD (median 19 cells/mL)123
but rarely in MS. Cells are usually predominantly lymphocytes121–123 although also
monocytes (MOGAD),121,122 neutrophils (both AQP41NMOSD and MOGAD),121–123
or eosinophils (AQP41NMOSD)123 can be found. In MOGAD, CSF abnormalities
may vary by phenotype and are more common in patients with brain and/or spinal
Fig. 9. Brain lesions in patients with AQP4DNMOSD. Top row shows brain findings during
the acute phase, whereas follow-up imaging is displayed in the bottom row. Images are all
shown on axial view. T2-lesion in the area postrema (A) smaller but still present at follow-up
(F). Posterior T2-lesion abutting to the fourth ventricle (B) smaller but still present at follow-
up (G). T2-lesion in the corticospinal tract and splenium of the corpus callosum (C) smaller
but still present at follow-up (H). Multiple small nonspecific T2-lesions in the subcortical
white matter (D), persisting unchanged at follow-up (I). Additional interval T2-lesions are
observed as well (I). The presence of linear ependymal enhancement (E), resolving at
follow-up (J) is typical of AQP41NMOSD. (Used with permission of Mayo Foundation for
Medical Education and Research, all rights reserved.) Abbreviations: AQP41NMOSD,
aquaporin-4-IgG positive neuromyelitis optica spectrum disorder; FLAIR, fluid-attenuated
inversion recovery; Gd, postcontrast T1-weighted images.
cord lesions.124 CSF oligoclonal bands are rarely encountered in patients with
MOGAD and AQP41NMOSD (approximately 10%–20%)121–124 compared with 88%
of patients with MS.125
Approximately 2% to 3% of patients with AQP41NMOSD can have coexistent
myasthenia gravis.126,127 Although AQP41NMOSD diagnosis usually follows that of
myasthenia,128 antiacetylcholine receptor antibody in serum should be checked in
case of compatible clinical manifestations. Rarely MOG-IgG was also found coexisting
with AQP4-IgG and in most cases is likely related to its background rate being found in
1% to 2% of disease controls. Most patients with dual AQP4-IgG and MOG-IgG pos-
itivity had high-titer AQP4-IgG and low-titer MOG-IgG and a phenotype more sugges-
tive of AQP41NMOSD.129
The laboratory features and antibody testing of AQP41NMOSD and MOGAD are
summarized in Table 3.
Diagnostic Criteria
The latest diagnostic criteria for AQP41NMOSD and MOGAD are dated 2015 and
2023, respectively, and are summarized in Table 4.
In both cases, the diagnostic algorithm starts from the evidence of core clinical fea-
tures, and then dichotomizes based on antibody-serostatus. Clear evidence of the
pathogenetic antibody in a patient with typical clinical manifestations allows the
achievement of the diagnosis; alternatively, additional clinical or MRI requirements
Fig. 10. MRI examples of brain lesions in patients with MS. Top row shows MRI findings dur-
ing the acute phase, whereas follow-up imaging is displayed in the bottom row. Unless other-
wise specified, images are all shown on FLAIR sequences, axial view. Small T2-lesion in the
anterior medulla (A, arrow), unchanged at follow-up (E, arrow). Multiple T2-lesions in the
peripheral pons and abutting on the fourth ventricles (B, arrows), still visible at follow-up
(F, arrows) with additional interval T2-lesions (F, green arrow). Multiple ovoid periventricular
T2-lesions abutting on the lateral ventricles (C, arrows). T2-lesions persisted at follow-up (G,
arrows), at times increasing in size (G, blue arrow). Additional interval T2-lesions (G, green ar-
rows) are shown as well. White matter T2-lesions (D, arrows), one showing ring enhancement
(zoom-in picture, postcontrast T1-weighted sequence). T2-lesions persisted at follow-up (H,
arrows), at times increasing in size (H, blue arrow). Additional interval T2-lesions (H, green ar-
rows) are shown as well. Abbreviations: FLAIR, fluid-attenuated inversion recovery; Gd, post-
contrast T1-weighted images; MS, multiple sclerosis.
are needed. The comparison of AQP41NMOSD and MOGAD diagnostic criteria high-
lights several differences. First, for AQP41NMOSD diagnosis, but not MOGAD, there
is a seronegative or unknown antibody status category.1 Because MOG-IgG is found
in up to 30% of seronegative patients with NMOSD,130,131 future iterations of AQP4-
IgG seronegative NMOSD will likely require a negative MOG-IgG test. The reason
for this is that MOG-IgG positive patients with a compatible syndrome should be diag-
nosed with MOGAD rather than AQP4-IgG seronegative NMOSD. MOGAD diagnostic
criteria, but not AQP41NMOSD, have additional requirements for low-positive or CSF
MOG-IgG positive tests given the challenges with low-positive results and limited data
on CSF MOG-IgG, respectively.
AQP4DNMOSD AND MOGAD TREATMENT
Treatment in autoimmune disorders has two main goals: (1) promote recovery after an
acute attack and (2) prevent subsequent relapses. In this section, we will describe the
main treatment strategies in AQP41NMOSD and MOGAD.
Acute Treatment of Attacks

