Neuromyelitis Optica Spectrum Disorders10

Neuromyelitis Optica REVIEW ARTICLE

Spectrum Disorders C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE
By Fiona Costello, MD, FRCPC
ABSTRACT
PURPOSE OF REVIEW: This article reviews the cardinal clinical features, distinct
immunopathology, current diagnostic criteria, relapse-related risk factors,
emerging biomarkers, and evolving treatment strategies pertaining to
neuromyelitis optica spectrum disorders (NMOSD).
RECENT FINDINGS: The discovery of the pathogenic aquaporin-4 (AQP4)-IgG

autoantibody and characterization of NMOSD as an autoimmune
astrocytopathy have spearheaded the identification of key immunologic CITE AS:
CONTINUUM (MINNEAP MINN)
therapeutic targets in this disease, including but not limited to the complement
2022;28(4, MULTIPLE SCLEROSIS
system, the interleukin 6 (IL-6) receptor, and B cells. Accordingly, four AND RELATED DISORDERS):
recent randomized controlled trials have demonstrated the efficacy of 1131–1170.
three new NMOSD therapies, namely eculizumab, satralizumab, and

Address correspondence to
inebilizumab. Dr Fiona Costello, Foothills
Medical Centre, Clinical
SUMMARY: Currently, NMOSD poses both diagnostic and treatment Neurosciences, 12th Floor, 1403
29 St NW, Calgary, Alberta,
challenges. It is debated whether individuals who are seropositive for Canada T2N 2T9, Fiona.Costello@
myelin oligodendrocyte glycoprotein (MOG)-IgG belong within the albertahealthservices.ca.
neuromyelitis optica spectrum. This discussion is fueled by disparities in
RELATIONSHIP DISCLOSURE:
treatment responses between patients who are AQP4-IgG seropositive and Dr Costello has received
seronegative, suggesting different immunopathologic mechanisms may personal compensation in the
range of $500 to $4999 for
govern these conditions. As our understanding regarding the immune serving as a consultant for
pathophysiology of NMOSD expands, emerging biomarkers, including Alexion Pharmaceuticals, Inc,
serum neurofilament light chain and glial fibrillary acidic protein (GFAP), and F. Hoffmann-La Roche Ltd
and for serving on a speakers
may facilitate earlier relapse detection and inform long-term treatment bureau for Accure Therapeutics,
decisions. Future research focal points should include strategies to Alexion Pharmaceuticals, Inc,
optimize relapse management, restorative treatments that augment Novartis AG, and The Sumaira
Foundation.
neurologic recovery, and practical solutions that promote equitable
access to approved therapies for all patients with NMOSD. UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
Dr Costello discusses the
unlabeled/investigational use of
INTRODUCTION numerous immunosuppressive
N
euromyelitis optica spectrum disorders (NMOSD), previously agents including azathioprine,
cyclophosphamide, IV
referred to as neuromyelitis optica (NMO), has been an enigmatic
immunoglobulin G,
condition since it was first described more than a century ago by methotrexate, mitoxantrone,
Eugene Devic, for whom it was originally named.1 For many years, mycophenolate mofetil,
rituximab, and tocilizumab for
NMO was considered an overlap syndrome with multiple sclerosis the treatment of neuromyelitis
(MS), distinguished from the latter only by its relative severity and specific optica spectrum disorders.
predilection for optic nerve and spinal cord involvement.2 The recognition of
NMOSD as an autoimmune astrocytopathy has been relatively recent. In 2004, © 2022 American Academy
Lennon and colleagues3 discovered serum antibodies that target the water of Neurology.
CONTINUUMJOURNAL.COM 1131
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

NEUROMYELITIS OPTICA SPECTRUM DISORDERS
FIGURE 7-1
Schematic of the immune pathophysiology of neuromyelitis optica spectrum disorder
(NMOSD), myelin oligodendrocyte glycoprotein (MOG), glial fibrillary acidic protein (GFAP),
and multiple sclerosis (MS) optic neuritis. NMOSD: Aquaporin-4 (AQP4)-immunoglobulin
G (IgG) enters through defects in the blood-brain barrier (BBB), binds to astrocytes (ASTs),
and initiates complement dependent cytotoxicity (CDC) by assembling complexes for
complement C1q (C1q) binding. AQP4-IgG also activates antibody-dependent cell-mediated
cytotoxicity (ADCC) by natural killer (NK) cells, and complement products stimulate
degranulation of polymorphonuclear cells (PMNs). Membrane attack complex (MAC) may
transit to adjacent oligodendrocytes, resulting in damage represented histopathologically
by myelin vesiculation. Degenerating ASTs alter oligodendrocyte physiology, resulting in
axonal swelling. Myelin debris is removed by infiltrating macrophages (MΦ). MOG:
Perivenous and confluent demyelination are mediated by combined humoral and cellular
mechanisms. CD4-lymphocyte and granulocytic infiltrates emerging from venous and
meningeal sources result in focal and confluent regions of demyelination highlighted by
nascently demyelinated axons with split myelin sheaths and vesiculation, myelin-laden
macrophages within active demyelinating regions, and activated microglia (MG) in the
periplaque area. Peripherally generated MOG-IgG may contribute to myelin destruction
through CDC and ADCC, as well as activated T-cell infiltration by facilitating phagocytosis
and antigen presentation. Perivenous MAC deposition and diffuse myelin protein loss are
histologic features supporting diffuse antibody-mediated myelin destruction. GFAP: GFAP
papillitis results from secondary axonal swelling. GFAP-IgG is predominantly generated
intrathecally; however, its role in driving disease pathology is unclear. Animal models
demonstrate predominantly perivascular, meningeal, and vascular CD8 T-cell infiltrates.
MS: Active MS lesions are characterized by the deposition of complement and immunoglobulin.
The perivenous inflammatory infiltrates are mainly composed of CD8+ T cells and B cells
producing intrathecal IgG in association with activated microglia and macrophages. MAC
complexes are observed along myelin sheaths and within myelin-laden MΦ, suggestive of
active CDC.
Reprinted with permission from DeLott L, et al, J Neurol.13 © 2022 Springer-Verlag GmbH.
1132 AUGUST 2022

channel aquaporin-4 (AQP4)-IgG. The AQP4 water channel is expressed on the KEY POINT
end-feet of astrocytes, which represent a key target in NMOSD.4,5 Importantly,
● The discovery of the
AQP4-IgG is not merely a bystander; it plays a pathogenic role in astrocytic pathogenic aquaporin-4–IgG
injury.5 Complement and cell-mediated antibody-dependent astrocyte antibody has helped
destruction is a primary event in NMOSD, which in turn causes secondary loss of distinguish neuromyelitis
oligodendrocytes and demyelination, distinct from MS.4-6 optica spectrum disorders
(NMOSD) as an autoimmune
Although NMOSD may manifest at any age, the disease predominantly affects
astrocytopathy, distinct
middle-aged women. The mean age of symptom onset is 40 years, and the from multiple sclerosis.
female-to-male ratio is approximately 9:1.2,7,8 The annual incidence of NMOSD is
approximately 0.5 to 0.8 per 1,000,000, and the annual worldwide prevalence
range is 0.5 to 4 per 100,000.7,8 Notably, the highest estimates of incidence (0.73
per 100,000 person-years; 95% confidence interval [CI], 0.45 to 1.01) and
prevalence (10 per 100,000 people; 95% CI, 6.8 to 13.2) of NMOSD occur in
Afro-Caribbean regions.8 In contrast, the incidence and prevalence of NMOSD
are much lower (0.037 per 100,000 person-years [95% CI, 0.036 to 0.038] and
0.7 per 100,000 people [95% CI, 0.66 to 0.74], respectively) in Australia and
New Zealand.8 Recurrent attacks and event-related disability are common in
NMOSD, which has an overall relapse rate between 60% and 98%.9,10 Until
recently, off-label use of conventional immunosuppressive therapies has been
the mainstay of therapy for patients with NMOSD, with the goals of preventing
relapses and ameliorating risk of chronic neurologic disability. The treatment
armamentarium has included rituximab, mycophenolate mofetil, azathioprine,
and prednisone.11 The seminal work of Lennon and colleagues3 leading to the
discovery of AQP4-IgG as a pathogenic antibody in NMOSD facilitated the
identification of key immunologic targets in the condition, including the terminal
complement system, the interleukin 6 receptor, and B cells.11 Four randomized
controlled trials have recently tested the efficacy of eculizumab, satralizumab,
and inebilizumab in patients with NMOSD; these newly approved agents all
showed benefit in preventing future attacks.11 The utility of these drugs will
depend on their mechanisms of action, rapidity of onset, duration of efficacy,
and long-term safety.11,12 As the therapeutic landscape continues to evolve, it is
imperative that neurologists be familiar with the clinical features, diagnostic
evaluation, and management approach to NMOSD.
AN AUTOIMMUNE ASTROCYTOPATHY
A detailed review of NMOSD immunopathology is beyond the scope of this
review, yet it is important to highlight immune pathophysiologic aspects that
distinguish this condition from other inflammatory disorders of the central
nervous system (CNS) such as MS, myelin oligodendrocyte glycoprotein
(MOG)-IgG–associated disorders, and glial fibrillary acidic protein (GFAP)
astrocytopathy (FIGURE 7-1).13 As a point of clarification, NMOSD is no longer
considered an especially severe inflammatory demyelinating disease of the CNS
but is recognized instead as an autoimmune astrocytopathy.2,4,6,14 Specifically,
the pathologic lesions in NMOSD are heterogeneous and different from MS,14
showing more extensive loss of immunostaining for AQP4 and GFAP than
myelin damage.2 Owing to severe astrocyte injury, GFAP levels are higher in the
CSF of seropositive patients with NMOSD during acute exacerbations compared
with levels seen with MS relapses.2 The binding of APQ4-IgG antibody to
AQP4 on astrocytic foot processes initiates the complement pathway, with
immunologic consequences that ultimately disrupt the blood-brain barrier,