Acute treatment in both AQP41NMOSD and MOGAD is similar to MS. It mainly in-
cludes intravenous steroids and plasma exchange although occasionally, intravenous
Fig. 11. Brain lesions in patients with MS. Top row shows brain findings during the acute
phase, whereas follow-up imaging is displayed in the bottom row. Images are all shown
on axial view. Small peripheral T2-lesion in the anterior medulla (A), substantially un-
changed at follow-up with additional interval T2-lesion (F). Multiple T2-lesions in the pe-
ripheral pons, trigeminal nerve, and abutting on the fourth ventricles (B), substantially
unchanged at follow-up with additional interval lesion (G). Multiple ovoid periventricular,
juxtacortical, and deep white matter T2-lesions (C). T2-lesions persisted at follow-up (H),
at times increasing in size. Additional juxtacortical interval T2-lesions are also visible (H).
White matter T2-lesions and one cortical T2-lesion (D) persisting at follow-up with addi-
tional interval lesions development (I). Two of the lesions shown in C demonstrate open
or closed ring enhancement, which is typically observed in MS (E) and resolves at follow-
up (J). (Used with permission of Mayo Foundation for Medical Education and Research,
all rights reserved.) Abbreviations: FLAIR, fluid-attenuated inversion recovery; Gd, postcon-
trast T1-weighted images; MS, multiple sclerosis.
immunoglobulin (IVIg) is also used. The details are summarized in Table 5. There is ev-
idence that early treatment (ie, <7 day-delay from symptoms onset) reduces the likeli-
hood of residual deficits in both AQP41NMOSD and MOGAD.132 Moreover, the use of
both steroids and plasma exchange may be more common in these conditions, given
the greater severity of symptoms at nadir and the high efficacy of early plasma ex-
change or apheresis by immunoadsorption in patients with AQP41NMOSD.133–135
In AQP41NMOSD, transitional corticosteroids for a few weeks are often used while
awaiting attack-prevention treatments to work, and the duration varies depending
on the type of immunosuppressant used.103,136 In MOGAD, longer steroid tapers for
many months have sometimes been used to prevent early relapses but the majority
of patients will not have an early relapse and prolonged steroids has a large side effect
burden, particularly in growing children.10,137,138 Therefore, using such an approach in
all patients is problematic and further studies are needed to determine the role of a
more prolonged corticosteroid taper.
Chronic Attack-Preventive Treatment

Because AQP4-IgG positive patients with AQP41NMOSD at first clinical attack are at
high risk of relapses in the first year (70%) and disability worsening is strongly associ-
ated with acute attacks, all newly diagnosed patients should undergo a chronic treat-
ment aimed to prevent attacks.103 In contrast with AQP41NMOSD, approximately
96
Cacciaguerra & Flanagan
Table 2
Imaging findings in AQP4DNMOSD, MOGAD, and MS
AQP4DNMOSD MOGAD MS
Optic nerve
Bilateral involvement 11 11 -
Longitudinally extensive lesions (>50% 11 11 -
length of optic nerve)
Location Posterior with chiasm Anterior Anterior/middle
Optic nerve enhancement 111 111 111
Optic nerve sheath enhancement - 11 -
Perioptic fat enhancement - 11 -
Spinal cord
Multiple lesions - 11 111
Longitudinally extensive lesions 111 111 -
Location (axial) Central Central Peripheral
Gray matter involved 111 111 1
White matter involved 11 1 111
Location (sagittal) Cervico-thoracic Cervico-thoracic Cervico-thoracic
Conus involved 1 11 1
Parenchymal enhancement Lens-shape, heterogeneous Faint, ill-defined Ring, nodular
Leptomeningeal enhancement 1 11 -
Brain
Shape Along white matter tracts Poorly demarcated Ovoid
Cortical lesions - 1 11
Juxtacortical lesions - 11 111
Subcortical lesions 11 1 -
Periventricular lesions Peri-3rd/4th ventricle and peri-ependymal - Dawson’s fingers
lateral ventricles
Corpus callosum lesions 11 11 111
Deep gray matter lesions 1 11 -
Diffuse pons/middle cerebellar peduncle 1 111 -
lesions
T1-hypointense lesions 1 1 111
Ring enhancement - - 11
Ependymal enhancement 11 - -
Leptomeningeal enhancement - 11 -a
T2-lesion resolution 1 111 -
Interattack asymptomatic accumulation of - - 11b
new T2-lesions
Note that: “-” indicates rare findings (<5%), “1” infrequent findings (5%–30%), “11” common findings (30%–69%), “111” very common findings (>570%).
Abbreviations: AQP41NMOSD, aquaporin-4-IgG positive neuromyelitis optica spectrum disorder; MOGAD, myelin-oligodendrocyte glycoprotein antibody-
associated disease; MS, multiple sclerosis.
NMOSD and MOGAD Diagnosis and Treatment

a
May be seen with more sophisticated MRI techniques (eg, postcontrast fluid-attenuated inversion recovery or at 7.0 T field strength).
b
Dependent on treatment and is common with low or moderate efficacy MS disease modifying treatments but rare with high-efficacy treatments.
97
98
Table 3
Recommendations and laboratory features of AQP4DNMOSD and MOGAD
AQP4DNMOSD MOGAD
Antibody AQP4-IgG1 MOG-IgG1
Sample
Serum Yes (preferred) Yes (preferred)
CSF No (isolated CSF AQP4-IgG extremely rare) Yes (z10% isolated CSF MOG-IgG)
Test assay
Live CBA Yes (gold standard) Yes (gold standard)
Fixed CBA Yes Yes
Murine tissue-based assays Intermediate sensitivity but very good specificity May have white matter staining when CSF tested but very
insensitive24
ELISA Good performance but reduced sensitivity and risk of false Not recommended due to inconsistent results
positives at low titer vs CBAs
Quantitative results important No Yes (risk of false positives at low titer)
Seroconversion important No Yes (relapse-risk)
CSF findings
Pleocytosis 11 11
High protein 11 11
Oligoclonal bands 1 (<20%) 1 (<20%)
Note that: “-” indicates rare findings (<5%), “1” infrequent findings (5%–30%), “11” common findings (30%–69%), “111” very common findings (>570%).
Abbreviations: AQP4, aquaporin-4; AQP41NMOSD, aquaporin-4-IgG positive neuromyelitis optica spectrum disorder; CBA, cell-based assay; CSF, cerebrospinal
fluid; ELISA, enzyme-linked immunosorbent assay; MOG, myelin oligodendrocyte glycoprotein; MOGAD, myelin-oligodendrocyte glycoprotein antibody-
associated disease.
Table 4
Diagnostic criteria of AQP4DNMOSD and MOGAD
AQP4DNMOSD MOGAD
Antibody test (CBA) positive Core clinical features Optic neuritis Optic neuritis
(AQP41NMOSD) or clear positive Myelitis Myelitis
(MOGAD) Area postrema syndrome Brainstem or cerebellar deficits
Acute brainstem syndrome
Symptomatic cerebral syndrome ADEM
with AQP41NMOSD-typical
brain MRI lesions
Symptomatic narcolepsy or acute Cerebral monofocal or polyfocal
diencephalic clinical syndrome deficits
with AQP41NMOSD-typical
diencephalic MRI lesions
Cerebral cortical encephalitis often
NMOSD and MOGAD Diagnosis and Treatment