causing an astrocytopathy, followed by secondary oligodendrogliopathy and

neuronal death in NMOSD.5 Although complement-mediated cytotoxicity is a
major cause of injury to AQP4-expressing astrocytes, astrocytic damage in
NMOSD can also occur via antibody-dependent cellular cytotoxicity,
AQP4-reactive T cells, and inflammatory cytokines.2 Astrocytic injury has
deleterious consequences because these cells carry out several important
functions in the CNS including but not limited to forming and maintaining the
blood-brain barrier, preserving energy balance, orchestrating immune
responses, and facilitating synaptic transmission.4,15 The pathogenicity of
AQP4-IgG is widely recognized, yet it is still not entirely clear what triggers
disease expression in patients with NMOSD.5 The application of AQP4 antibodies
to healthy animals often fails to induce NMOSD-like disease activity in
experimental models.5 Moreover, AQP4 seropositivity can be detected in
NMOSD long before the onset of clinical disease.5 Systemic infection, immune
tolerance breakdown, and oxidative stress are factors believed to accompany the
onset of clinical manifestations, suggesting that disease expression requires an
intersection among pathogenic antibodies, local inflammation, and blood-brain
barrier disruption.5 Insights regarding the immunopathology of NMOSD have
given rise to novel therapies and management strategies for NMOSD, which may
improve prognosis.
FIGURE 7-2
Two cases of transverse myelitis associated with neuromyelitis optica spectrum disorder
(NMOSD). A 21-year-old woman presented with a 1-week history of hiccups, a burning
sensation in her neck, trunk, and legs, decreased rectal tone, and lower limb weakness.
A, Sagittal T2-weighted MRI shows poorly delineated hyperintense signal changes within an
enlarged spinal cord extending over eight to nine spinal segments (longitudinally extensive
transverse myelitis). A hyperintense dorsal medulla/area postrema lesion is also seen (arrow).
B, Sagittal postcontrast T1-weighted MRI shows patchy enhancement of the spinal cord
lesion. As a second example, a 37-year-old man presented with left monocular vision loss
and progressive upper extremity weakness. C, Axial fluid-attenuated inversion recovery
(FLAIR) MRI shows hyperintense signal change in the left retrobulbar optic nerve (arrow).
D, Sagittal T2-weighted MRI shows hyperintense signal changes in the cervical cord
extending over five to six spinal segments. The lesion occupied more than two-thirds of the
cross-sectional diameter of the cord and did not enhance (not shown).
Reprinted with permission from Costello F and Scott JN, Continuum (Minneap Minn).21
© 2019 American Academy of Neurology.
1134 AUGUST 2022

CLINICAL FEATURES AND DIAGNOSTIC CRITERIA KEY POINT
Understanding regarding disease expression in patients with NMOSD continues
● Although optic neuritis
to evolve. NMOSD was once viewed erroneously as a monophasic disease and transverse myelitis are
characterized by severe optic neuritis and transverse myelitis, hence its early common features, the full
moniker NMO.9 In fact, very few patients with NMOSD (4%) experience a breadth of neurologic,
monophasic course; the vast majority, instead, experience recurrent events.9,10,16,17 ophthalmic, and systemic
disease manifestations of
Ninety-two percent of patients with seropositive NMOSD (AQP4-IgG positive)
NMOSD continues to
experience relapses, and 93% of AQP4-IgG–positive patients have relapses, on expand.
average, 1.3 times per year.12,17-20 Certainly, optic neuritis and transverse myelitis
events are predominant features of NMOSD (FIGURE 7-2)21; 85% of patients
present with transverse myelitis (50%) or optic neuritis (35%) (10% with both)
as their initial event, with a minority (4%) of patients manifesting other clinical
syndromes at disease onset.12,22-24 The spectrum of neurologic, ophthalmic,
systemic, and indeed psychiatric features that typify NMOSD continues to
expand. A list of clinical features and manifestations of NMOSD is found in
9,10,13,25-32
TABLE 7-1.
In 2015, an international panel revised existing diagnostic criteria and
formally designated NMOSD as a unifying term for the entire clinical spectrum
of disease expression.9 As part of the revision process, the term NMOSD was
extended to encompass cases of associated autoimmune disorders, including
systemic lupus erythematosus (SLE), Sjögren syndrome, and myasthenia
gravis.9 The new diagnostic criteria stratified NMOSD by antibody serostatus
(AQP4-IgG positive versus AQP4-IgG negative) (TABLE 7-2).9 For patients
who are AQP4-IgG positive, NMOSD diagnosis can be rendered with fulfillment
of at least one core clinical feature, whereas seronegative patients (or those
with unknown serum antibody status) must demonstrate at least two or more
core clinical features (at least one core clinical characteristic must be optic
neuritis, acute myelitis, or area postrema syndrome) with supporting MRI
features (TABLE 7-2).9 The purpose of the revised criteria was to optimize the
sensitivity and specificity for NMOSD diagnosis while excluding potential
mimics.9
RED FLAGS FOR MISDIAGNOSIS

NMOSD is, by definition, a diagnosis of exclusion.9 For this reason, certain red
flags should prompt concern for alternative diagnoses and signal the need for
additional investigations; these red flags include the following9:
u Acute symptom onset (less than 4 hours)

u Chronic progressive course
u Active coexisting disorder that could mimic NMOSD clinical presentation
u Cerebral MRI lesions showing persistent gadolinium enhancement for more than 3 months
u Presence of CSF oligoclonal bands
The patient’s clinical presentation and course can provide important clues.
Symptoms of NMOSD are not hyperacute in onset (nadir reached within
4 hours) nor are they protracted (worsening over 4 or more weeks).9
Furthermore, neurologic deficits in patients with NMOSD are tied to relapses as
opposed to interevent progression, as is seen in individuals with MS. Therefore,
neurologic deficits that progress over weeks to months would be atypical for

patients with NMOSD and suggest an alternative etiology.9 Ancillary tests should
be evaluated with due diligence because virtually every radiologic feature of
NMOSD can be caused by something else. Specifically, clinical and radiologic
features of myelopathy may be caused by sarcoidosis and other systemic
inflammatory disorders, MOG-associated disorders, GFAP astrocytopathy,
spondylotic myelopathy, ischemia, metabolic disorders (deficiency in vitamin
B12, copper, folate, or vitamin E), neoplasms, paraneoplastic myelopathy, spinal
dural arteriovenous fistulas, and Leber hereditary optic neuropathy plus
syndromes.32-34 MRI findings indicating possible chiasmatic/optic neuritis have
TABLE 7-1 Clinical Features of Neuromyelitis Optic Spectrum Disorders
Neurologic, systemic, and

psychiatric syndromes Clinical features
Optic neuritis Vision loss often characterized by severe, painless decline in visual acuity to Snellen equivalent of
20/200 or worse, with altitudinal visual field defects at presentation9; acutely, the optic nerve
may be swollen or normal in appearance; prognosis for visual recovery is guarded13
Transverse myelitis Sensory and motor dysfunction is often severe, with associated painful tonic spasms at times and
pruritis; neurologic recovery may be limited, and worse outcomes are predicted by more
extensive longitudinally extensive transverse myelitis lesions with subsequent cord atrophy9,32
Area postrema syndrome Area postrema syndrome is characterized by persistent nausea, vomiting, and hiccups9 and may
be initially misdiagnosed as a primary gastrointestinal syndrome, causing treatment delay;
approximately 58% of patients with neuromyelitis optic spectrum disorders (NMOSD) experience
area postrema syndrome during the course of their disease, and this syndrome often heralds
other NMOSD-related relapses over the disease course10
Brainstem syndromes Variable presentations of cranial nerve palsies, including hearing loss, gaze palsies, opsoclonus,
myoclonus, ataxia, and limb weakness may occur9,30
Diencephalic syndromes Patients may manifest narcolepsy, hypothermia, syndrome of inappropriate secretion of
antidiuretic hormone (SIADH), anorexia, daytime somnolence, and obesity9,30
Cerebral syndromes Encephalopathy (acute disseminated encephalomyelitis [ADEM]-like), posterior reversible