with seizures
Antibody test (CBA) negative/ Supporting features
unknown (AQP41NMOSD) or Optic neuritis Normal findings or only nonspecific Bilateral simultaneous clinical
low positive/positive without white matter lesions in the brain involvement
titer in serum or negative in Longitudinal optic nerve Longitudinal optic nerve
serum but CSF positive (MOGAD) involvement (>50% length of the involvement (>50% length of the
optic nerve on T2 or optic nerve)
postgadolinium T1)
Optic chiasm Perineural optic sheath
enhancement
Optic disc edema
Myelitis Longitudinally extensive myelitis Longitudinally extensive myelitis
Longitudinally extensive focal Central cord lesion or H-sign
spinal cord atrophy in patients
(continued on next page)
99
100
Table 4
(continued )
AQP4DNMOSD MOGAD
with history compatible with
acute myelitis
Conus lesion
Area postrema syndrome Dorsal medulla/area postrema -
lesions
Brain, brainstem, or cerebral Periependymal brainstem lesions Multiple ill-defined T2
syndromes hyperintense lesions in
supratentorial and often
infratentorial white matter
Deep gray matter involvement
Ill-defined T2-hyperintensity
involving pons, middle cerebellar
peduncle, or medulla
Cortical lesion with or without
lesional and overlying meningeal
enhancement
Exclusion of better diagnoses Yes Yes
including MS
Abbreviations: AQP41NMOSD, aquaporin-4-IgG positive neuromyelitis optica spectrum disorder; CBA, cell-based assay; CSF, cerebrospinal fluid; MOGAD, myelin
oligodendrocyte glycoprotein antibody-associated disease.
Table 5
Main treatment protocols in AQP4DNMOSD and MOGAD
Protocol AQP4DNMOSD MOGAD