encephalopathy syndrome (PRES), hydrocephalus, and seizures have been reported30
Acute myopathy with Recurrent hyperCKemia with muscle pathology compatible with complement-activating IgG
hyperCKemia targeting sarcolemmal aquaporin-4 (AQP4) confirms organ involvement beyond the central
nervous system (CNS) as a component of NMOSD30,31
Myeloradiculopathy Clinical features of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) including

weakness and sensory loss with lower motor neuron features on examination; MRI shows
evidence of cauda equina and spinal root enhancement28
Neuropsychiatric Psychiatric manifestations may be more common in NMOSD than multiple sclerosis (MS), with
recurrent major depressive disorder being the most commonly reported psychiatric diagnosis;
patients with NMOSD may also have mania, dysthymic disorder, anxiety, psychosis, and eating
disorders; suicide risk is reported to be higher in NMOSD than MS25-27
Uveitis Vision loss, blurred vision, floaters, and photosensitivity due to inflammation of the uveal tract
may occur in 1% of NMOSD cases, with bilateral anterior uveitis being the most common subtype;
uveitis attacks may precede relapses among 67% of patients29
IgG = immunoglobulin G; MRI = magnetic resonance imaging.
1136 AUGUST 2022

Neuromyelitis Optica Spectrum Disorder Diagnostic Criteriaa TABLE 7-2
Diagnostic criteria for neuromyelitis optica spectrum disorder (NMOSD) with positive
aquaporin-4 (AQP4)-IgG
◆ At least one core clinical characteristic
◆ Positive test for AQP4-IgG using best available detection method (cell-based assay
strongly recommended)
◆ Exclusion of alternative diagnoses
Diagnostic criteria for NMOSD without AQP4-IgG or NMOSD with unknown AQP4-IgG status
◆ At least two core clinical characteristics occurring as a result of one or more clinical
attacks and meeting all of the following requirements:
◇ At least one core clinical characteristic must be optic neuritis, acute transverse myelitis
with longitudinally extensive transverse myelitis (LETM), or area postrema syndrome
◇ Dissemination in space (two or more different core clinical characteristics)
◇ Fulfillment of MRI requirements below as applicable
◆ Negative tests for AQP4-IgG using best available detection method or testing unavailable
◆ Exclusion of alternative diagnoses
Core clinical characteristics
◆ Optic neuritis
◆ Acute transverse myelitis
◆ Area postrema syndrome: episode of otherwise unexplained hiccups or nausea and vomiting
◆ Acute brainstem syndrome
◆ Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical
diencephalic MRI lesions
◆ Symptomatic cerebral syndrome with NMOSD-typical brain lesions
Additional MRI requirements for seronegative NMOSD
◆ Acute optic neuritis: requires brain MRI showing (1) normal findings or only nonspecific
white matter lesions, OR (2) optic nerve MRI with a T2-hyperintense lesion or T1-weighted
gadolinium-enhancing lesion extending over more than half the optic nerve length or
involving optic chiasm
◆ Acute transverse myelitis: requires associated intramedullary MRI lesion extending over
three contiguous segments (LETM) OR three contiguous segments of focal spinal cord
atrophy in a patient who has a history that is compatible with acute transverse myelitis
◆ Area postrema syndrome: requires associated dorsal medulla/area postrema lesions
◆ Acute brainstem syndrome: requires associated periependymal brainstem lesions
IgG = immunoglobulin G; MRI = magnetic resonance imaging.

a
Modified with permission from Wingerchuck DM, et al, Neurology.9 © 2015 American Academy of
Neurology.

been reported with chronic infections (tuberculosis, syphilis), neoplasms, SLE,

and sarcoidosis.35-37 Finally, radiologic lesions that show persistent enhancement
for more than 3 months9,32 and/or the presence of positive CSF oligoclonal bands
(20% of NMOSD versus 80% of MS cases) are uncommon in NMOSD and should
prompt further investigations.9
ANTIBODY STATUS, DIAGNOSIS, AND DISEASE COURSE

AQP4 antibodies are produced in the extrathecal space; therefore higher levels
are found in serum than CSF. For this reason, serum, not CSF, antibody testing is
recommended in the evaluation of patients with suspected NMOSD.9,30
Cell-based assays are recommended and yield a sensitivity of between 80% and
100%, with specificity scores of 86% and 100%.9,30 Earlier-generation enzyme-
linked immunosorbent assay (ELISA) testing techniques offered a sensitivity of
75% to 80% and specificity of greater than 99% but also carried a five-fold higher
risk of false-positive results.30 It is important to note that AQP4-IgG serostatus
may change during the course of disease for some patients, but seropositivity
usually persists even during periods of remission. Unfortunately, serum
AQP4-IgG titers may not predict long-term disease course, and NMOSD
serostatus (positive versus negative) does not reliably predict response to
therapy. An unmet need exists for better serologic biomarkers to gauge disease
severity and predict disease activity.10,38-40 In a 2021 meta-analysis, Liu and
colleagues41 systematically assessed the association between serum AQP4-IgG
titer and NMOSD disease course and noted no significant differences in serum
AQP4-IgG titers between relapses and remission phases of the disease. Akaishi
and colleagues42 studied repeat serum AQP4-IgG titers derived with cell-based
assay techniques in 45 patients with NMOSD and reported no correlation
between AQP4-IgG titer at disease onset and relapse frequency 10 years later. In
their study, serum AQP4-IgG titers at onset also failed to correlate with
neurologic disability accrued 5 to 10 years after diagnosis.42 Thus, determining
serum AQP4-IgG status is critical at the diagnostic stage of NMOSD, but the yield
of repeating titers with the intent to predict relapses may be limited. Instead,
clinicians should consider what other factors, other than serum AQP4-IgG titers,
more robustly reflect attack occurrence and disease activity in patients
with NMOSD.
From a diagnostic standpoint, approximately 75% of patients with NMOSD
are seropositive for AQP4-IgG.2,9,10 Approximately 30% of AQP4-IgG–
seronegative patients with NMOSD harbor MOG-Ig antibodies.43 Seronegative
patients with NMOSD are more likely to be male, young, and of White European
descent. Moreover, these patients may experience less severe visual impairment
than their seropositive counterparts.2 Debate is ongoing about whether
MOG-associated disorders and NMOSD represent truly distinct conditions or
occupy different points on the same disease spectrum. Some patients who are
MOG-IgG positive meet the 2015 criteria for AQP4-IgG–negative NMOSD, and
early reports of NMO likely included MOG-associated disorder cases.2 The crux
of this matter is really one of “lumping” versus “splitting.” Those who “lump”
MOG-associated disorders and NMOSD together argue that MS, NMOSD, and
MOG-associated disorders should all be integrated within the spectrum of
idiopathic inflammatory-demyelinating diseases.43 These proponents assert that,
although patients with AQP4-IgG and MOG-IgG antibodies may display
different epidemiologic and clinical features, common denominators link both
1138 AUGUST 2022