Acute treatment of attacks
Importance - Residual disability Residual disability
Steroids Intravenous 111 111
methylprednisolone
1000 mg/d for 5 da
Plasma exchangeb Every other day for 5–7 111 11
cycles
Steroid tapering Oral steroids 20–40 mg Weeksc Weeks–months
followed by a taper
Chronic attack-preventive treatmentd
Importance - Affects long-term Unknown
prognosis
Start at first - 111 1
clinical attack
Complement inhibitors
Eculizumab 900 mg intravenous every 111 Not tried in trials
week for the first 4 wk,
then 1200 mg every 2 wk
Ravulizumab Body-weight-based 111 Not tried in trials
intravenous loading dose
(2400–3000 mg) plus a
body-weight-based
maintenance dose
(3000–3600 mg) on day
15, then once every 8 wk
B cells depleters
Rituximab 375 mg/m2 intravenous 111 Trial ongoing
every week for the first
4 wk, or 1000 mg 2
doses 2 wk apart and
then 1000 mg 2 wk apart
every 6 mo
Inebilizumab 300 mg intravenous every 111 Limited data
15 d 2 doses, and then
every 6 mo
IL-6 receptors inhibitors
Satralizumab 120 mg subcutaneously 111 Trial ongoing
every 4 wk
Note that: “-” indicates rare (<5%), “1” infrequent (5%–30%), “11” common (30%–69%),
“111” very common/very high efficacy (>570%).
a
Alternatively, oral steroids bioequivalent (ie, prednisone 1250 mg) may be considered given its
similar efficacy in patients with optic neuritis.163
b
IVIg may be sometimes administered instead of expanded Disability Status Scale (EDSS).
c
Duration may vary depending on steroid-sparing treatment making effect.
d
We focused here on level 1 evidence of efficacy, although biosimilars of rituximab, tocilizu-
mab, mycophenolate, and azathioprine may be used and a trial on rozanolixizumab is ongoing
in MOGAD.
50% of patients with MOGAD will ultimately have a relapsing disease course.12 There-
fore, treatment is usually recommended only after the second clinical event in patients
with MOGAD, although exceptions may be made in those with a severe first attack
with residual disability.
AQP41NMOSD represents one of the few neurological disorders with tailored
proven treatments available, where drugs target key elements of disease pathophys-
iology, namely (1) IL-6 (satralizumab), (2) B cells and their subsets (inebilizumab and
rituximab), and (3) complement (eculizumab, ravulizumab). The very high efficacy of
these biologic drugs was demonstrated in phase 3 clinical trials (level 1 evidence of
efficacy), although only in AQP41NMOSD. Biosimilars of rituximab are potential al-
ternatives to reduce costs. In resource-limited settings, azathioprine and mycophe-
nolate mofetil have been used but their efficacy appears to be less,139 and they
have drawbacks including the need for at least 6 months of concomitant corticoste-
roids with its high side effect burden and risk of secondary lymphoproliferative dis-
orders with long-term use.140,141 Tocilizumab is another off-label IL-6 blocking
medications with some data supporting its use.142 In this review, we will focus on
treatments that have class 1 evidence. A summary of treatment efficacy and the
main side effects during the trials and in the open label phase (if available) are pro-
vided below and in Table 5.
Complement Inhibitors
Eculizumab
This humanized monoclonal antibody inhibits C5 preventing the membrane attack
complex formation. The phase-3 trial included only adult patients with AQP41NMOSD
and the treatment showed a 94% relapse-risk reduction compared with the placebo
arm,143 and similar results during the open-label extension.144 Although eculizumab
was administered as add-on therapy in most patients, efficacy was confirmed in the
subgroup of patients receiving eculizumab monotherapy145 and was not influenced
by the main demographic/clinical variables, including age, sex, race, disease duration,
annualized relapse rate, EDSS, prior treatment with rituximab, and additional autoim-
mune conditions.146
All patients received Neisseria meningitidis vaccination before eculizumab adminis-
tration to reduce the risk of capsulated bacterial infection, with no evidence of menin-
gitis during the trial and its extension so far,144 although one case occurred in the initial
phase 2 open label trial of this medication.147 Adverse effects were generally mild or
moderate. Headache, upper respiratory tract infections, nasopharyngitis, and urinary
tract infections were the most common.143,144 A single death from pulmonary empy-
ema was registered.143,144
Ravulizumab
Ravulizumab is a humanized monoclonal antibody similar to eculizumab that also tar-
gets C5. The main difference with eculizumab is that the complementary binding region
and the neonatal fragment crystallizable region were modified in ravulizumab to
lengthen its half-life. It was administered to AQP4-IgG seropositive patients with
AQP41NMOSD in a phase-3 open label trial using the placebo arm of the PREVENT trial
as the control group.148 No patients relapsed during the trial, leading to a 98.6% reduc-
tion in relapse-risk. In addition, investigators found a significant improvement of the
ambulation index at study end.148 Similar to eculizumab, adverse events were generally
mild to moderate and included coronavirus disease 2019 infection, headache, back
pain, arthralgia, and urinary tract infections.148 However, despite prior vaccination,
two patients developed meningococcal meningitis but recovered with treatment.148
B Cell Depletion
Rituximab
Rituximab is a chimeric monoclonal antibody targeting the surface CD20 biomarker
expressed on B cells. Its efficacy was proven in patients with AQP41NMOSD in a ran-
domized placebo-controlled clinical trial. In this study, no treated patients relapsed
although the total number of patients (19 in each study arm) was smaller than some
of the other clinical trials. In addition, an improvement in the quantification of nerve
and spinal cord impairment scale was observed. No deaths occurred. Infusion reac-
tions, headache, nasopharyngitis, and upper respiratory tract infections were the
most common adverse effects, confirming rituximab’s good safety profile.149
Inebilizumab
This humanized monoclonal antibody targets surface CD19, which is a B-cell lineage
biomarker with a wider expression than CD20 because it is also present on plasma-
blasts and, to a lesser extent, on plasma cells. It was administered in monotherapy
to both patients with AQP41NMOSD and AQP4-IgG seronegative patients with
NMOSD (18 patients), showing an overall relapse-risk reduction of 77% when in pa-
tients with AQP41NMOSD.150 Secondary endpoints such as the risk of EDSS wors-
ening, radiological activity, and hospitalization were also met.150,151 No significant
benefit of treatment were observed among AQP4-IgG seronegative patients,150
although a post hoc analysis suggested that treated patients had a lower
annualized-relapse rate at study end than preenrollment.152
Post hoc analyses also provided interesting insights into treatment response
showing that patients with early and persisting B cell depletion (4 cells/mL at
6 months) were clinically stable for more than 2 years.153
Adverse events mainly included urinary tract infections, arthralgias, and infusion-
related reactions. In the open-label phase, a decrease of immunoglobulins over
time was observed, and further long-term analysis will be needed to determine its fre-
quency and impact on risk of infections.154 Two deaths due to respiratory failure within
a relapse and an indeterminate neurological condition occurred.150
IL-6 Receptor Inhibitors