disorders. Specifically, MOG-IgG and AQP4-IgG autoantibodies belong to the KEY POINT
IgG1 subclass, bind to glial proteins, and activate complement to induce tissue
● Red flags for an
injury.43 From an immunologic perspective, both conditions are associated with a alternative diagnosis rather
T-helper 17 cytokine profile that drives antibody production.43 Significant than NMOSD include acute
overlap exists in the radiologic expression of MOG-associated disorders and symptom onset (less than
NMOSD.43 In addition, both disorders respond to oral immunosuppressants and/ 4 hours), a chronic
progressive course, a
or anti-CD20 therapies that inhibit the T-helper 17 cytokine–related cascade.43
comorbidity that could
Because 88% of MOG-IgG–positive patients fulfill criteria for an NMOSD mimic clinical features of
diagnosis, the “lumpers” argue that a positive MOG-IgG result should be NMOSD, cerebral MRI
considered an alternative to AQP4-IgG status.43 The “splitters” on this issue lesions showing persistent
enhancement (for more than
counter that, although NMOSD, MOG-associated disorders, and indeed patients
3 months), and the presence
with MS have many overlapping clinical and radiologic features, these CNS of oligoclonal bands in
inflammatory disorders have different immunopathologic mechanisms driving the CSF.
neurologic impairment and accordingly require different therapeutic
management.2 MOG-associated disorders are not simply milder variants of
NMOSD because NMOSD is an autoimmune astrocytopathy, whereas
MOG-associated disorder is a primary inflammatory demyelinating
condition.2,44-46 NMOSD-related neurologic syndromes tend to be more
clinically severe and feature different paraclinical findings. NMOSD optic
neuritis, for example, is associated with severe vision loss and often involves
posterior regions of the optic nerves and chiasm, whereas patients with MOG
optic neuritis often present with significant optic disc edema
(CASE 7-1) and intraorbital optic nerve involvement.47 Orbital MRI in MOG optic
neuritis often shows extensive T2-weighted/short tau inversion recovery (STIR)
optic nerve lesions with contrast enhancement and perineural edema sparing the
optic chiasm.44,47 Similarly, the transverse myelitis associated with
MOG-associated disorders demonstrates prominent sensory and autonomic
dysfunction, often with milder motor deficits than are typically seen with
AQP4-IgG–positive NMOSD.44,47 Spinal imaging in MOG-associated disorders
differs from NMOSD; a greater predilection for lower spinal cord involvement is
seen, including the conus region in the former.9,44 Acute disseminated
encephalomyelitis (ADEM)-like lesions and seizures are more common in
MOG-associated disorders than in NMOSD, whereas NMOSD is more likely to
involve the hypothalamic and area postrema CNS regions.30,44 In contrast,
MOG-associated disorders have a predilection for involvement of the cerebellar
peduncles.30,44 Unlike NMOSD, MOG-associated disorders do not seem to have a
racial or sex predilection.2,31,44 Moreover, clinical features of MOG-associated
disorders may be age-related such that ADEM-like lesions and optic neuritis are
more likely to affect children and young adults whereas isolated transverse
myelitis may predominantly impact older adults.44
Finally, in terms of disease course, approximately half of patients with
MOG-associated disorders have a monophasic process in contrast to the vast
majority of patients with NMOSD who experience recurrent attacks.10,44 Patients
with monophasic MOG-associated disorders may seroconvert to a negative status
and remain relapse free, unlike patients with NMOSD who are at risk of relapse
throughout the course of their disease, regardless of AQP4-IgG antibody levels.44
Going forward, a more refined classification of MS, NMOSD, and
MOG-associated disorders will likely emerge, potentially relying on
biomarker-based strategies.46 Questions regarding where MOG-associated
disorders end and NMOSD begins will best be answered with robust pathologic,

immunologic, radiologic, and clinical characterization of patients affected by

these different disorders.
EVERY RELAPSE MATTERS

An NMOSD relapse has been likened to a “neuro-immunological stroke” with
a poor prognosis for recovery.12 Indeed, neurologic disability accrued from
optic neuritis and acute myelitis relapses is significant: historically, 41% of
AQP4-positive patients become legally blind, and 22% of patients require a
walker within 5 years of disease onset.12,18,20 Moreover, before the era of
approved therapies, 23% of patients developed wheelchair dependency, and
9% died from the effects of their disease within 75 months of follow-up.12,20
CASE 7-1 A 34-year-old man who was previously well presented with a 3-day
history of pain and vision loss in his right eye. His examination showed a
best-corrected Snellen visual acuity of 20/200 in the right eye and 20/20
in the left eye. His pupils were 6 mm in darkness constricting to 3 mm in
bright light with a right relative afferent pupillary defect. The fundus
examination of the right eye showed optic disc edema with hemorrhage
superior to the optic disc (FIGURE 7-3A). Fundus findings were normal in the
left eye (FIGURE 7-3B). Ocular motility was normal, and the remaining
findings on the neurologic examination were unremarkable.
MRI of the brain was normal. Yet, fat-suppressed T1-weighted,
gadolinium-enhanced views of the orbits (FIGURE 7-3C) showed
enhancement of the right optic nerve at the level of the optic canal. The
patient underwent serologic testing for aquaporin-4 (AQP4)-IgG
antibodies, which proved negative. Serum testing for myelin
oligodendrocyte glycoprotein (MOG)-IgG antibodies (cell-based assay)
was positive. The patient was treated with high-dose IV
methylprednisolone for 5 days and had good visual recovery within
2 weeks of symptom onset.
COMMENT Several features of this case are typical for MOG-associated disorders. The
patient is a young man; although neuromyelitis optica spectrum disorder
(NMOSD) is more likely to affect middle-aged women, MOG-associated
disorders may be just as likely to affect men as women. The manifestations
of prominent optic disc edema with hemorrhage are more typical findings
of MOG-associated optic neuritis than NMOSD optic neuritis or optic
neuritis associated with multiple sclerosis. The patient has prominent optic
nerve enhancement extending through the optic canal. Accordingly,
patients with MOG-associated optic neuritis may be more likely to
demonstrate longitudinal lesions affecting the intraorbital optic nerve
segments, with prominent perineural enhancement as compared with
patients who have optic neuritis with MS or NMOSD. Finally, the patient
experienced very good visual recovery with high-dose IV
methylprednisolone, which is more likely to occur in cases of
MOG-associated optic neuritis than NMOSD optic neuritis.
1140 AUGUST 2022

Optic neuritis relapses tend to occur more frequently in NMOSD before
the age of 30 years, with transverse myelitis relapses occurring more
often in older patients.48 Importantly, only 25% of long-term disability in
patients with NMOSD is tied to the initial presentation, which means that
the bulk of disability is linked to recurrent attacks.49 Thus, with early
diagnosis and appropriate therapy, long-term disability in NMOSD may be
preventable.
Relapses Versus Pseudorelapses

In the setting of NMOSD, a relapse refers to clinical worsening caused by new
symptoms or an exacerbation of preexisting deficits lasting longer than 24 hours
FIGURE 7-3
Imaging findings from the patient in CASE 7-1. A, The
fundus examination of the right eye shows optic
disc edema with hemorrhage superior to the optic
disc. B, Fundus findings are normal in the left eye.
C, A Fat-suppressed axial postcontrast
T1-weighted view of the orbits shows
enhancement of the right optic nerve at the level
of the optic canal and orbital apex (arrow).

and not otherwise explained by mitigating circumstances such as fever or

infection.10 The gold standard for relapse definition is met when corresponding
evidence of a new or enhancing MRI lesion also exists.10,49-51 In contrast, a
pseudorelapse is a clinical exacerbation of preexisting neurologic symptoms that
worsen because of systemic metabolic factors. Pseudorelapses are not
accompanied by new MRI findings, and they resolve with treatments targeting
the underlying cause.49-51 On a more granular level, some studies have defined a
relapse as an increase of at least 0.5 points on the Expanded Disability Status Scale
(EDSS), an increase of at least 1 point on two functional system scales, or an
increase of at least 2 points on one functional scale.10 In a retrospective analysis of
74 hospitalizations of patients with NMOSD, the most common causes of
pseudorelapse were infection, pain, and dysautonomia.50 Area postrema
syndrome relapses are characterized by nausea, vomiting, or hiccups and ideally
should last more than 48 hours or be supported by MRI findings.10 In the clinical
arena, it can often be quite difficult to distinguish true NMOSD relapses from
pseudorelapses. Worsening visual acuity is one clinical finding that has been
shown to correlate with a new optic neuritis event; in contrast, worsening motor
dysfunction, sensory loss, and bowel and/or bladder symptoms may not reliably
differentiate new transverse myelitis from a pseudorelapse event.50 It is of
paramount importance to identify true breakthrough relapses in NMOSD
because these events can worsen disability. That said, failing to recognize a basis
for pseudorelapse may inappropriately expose patients to acute
immunosuppressive treatments (such as high-dose corticosteroids or plasma
exchange therapy) and paradoxically delay appropriate care.
Predicting and Managing Neuromyelitis Optica Spectrum Disorder Relapses

The risk of relapse for NMOSD may be linked to patient-related factors, disease
duration, paraclinical findings, and treatment regimens.10,49,50-53 Female sex,
younger age, and either European or African descent are factors associated with a
higher risk of relapse.10,49-51 Japanese patients have a lower overall predilection
toward relapses but have higher rates of brainstem attacks than do patients of
European or African descent.49 Patients of African descent have the highest rates
of cerebral relapses and are at higher overall risk of blindness due to NMOSD.49
Before the age of 30 years, optic neuritis attacks are more common than
transverse myelitis among patients with NMOSD, whereas after the age of 30 this
pattern is reversed.48 Disease duration also affects relapse rates in patients with
NMOSD, such that patients with shorter disease duration exhibit more attacks.10,49
A recent past history of relapse may be the best predictor of future events, and
the severity of prior relapses may portend higher risk of disability with
subsequent attacks.10 Coexisting medical conditions should also be considered
when evaluating a patient with NMOSD for potential relapse. For example,
patients with thyroid antiperoxidase antibodies may be predisposed to recurrent
transverse myelitis events.10 Similarly, patients with NMOSD who have
underlying cancers may have a relapse in the setting of disseminated or recurrent
disease.10 Systemic infections may compromise the blood-brain barrier, thus
exacerbating disease in NMOSD.10 Indeed, approximately 15% to 35% of patients
with NMOSD have clinical symptoms of acute infection before a relapsing
episode.10 Importantly, the overall prognosis for patients with NMOSD with
infections is poor, such that only 25% may experience full recovery.10
Accordingly, efforts should be made to mitigate risk of infection for these
1142 AUGUST 2022

patients. The issue of vaccination and relapse risk in NMOSD has contemporary KEY POINTS
relevance: although vaccination may increase the risk of relapse within 30 days of
● Only 25% of long-term
inoculation, studies indicate that vaccination is generally safe for patients with disability for patients with
NMOSD who are receiving appropriate immunosuppressant therapy.10 NMOSD is related to the
Pregnancy and the peripartum period also represent vulnerable states for female initial presentation, which
patients with NMOSD, who are more likely to have a relapse during the third means a significant amount
of neurologic impairment is
trimester of pregnancy and have a high relapse risk within 3 to 6 months after
preventable. The best way
delivery.10 Relapses can also be forecasted by prodromal symptoms such as to treat an NMOSD relapse is
painful tonic spasms.10 While it is uncommon for area postrema syndrome to to prevent it.
occur at initial onset (CASE 7-2), 58% of area postrema syndrome attacks occur
before other NMOSD-related relapses by a median of 10 days.10 ● Vaccination may increase
the risk of relapse for
Ancillary studies can offer some predictive value with respect to anticipating 30 days after inoculation,
NMOSD relapses. Orman and colleagues52 have shown that the presence of yet studies indicate that
contrast enhancement on cranial MRI performed during acute neurologic vaccination is generally safe
events is associated with a higher annualized relapse rate, particularly when for patients with NMOSD
who are receiving
periependymal contrast enhancement is present. Medullary lesions are also appropriate
associated with an increased risk of LETM, which may, in turn, be a marker of immunosuppressant
severe symptoms and poor prognosis in NMOSD.53 In addition, spinal cord therapy.
atrophy and spinal cord lesion length may have predictive value for future
● High-dose corticosteroid
neurologic impairment. In several studies, longer spinal cord lesion length at the
treatment represents the
time of an attack was associated with increased disability, both at attack nadir mainstay of acute
and after recovery.10,32,54,55 The use of immunosuppressive treatments is management for NMOSD
associated with reduced relapse rates for patients with NMOSD, whereas MS relapses, but occasionally
adjunctive treatment with
disease–modifying agents are associated with an increased likelihood for
plasma exchange or
breakthrough attacks.10 Ultimately, understanding relapse patterns and immunoadsorption may be
predictive factors will help optimize treatment approaches for patients needed for refractory
with NMOSD. attacks. In this setting, the
Currently, high-dose corticosteroid treatment, namely IV methylprednisolone, role of IVIg for NMOSD
relapses is less clear.
is considered first-line therapy in the acute phase of NMOSD, followed by a
gradual taper with oral steroids and long-term maintenance with
immunosuppression.56-67 A typical starting dose for treatment of acute relapses is
1000 mg IV methylprednisolone daily for 5 days, followed by an oral steroid
taper for 2 to 8 weeks depending on the severity of the attack.56 Arguably,
equivalent doses of other corticosteroids such as high-dose oral prednisone
(1250 mg daily) would likely be just as effective because the bioavailability of IV
versus oral corticosteroids is approximately the same.56 High-dose
corticosteroids are believed to suppress inflammatory cytokines.2 For long lesions
or severely inflamed attacks, additional steroid doses may be tried.32,56 Yet, IV
methylprednisolone does not always improve the effects of relapses, and the
benefit in administering repeat steroid courses for a given relapse event may be
limited. Plasma exchange (replaced with 5.0% human albumin solution,
replacement volume 30 mg/kg to 40 mg/kg, four to eight sessions) or
immunoadsorption may be needed as adjunctive therapy for attacks refractory
to steroid treatment.30,56-59,61-67 The mechanisms by which plasma exchange
ameliorates the effects of NMOSD relapses are not entirely clear, but they likely
involve removal of autoantibodies and clearance of inflammatory cytokines and
complement factors.56,63 It is not known whether plasma exchange should be used
simultaneously with IV methylprednisolone or after IV methylprednisolone
treatment.58,59,61,63,66,67 It is similarly unclear whether IVIg (0.4 g/kg/d for a total
of 5 days) has therapeutic efficacy in NMOSD.57 For individuals who are

CASE 7-2 A 42-year-old woman presented with a history of painless, subacute-

onset vision loss in the left eye that progressed over 2 days. Despite a
3-day course of IV methylprednisolone administered 5 days after
symptom onset, she reported no improvement in her visual function
8 weeks later. On further inquiry, she reported a 10-day episode of
intractable hiccups with nausea and vomiting 3 months earlier, which was
presumed to be caused by viral gastroenteritis, and these symptoms
improved spontaneously. She was otherwise well and used no
medications. Her family history was noncontributory.
On examination, her blood pressure was 120/70 mm Hg, her heart rate
was 70 beats per minute (regular), and she was afebrile. Her
best-corrected Snellen visual acuity was 20/20 in her right eye and hand
motions at 2 feet in her left eye. Her pupils measured 5 mm in darkness
FIGURE 7-4
Imaging findings from the patient in CASE 7-2. The fundus examination shows a normal-
appearing optic nerve in the right eye (A) and temporal optic disc pallor in the left eye (B).
MRI of the orbits shows a longitudinal fat-suppressed fluid-attenuated inversion recovery
(FLAIR) hyperintensity within the left optic nerve (white arrow), affecting the intraorbital
segment of the nerve and extending along its length to the optic chiasm (C). Axial FLAIR
imaging of the brain reveals several subcortical white matter signal changes (D, open arrow).
1144 AUGUST 2022

and constricted to 3 mm in bright light with a large left relative afferent
pupillary defect. Automated perimetry was normal in her right eye and
showed a large dense central scotoma in her left eye. The fundus
examination showed a normal-appearing optic nerve in her right eye
(FIGURE 7-4A), whereas she had temporal optic disc pallor in her left eye
(FIGURE 7-4B). Ocular motility was normal as were the remaining cranial
nerve findings. The neurologic examination was otherwise normal.
MRI of the orbits showed a longitudinal T2-weighted and
fluid-attenuated inversion recovery (FLAIR) hyperintense signal within the
left optic nerve, affecting the intraorbital segment of the nerve and
extending along its length to the optic chiasm (FIGURE 7-4C). Axial FLAIR
sequences of the brain revealed numerous subcortical white matter
signal changes (FIGURE 7-4D). Initial interpretations of the MRI suggested
the possible diagnosis of multiple sclerosis (MS), but serum aquaporin-4
(AQP4)-IgG testing (cell-based assay) proved positive, indicating the
diagnosis of neuromyelitis optica spectrum disorder (NMOSD). The
patient experienced poor visual recovery in the left eye. She was
subsequently treated with chronic immunosuppressive therapy
(rituximab) and had no recurrent optic neuritis events.
This case illustrates several important points that ultimately helped render COMMENT
the diagnosis of NMOSD but not before the patient was left with
permanent vision loss. The older age of the patient and absence of any
visual recovery after 8 weeks were atypical features for sporadic optic
neuritis or optic neuritis heralding a diagnosis of MS. In “typical” cases of
optic neuritis, patients regain a line or two of Snellen visual acuity function
within 3 weeks of symptom onset. The orbital images in this case
demonstrated a longitudinal lesion affecting the left intraorbital optic
nerve, extending to involve the chiasm, which can be seen in NMOSD.
Importantly, the patient experienced symptoms consistent with area
postrema syndrome 3 months before her left optic neuritis event, which
were mistakenly attributed to a gastrointestinal illness. Regrettably, a
cranial MRI was not performed at that time, which may have shown
classical features for area postrema syndrome in the dorsal medulla.
Furthermore, had high-dose corticosteroid therapy and
immunosuppressive treatment been administered, the patient may or may
not have experienced an optic nerve relapse shortly thereafter. Given the
patient’s core clinical characteristics (optic neuritis and area postrema
syndrome), positive serum APQ4-IgG result, and lack of another diagnosis
that could otherwise explain her clinical presentation, she fulfilled
diagnostic criteria for NMOSD as outlined in TABLE 7-2.

unresponsive to IV methylprednisolone and plasma exchange, immunosuppression

with IV cyclophosphamide (dosing regimens vary) may be considered and may
represent a “final resort”; however, because of related risks, careful patient
selection and an experienced hospital team are advised.
Generally speaking, the benefits of acute treatments for NMOSD attacks are
believed to correlate with early administration.2,10,56-67 Approximately
two-thirds of NMOSD relapses may be associated with good recovery when
high-dose corticosteroids (with or without plasma exchange) are administered
within 14 days of symptom onset.65 Unfortunately, long-term outcomes from
relapses may be more tightly correlated with the severity of the attack at
presentation regardless of treatment timing, thus implicating the need for
chronic immunosuppressive therapies.65 Otherwise stated, the best way to treat a
relapse is to prevent it.
ESTABLISHED AND EMERGING BIOMARKERS