Satralizumab
Satralizumab is a humanized monoclonal antibody inhibiting the IL-6 receptor. It was
administered monotherapy or add-on in patients with AQP41NMOSD and AQP4-IgG
seronegative patients with NMOSD, demonstrating an overall relapse-risk reduction of
74% to 79% in patients with AQP41NMOSD.155,156 In contrast to the other medica-
tions, satralizumab administration is a subcutaneous injection, so it can be given at
home. The adverse effects included upper respiratory or urinary infections and
injection-related reactions. Efficacy and safety results were confirmed in the open la-
bel extension of the trial, and no deaths were reported.157 Seronegative patients did
not show a benefit but larger cohort studies are needed.155,156
So far, no level 1 evidence of treatment efficacy is available in patients with MOGAD,
and empiric treatment decisions are based on retrospective analyses and expert
opinion.158,159 Treatment currently administered in clinical practice includes old immu-
nosuppressants (azathioprine, mycophenolate mofetil), B cell depleting therapies (ritux-
imab), IL-6 receptor inhibitors (tocilizumab), and IVIg.160 Among them, multicenter
retrospective studies demonstrated that rituximab and IVIg161 are effective mainte-
nance treatments. However, rituximab seems less effective in MOGAD than AQP4-
IgG positive AQP41NMOSD, despite B cell depletion.162 Thus, IVIg or tocilizumab are
often favored in clinical practice. Clinical trials evaluating the efficacy of rituximab
(NCT05545384), satralizumab (NCT05271409), and rozanolixizumab (an inhibitor of the

neonatal Fc receptor, NCT05063162) versus placebo are currently ongoing.
SUMMARY
The recent identification of AQP41NMOSD and MOGAD as separate disorders has