A biomarker is viewed as “a characteristic that is objectively measured and
evaluated as an indication of normal biological processes, pathogenic processes,
or pharmacologic responses to a therapeutic intervention.”68 Features of a good
biomarker include a strong association between the biomarker and the outcome.
Moreover, the benefits of treatment should affect the biomarker and the aspects
of the disease it represents, and time course changes captured by the biomarker
should parallel changes in the disease. Finally, plausible mechanisms should link
the biomarker with the pathogenesis of the disease.69-71 Biomarkers may be used
to facilitate diagnosis, track disease relapses and disability accrual, and gauge
therapeutic responses in patients with NMOSD. Currently, the diagnosis of
NMOSD requires fulfillment of explicit criteria with some overlap occurring
between MOG-IgG–positive and AQP4-IgG–negative cases. However, “gray
zone” areas still challenge distinctions among MS, MOG-associated disorders,
and NMOSD, for which better biomarkers are needed, particularly because MS
disease–modifying treatments can be detrimental to patients with NMOSD.10 A
list of established and emerging biomarkers for the diagnosis and management of
NMOSD is shown in TABLE 7-3.
Serum Testing
In addition to the known specificity and sensitivity of the AQP4-IgG antibody as
a diagnostic biomarker, serum neurofilament light chain has also gained recent
interest in the evaluation of patients with NMOSD. Neurofilament light chain is a
scaffolding protein in the neuronal cytoskeleton that is released in the
extracellular space following axonal damage, eventually making its way into CSF
and serum.72-74 Neurofilament light chain levels are increased in the CSF of
patients with neurodegenerative and traumatic disorders, including MS and
NMOSD. Initially, neurofilament light chain was measured in the CSF, which
posed obvious challenges in the clinical arena because testing was likely
considered too invasive to be practical. The debut of single-molecule array
testing enabled highly accurate and reproducible serum neurofilament light
chain measurements, which consistently parallel neurofilament light chain levels
in CSF.72-74 Studies have shown that higher serum neurofilament light chain
levels are observed in patients with MS compared with healthy controls.
Moreover, serum neurofilament light chain levels correlate with an increased
burden of T2-weighted and gadolinium-enhancing MRI lesions and worsening
1146 AUGUST 2022

disability scores in patients with MS. Serum neurofilament light chain levels
increase in the setting of MS relapses, decrease with disease-modifying therapy,
and correlate with a higher risk of future relapses in MS.72-74 Among patients
with NMOSD, by way of comparison, serum neurofilament light chain levels are
higher in patients with worse disability scores and older age.10,75 Furthermore,
serum neurofilament light chain levels in patients with NMOSD remain higher
for longer after relapses, relative to their counterparts with MS.10,75 These
findings suggest that neuroaxonal damage is more pronounced in NMOSD than
in MS, owing to fundamental differences in pathogenic mechanisms between the
two diseases. As a biomarker, serum neurofilament light chain may have a role in
measuring the severity of relapses. Its utility in the clinical arena will be best
determined with more longitudinal experience in larger patient populations.
CSF
CSF analysis is supportive for the diagnosis of NMOSD if oligoclonal bands
are absent, in the appropriate clinical context.9 Yet, oligoclonal bands may be
found in approximately 20% to 30% of patients with NMOSD, most often
during an attack. In contrast, oligoclonal bands are present in more than 85% of
patients with MS. Analysis of CSF from patients with NMOSD often shows
normal to highly inflammatory profiles, and this is typically more prominent for
episodes of transverse myelitis than optic neuritis. Pleocytosis of the CSF,
frequently with neutrophilic or eosinophilic predominance, is useful for
distinguishing NMOSD from MS.6,9 In addition to oligoclonal bands, CSF GFAP
levels have gained interest as a biomarker in NMOSD. GFAP is a principal
intermediate filament that forms the astrocyte cytoskeleton. Accordingly,
patients with NMOSD have elevated GFAP levels in the CSF and serum, owing to
astrocyte injury. Higher serum and CSF GFAP levels have been reported during
NMOSD attacks and predict the presence of relapses.10 Akin to neurofilament
light chain, CSF and serum GFAP levels show strong correlations, meaning
serum GFAP has the potential role as a biomarker for disease severity and
predictor of future disease activity in patients with AQP4-IgG–positive NMOSD,
even in phases of clinical remission. Finally, a higher serum GFAP/serum
neurofilament light chain quotient at relapse may help differentiate NMOSD
from MS,75 but this has been more practically calculated based on serum levels.
Optical Coherence Tomography

Optical coherence tomography (OCT) is an ocular imaging technique that uses
light properties to generate high-resolution images of the inner retina with a
resolution of within microns. OCT-measured peripapillary retinal nerve fiber
layer thickness is viewed as a surrogate marker of axonal injury in the afferent
visual pathway, and macular ganglion cell inner plexiform layer thickness is
interpreted to represent neuronal health.76,77 Patients with optic neuritis from
NMOSD typically have more severe vision loss and correspondingly extensive
retinal nerve fiber layer and ganglion layer thinning than patients with MS and
MOG with optic neuritis. It was originally suggested that microcystic macular
edema in eyes affected by optic neuritis represents a breakdown of the
blood-retina barrier and integrity of tight junctions in the myelin-free retina.
More recently, microcystic macular edema has been interpreted to reflect effects
of retrograde transsynaptic degeneration and retinal traction.78 Macular
microcysts are more frequently observed in eyes affected by NMOSD optic

TABLE 7-3 Established and Emerging Biomarkers in Neuromyelitis Optic Spectrum

Disorder
Biomarker Findings Role Key points
Serology
Aquaporin-4 80% of patients with neuromyelitis Diagnostic Cell-based assay preferred

(APQ4)-IgG optic spectrum disorder (NMOSD)
are seropositive
Other autoantibodies Positive systemic lupus Support diagnosis of Higher autoantibody levels are
erythematosus, Sjögren syndrome, NMOSD, particularly in seen with cases of clinically
myasthenia gravis antibodies AQP4-IgG– active connective tissue
seronegative cases diseases that co-associate with
NMOSD
Serum neurofilament Serum neurofilament light chain May have a role in Single-molecule array allows for
light chain correlates with clinical and MRI facilitating diagnosis accurate, reproducible levels
measures of disease activity, and detecting relapses that closely correlate with CSF
reflects drug effects, and captures neurofilament light chain;
NMOSD relapse effects notably, serum neurofilament
light chain will increase with
other pathologic states of the
central nervous system
Serum glial fibrillary GFAP is a principal intermediate Relapse detection Serum GFAP levels correlate
acidic protein (GFAP) filament that forms the astrocyte well with CSF GFAP levels
cytoskeleton; patients with NMOSD
have elevated GFAP levels in the CSF
and serum owing to astrocyte injury;
higher CSF GFAP levels have been
reported during NMOSD attacks
CSF
Oligoclonal bands Oligoclonal bands are commonly May have a role in Oligoclonal bands may be found
found in patients with multiple facilitating diagnosis in a minority of patients with
sclerosis (MS) and rare in NMOSD NMOSD (15%) and do not
exclude the diagnosis
GFAP GFAP is a principal intermediate Relapse detection: Serum GFAP levels correlate
filament that forms the astrocyte higher CSF GFAP levels well with CSF GFAP levels
cytoskeleton; patients with NMOSD have been reported
have elevated GFAP levels in the CSF during NMOSD attacks
and serum owing to astrocyte injury and predict the
presence of relapses
Optical coherence tomography
Peripapillary retinal Peripapillary retinal nerve fiber layer Relapse (optic Peripapillary retinal nerve fiber
nerve fiber layer changes represent axonal injury in the neuritis) detection and layer changes are not specific to
thickness afferent visual pathway; owing to the follow-up NMOSD and should be
severity of optic neuritis in patients interpreted in the context of a
with NMOSD, more peripapillary thorough ophthalmologic
retinal nerve fiber layer thinning examination
occurs over weeks to months after
NMOSD optic neuritis relative to MS
optic neuritis
CONTINUED ON PAGE 1149
1148 AUGUST 2022

CONTINUED FROM PAGE 1148
Macular ganglion cell Macular ganglion cell inner plexiform Optic neuritis relapse Macular ganglion cell inner
layer/ganglion cell inner layer thinning represents retinal detection and follow-up plexiform layer changes are not
plexiform layer thickness ganglion cell (neuronal) injury in specific to NMOSD and should
NMOSD be interpreted in the context of
a thorough ophthalmologic
examination
Microcystic macular Microcystic macular edema may be Relapse (optic neuritis) Microcystic macular edema is a
edema a marker of more severe optic detection and follow-up nonspecific finding and may be
neuritis and is more often seen in observed across a spectrum of
NMOSD optic neuritis than MS optic optic neuropathies
neuritis
MRI
Optic nerve lesions Longitudinal intracranial optic nerve Diagnosis and follow-up Longitudinal optic nerve and
lesions extending to the chiasm are chiasmal lesions can be found in
characteristic of NMOSD other disorders (eg, neoplasms,
sarcoidosis, lymphoma)
Optic nerve lesion length Optic nerve lesion length, Prognostic Worse optical coherence
particularly affecting the intraorbital tomography–measured retinal
and canalicular segments, correlates ganglion layer and ganglion layer
with long-term visual acuity in thinning can be paired with MRI
NMOSD measures to predict
vision-related quality of life
outcomes
Longitudinally extensive Spinal cord relapses in NMOSD Diagnosis, follow-up, Spinal lesions may evolve over
transverse myelitis usually cause an LETM, with the and predicting future time, so longitudinal follow-up
(LETM) spinal cord lesion spanning three or relapses may be needed
more consecutive vertebral
segments; up to 20% of patients may
present with a short-segment
transverse myelitis
Dorsal medulla lesions Lesions in the area postrema are May have a role in Area postrema lesions may be
common in NMOSD and may herald facilitating diagnosis in transient; therefore, it is
disease onset; patients present with the right clinical important to image soon after
hiccups, nausea, and emesis context symptom onset because
gadolinium-enhanced
sequences may improve
detection
Periependymal lesions Periependymal lesions are located May have a role in Periaqueductal lesions are seen
around the cerebral aqueduct and facilitating diagnosis in in NMOSD and MOG-associated
the third and fourth ventricles in the right clinical setting disorders but are rare in MS
circumventricular regions that are
highly vascularized and lack a
blood-brain barrier; these include
lesions in the diencephalon
(hypothalamus and thalamus) and
brainstem, which represent areas of
high AQP4-IgG expression


Bridge-arch lesions NMOSD corpus callosal lesions are May have a role in Callosal lesions in MS
often extensive and oriented along facilitating diagnosis in are characteristically
the long axis in a “bridge-arch” the right clinical setting well-circumscribed and ovoid
pattern; these lesions are shaped, oriented perpendicular
sometimes acutely edematous with to the lateral ventricles (Dawson
a marbled pattern fingers)
Brain lesion The enhancement pattern of brain May have a role in MS lesions are often
enhancement patterns lesions in NMOSD often shows facilitating diagnosis, open-ring or nodular with
pencil-thin linear periependymal or detecting disease well-demarcated enhancement
cloudlike configuration with poorly activity, and
marginated enhancement; prognostication
leptomeningeal enhancement may
also occur; enhancing lesions may
predict future relapses and later
disability
Cervical cord Mean upper cervical cross-sectional Detecting disease The association between
(cross-sectional area) area as a measure of spinal cord activity and cervical cord cross-sectional
atrophy is associated with an prognostication area and disability has been
increased number of myelitis found even in patients with
relapses and has been predictive of NMOSD with and without a
subsequent clinical disability clinical history of myelitis
(evidence is conflicting)
Bright spotty lesions Bright spotty lesions appear as May have a role in Bright spotty lesions may
discrete hyperintense lesions on facilitating diagnosis in facilitate the discrimination of
axial T2-weighted imaging that are the right clinical setting NMOSD from other LETM
more hyperintense or of equivalent causes; rarely bright spotty
intensity to the surrounding CSF lesions can occur with other
causes of transverse myelitis
Spinal cord lesion length Longer spinal cord lesion length at Prognostic Studies comparing patients with
time of attack is associated with NMOSD with long and short
increased disability, both at attack spinal cord lesions have
nadir and after recovery demonstrated that shorter
lesions are associated with
better prognosis for recovery
CSF = cerebrospinal fluid; IgG = immunoglobulin G; MRI = magnetic resonance imaging.
neuritis compared with those affected by MS optic neuritis.77 Yet, microcystic

macular edema is by no means unique to MS, NMOSD, or inflammatory optic
neuropathies as a whole; instead, this finding can be observed across a myriad of
ophthalmic conditions.76,77 In a practical sense, OCT has a role in distinguishing
optic neuritis from other non–optic neuritis causes of vision loss, rather than
distinguishing between optic neuritis subtypes related to MS, MOG-associated
disorders, or NMOSD.
Acute optic neuritis is associated with thickening of the peripapillary retinal
nerve fiber layer, with subsequent thinning over weeks to months.71 If the retinal
1150 AUGUST 2022

ganglion cells are permanently injured, the macular ganglion cell inner plexiform
layer measurements will begin to thin within 2 to 4 weeks of symptom onset. The
timing and severity of this progression can provide some clues as to the cause of
the optic nerve injury and corroborate suspicion for possible severe optic nerve
injury in patients with NMOSD. However, in the acute setting, retinal nerve fiber
layer and ganglion cell layer measurements provide limited additional diagnostic
information about optic neuritis subtypes than is available from the clinical
examination alone.71
MRI
MRI represents an important diagnostic biomarker, particularly for
seronegative individuals suspected of having NMOSD (TABLE 7-2). In most
cases of NMOSD, the cranial MRI scan is viewed as being unremarkable
relative to imaging in patients with MS. Yet, lesions are detected 50% to 85% of
the time in patients fulfilling the revised 2006 NMO diagnostic criteria.32
Nonspecific punctate and hyperintense subcortical changes (best seen with
fluid-attenuated inversion recovery [FLAIR] and T2-weighted sequences) have
been reported in 43% to 70% of patients with NMOSD at initial presentation.32
For patients presenting with specific clinical syndromes such as optic neuritis,
transverse myelitis, and area postrema syndrome, characteristic radiologic
lesions can help render the diagnosis (TABLE 7-2).9 In 2019, Cacciaguerra and
colleagues79 proposed criteria to distinguish MS from NMOSD. These criteria
included (1) the absence of combined juxtacortical/cortical lesions, (2) the
absence of ovoid periventricular lesions, (3) the absence of so-called Dawson
fingers, (4) the presence of an LETM (FIGURE 7-2), and (5) the observation of
periependymal lesions along the lateral ventricles. It was noted that fulfillment of
at least two of the five aforementioned criteria distinguished NMOSD from MS
with 92% sensitivity and 91% specificity in training samples (82% sensitivity and
91% specificity in validation samples).32,79 Unfortunately, the Cacciaguerra
criteria are less reliable in differentiating NMOSD and MOG-associated disorder
cases from one another.79
As stated, additional MRI findings may be relatively specific for NMOSD
diagnosis in the right clinical context. For example, a 2021 study found bilateral
involvement in almost 50% of NMOSD cases with optic nerve lesions.55 These
lesions tend to extend over 50% of the posterior aspects of the optic nerve as it
extends toward the chiasm.55 In cases of area postrema syndrome, a characteristic
high-signal lesion in the posterior medulla at the floor of the fourth ventricle
(best seen with T2-weighted and FLAIR MRI sequences) can help render the
diagnosis (FIGURE 7-5).55,80 Other brain MRI abnormalities observed in NMOSD
include large (greater than 3 cm) and confluent cerebral hemispheric lesions
located in the subcortical white matter.55 These lesions may resemble lesions of
ADEM or have a tumefactive appearance (FIGURE 7-5).55,80 MRI frequently
reveals corpus callosal lesions in both NMOSD and MS, but these are more likely
to be oriented in a “bridge arch” and show a marbled pattern in NMOSD
(FIGURE 7-5).32,55,80 Rounded lesions with a ground glass–like heterogeneous
appearance within the body of the corpus callosum are also considered specific
for NMOSD.55 In contrast, corpus callosal lesions in MS tend to be well
circumscribed, ovoid shaped, and oriented perpendicular to the lateral
ventricles.32 The central vein sign often seen in MS (in 80% of patients with MS)
is found in only one-third of patients with NMOSD.32,81 Diffuse leptomeningeal