prompted the development of separate diagnostic criteria for MOGAD diagnosis.
The stratification of patients based on the presence/absence of AQP4-IgG in NMOSD
and stratification by antibody-titer in MOGAD represents the main differences be-
tween the two criteria. Using CBA in serum, AQP4-IgG and MOG-IgG are sensitive
and highly specific but caution is needed with low-positive MOG-IgG, which is found
in 1% to 2% of disease controls. In addition, specific MRI features of the diseases are
described and included as supportive criteria in uncertain cases. NMOSD negative for
AQP4-IgG and MOG-IgG likely represents a heterogenous group of disorders that
should be a focus of research to potentially discover new antibodies that associate
with demyelination. A number of highly effective attack-prevention treatments are
now available for AQP41NMOSD and should be started promptly at diagnosis.
Empiric attack-prevention treatments in MOGAD are generally reserved for those
with 2 or more attacks. However, level 1 evidence is lacking in MOGAD. The approach
to developing treatments in AQP41NMOSD will be a useful template for MOGAD and
randomized clinical trials are now underway with the hope for a proven attack-
prevention treatment in the near future.
CLINICS CARE POINTS
AQP41NMOSD and MOGAD are separate antibody-mediated CNS disorders with different
antigenic targets.
Bilateral optic neuritis and extensive myelitis are common features of both AQP41NMOSD
and MOGAD; cerebral involvement can be encountered with both diseases, although
ADEM favors MOGAD.
It is important to recognize the MRI features of MOGAD and AQP41NMOSD because it helps
to select those that should be tested for MOG-IgG and AQP4-IgG.
Caution is needed with low-positive MOG-IgG because it can occur in 1% to 2% of other
diseases.
Long-term attack-prevention treatment is required after the first attack in AQP41NMOSD
but not MOGAD, where it is typically reserved for those with 2 or more attacks.
In AQP41NMOSD, level 1 evidence of efficacy is available for complement inhibitors
(eculizumab, ravulizumab), B cell depleting agents (rituximab, inebilizumab), and IL-6
receptor inhibitors (satralizumab).
High-level evidence of treatment efficacy is not available for MOGAD yet but clinical trials
are now underway.
DISCLOSURE
L. Cacciaguerra received speaker and consultant honoraria from ACCMED, Roche,

BMS Celgene, Sanofi and travel support for conferences by Merck Serono. E.P. Flana-
gan was a site primary investigator in a randomized clinical trial on Inebilizumab in neuro-
myelitis optica spectrum disorder run by Medimmune/Viela-Bio/Horizon Therapeutics,
has received funding from the NIH, United States (R01NS113828), and is a member of
the medical advisory board of the MOG project. Dr E.P. Flanagan is an editorial board
member of the Journal of the Neurological Sciences and Neuroimmunology Reports,
and a patent has been submitted on DACH1-IgG as a biomarker of paraneoplastic
autoimmunity.
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Updates in NMOSD and

MOGAD Diagnosis and

Aquaporin-4-IgG positive neuromyelitis optica spectrum disorder (AQP41NMOSD)

Neurol Clin 42 (2024) 77–114

are recently identified antibody-mediated autoimmune disorders of the central ner-

Epidemiology of AQP41NMOSD and MOGAD

Pathophysiology of AQP41NMOSD and MOGAD

AQP4DNMOSD AND MOGAD DIAGNOSIS

Abbreviations: APRIL, a proliferation-inducing ligand; AQP4, aquaporin-4; AQP41NMOSD,

in MOGAD (visual acuity of 20/30 or 20/25),35,36 whereas recovery can be partial

Major MRI Features

sagittal T2-weighted images.2,46 By contrast, longitudinally-extensive lesions in

or juxtacortical lesions, brainstem and cerebellar lesions, large hemispheric lesions,

controls,110–112 leading to the misconception that these antibodies may represent an

AQP4DNMOSD AND MOGAD TREATMENT

Acute Treatment of Attacks

Chronic Attack-Preventive Treatment

NMOSD and MOGAD Diagnosis and Treatment

NMOSD and MOGAD Diagnosis and Treatment

Protocol AQP4DNMOSD MOGAD

IL-6 Receptor Inhibitors

(NCT05545384), satralizumab (NCT05271409), and rozanolixizumab (an inhibitor of the

The recent identification of AQP41NMOSD and MOGAD as separate disorders has

CLINICS CARE POINTS

L. Cacciaguerra received speaker and consultant honoraria from ACCMED, Roche,

1. Wingerchuk DM, Banwell B, Bennett JL, et al. International consensus diag-

17. Mariotto S, Gajofatto A, Batzu L, et al. Relevance of antibodies to myelin oligo-

55. Ogawa R, Nakashima I, Takahashi T, et al. MOG antibody-positive, benign, uni-

90. Tahara M, Ito R, Tanaka K, et al. Cortical and leptomeningeal involvement in

110. Berger T, Rubner P, Schautzer F, et al. Antimyelin antibodies as a predictor of

161. Chen JJ, Huda S, Hacohen Y, et al. Association of Maintenance Intravenous

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