FIGURE 7-5
MRI lesions characteristic of
neuromyelitis optica spectrum
disorder. Axial brain MRI images
showing diencephalic lesions
surrounding (A) the third ventricles and
cerebral aqueduct, which include the
thalamus, hypothalamus (B), and
anterior border of the midbrain (C).
Axial brain MRI images reveal a dorsal
brainstem lesion adjacent to the fourth
ventricle (D), whereas a sagittal cervical
cord MRI image depicts a linear
medullary lesion that is contiguous with
cervical cord lesion (E); an edematous
and extensive dorsal brainstem lesion
involving the cerebellar peduncle is
shown in an axial brain MRI (F). The
sagittal (G, left) and coronal (G, right)
brain MRI images capture a callosal
lesion immediately next to the lateral
ventricle, following the ependymal
lining, a “marbled-pattern” callosal
lesion is shown on an axial MRI image
(H) whereas an axial image (I) shows the
classic “bridge-arch pattern” callosal
lesion. The series of axial brain MRI
images show tumefactive hemispheric
white matter lesions (J), a long
spindlelike or radial-shaped lesion
following white matter tracts (K), and
extensive and confluent hemispheric
lesions with increased diffusivity on
apparent diffusion coefficient maps
suggesting vasogenic edema (L), and
hemispheric lesions in the chronic phase with cystlike cavitary changes (M). Corticospinal
tract lesions are seen involving the posterior limb of the internal capsule (N) and on axial
lesions of the cerebral peduncle of the midbrain (O), whereas coronal images show a
longitudinally extensive lesion following the pyramidal tract ( P). Axial MRI images
demonstrate cloudlike enhancement (Q), and linear enhancement of the ependymal surface
of the lateral ventricles (R). The axial MRI image (S, left) and sagittal image (S, right) show
meningeal enhancement.
Reprinted with permission from Kim HJ, et al, Neurology.80 © 2015 American Academy of Neurology.
enhancement visualized on postcontrast T1-weighted cranial MRI has been noted

in NMOSD (FIGURE 7-5).80 Although this feature is rare in MS, it can be seen in
neurosarcoidosis and other forms of aseptic meningitis.32,55 Hyperintense
T2-weighted and FLAIR signal changes in the ependymal lining and adjacent
walls of the third ventricle may arise as an extension of a hypothalamic lesion or
as an isolated finding in NMOSD.55 In contrast to spinal imaging findings,
gadolinium-enhancing lesions are rarely seen on routine cranial imaging in
patients with NMOSD.55 Yet, imaging in patients with NMOSD may show diffuse
and heterogeneous T2-weighted and FLAIR lesions of the white matter with
patchy, faint gadolinium “cloudlike” enhancement (FIGURE 7-5).55,80 Notably,
cerebral T2-weighted lesions in NMOSD almost always decrease in size over
time.32,55 In contrast, these lesions tend to persist in cases of MS and resolve in
cases of MOG-associated disorders. Clinically silent brain MRI lesions are less
1152 AUGUST 2022

commonly seen in NMOSD than MS, yet recent work suggests surveillance KEY POINTS
imaging may have a role in these patients because the appearance of such lesions
● Serum measures of
may predict future clinical events.55 neurofilament light chain
Spinal imaging in patients with NMOSD often reveals LETM lesions located in and glial fibrillary acidic
the cervical cord (FIGURE 7-2) with frequent extension into the thoracic cord or protein (GFAP) may
into the brainstem. Thoracic cord lesions are less common, affecting only 30% of complement optical
coherence tomography and
patients with NMOSD.32,55 Long lesions in the cervical region that extend up into
MRI techniques to improve
the medulla are helpful in distinguishing NMSOD from MS,55 but they do not diagnosis, capture disease
always help distinguish NMOSD cases from other causes of LETM.32 Short- activity, and potentially
segment spinal cord lesions are also seen in approximately 15% of NMOSD predict outcomes for
people living with NMOSD.
cases.32 However, caution should be exercised when interpreting MRI studies
Although these biomarkers
because spinal cord lesions often evolve over time, impacting the length of the hold promise, their utility in
lesion and, potentially, recognition of the diagnosis.32 Short-segment spinal cord the clinical setting is yet to
lesions initially considered to be part and parcel of MS may lengthen.32 Moreover, be determined.
rostrally located medullary lesions may extend caudally into the cervical spinal
● Off-label
cord during a relapse.32 Therefore, it is possible that, if a patient with suspected immunosuppressive
NMOSD is imaged too early, an LETM may be missed. Extending on the theme of therapies including
“timing is everything,” lesions that are initially longitudinally extensive may azathioprine,
become discontinuous over time, with several shorter lesions evolving on serial mycophenolate mofetil, and
rituximab have traditionally
imaging with relapse resolution.32 Follow-up imaging with MRI of the spinal cord been used in the long-term
6 to 12 months after a relapse can be useful in determining how lesions evolve and management of NMOSD.
may help differentiate a new lesion from an old one if another attack occurs in a
similar anatomic distribution.32 Future studies may explore final spinal cord
lesion length and development of spinal cord atrophy following a myelitis relapse
as predictors of long-term disability outcomes.32
Similar to MRI of the brain, some specific patterns of spinal cord involvement
are highly suggestive of NMOSD (FIGURE 7-6). Approximately, 60% to 70% of
lesions observed in NMOSD occupy more than half of the cord area and involve
the central gray matter.32 Small areas of high signal predominantly seen on axial
T2 imaging of the spinal cord described as “bright spotty” lesions (FIGURE 7-6)
have been reported in NMOSD and are distinct from MS.32,55 Focal or generalized
atrophy is seen in up to 50% to 60% of patients with NMOSD who have a history
of myelitis on follow-up MRI, and these findings may correlate with future
disability and relapses.32,55 Significant reductions in cervical cord cross-sectional
areas have been reported in AQP4-positive patients with NMOSD, different
from MOG-associated disorders and MS.54 A 2021 study showed the benefit of
using brain, orbital, and spinal MRI protocols to both support and refute clinical
suspicion for relapses.32 As a biomarker, MRI can help facilitate diagnosis,
differentiate NMOSD from other disorders, and potentially provide prognostic
information about disease course.32
A NEW TREATMENT ERA

The goals of long-term immunosuppression therapy for patients with
NMOSD are to hasten recovery from acute exacerbations, prevent relapses,
and minimize risk of disability.2 Until recently, no agents were approved for
relapse prevention. Prior to the era of targeted therapies for NMOSD, a variety of
off-label immunosuppressive treatments had been used to control disease
activity, including azathioprine, prednisone, mycophenolate mofetil, and
rituximab (TABLE 7-4).11,12,82-93 Consensus treatment recommendations
regarding the use of these agents have been based on observational clinical

FIGURE 7-6
Imaging characteristics of spinal cord lesions in aquaporin-4 (AQP4)-positive neuromyelitis
optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein (MOG)-
positive myelitis. AQP4-immunoglobulin G (IgG)–positive disease, sagittal T2 sequences:
longitudinally extensive lesions, extension of cervical cord lesions rostrally into the dorsal
medulla, and subsequent cord atrophy and discontinuity of lesions in chronic longitudinally
extensive transverse myelitis (LETM). MOG-IgG–positive disease, sagittal and axial T2
sequences: short-segment spinal cord lesions are demonstrated, although LETM may also
occur. MOG-IgG–positive disease, sagittal T2 and sagittal and axial postcontrast T1-weighted
sequences: although bright spotty lesions are more frequently associated with AQP4-IgG–
positive NMOSD, they may rarely occur with other causes of transverse myelitis, as seen here.
The short length and peripheral location of this lesion, in addition to serologic testing, helped
confirm the diagnosis of MOG-IgG–positive disease.
Gd = gadolinium.
Reprinted from Solomon JM, et al, Ther Adv Neurol Disord.32 © 2021 The Authors.
1154 AUGUST 2022

studies that often lacked masking or control groups.11,12 The published literature KEY POINT
to date has shown that immune suppression prevents relapses compared with no
● Many disease-modifying
immunosuppressive therapy for patients with NMOSD.11 It is also well therapies used in the
established that many MS disease–modifying therapies (alemtuzumab, treatment of MS worsen
natalizumab, interferon beta, and fingolimod) should not be used for patients disease course in NMOSD.
with NMOSD because they exacerbate the disease course.12 Instead, patients with
NMOSD need targeted
Among the off-label immunosuppressive agents used in NMOSD, rituximab
immunosuppressive
has shown the most robust efficacy across studies. A meta-analysis by Damato therapies.
and colleagues90 evaluating 25 independent studies showed that rituximab
therapy decreased annual relapse rates (mean, 0.79) and EDSS scores (mean,
0.64) among patients with NMOSD. Kim and colleagues91 evaluated 100 patients
with NMOSD and reported a 96% reduction in annualized relapse rate with
rituximab therapy; in fact, 70% of patients with NMOSD were relapse free while
on therapy. Furthermore, a retrospective study by Mealy and colleagues89
demonstrated that rituximab and mycophenolate mofetil were superior to
azathioprine in annualized relapse rate reduction (97.9% and 90.2% versus
72.1%, respectively) with lower failure rates.
Various rituximab dosing regimens have been proposed in the treatment of
patients with NMOSD. A common induction approach is 372 mg/m2 per week
(four weekly doses) or two doses of 1000 mg given 2 weeks apart.2 Over time,
maintenance therapy is crucial for sustained suppression of B cell response. To
this end, a fixed regimen of 1000 mg rituximab every 6 months (based on the
average kinetics of the B-cell repopulation) may be used, or a patient-centric
approach guided by the reemergence of CD19+ lymphocytes (0.1% to 2% CD19+
cells among total lymphocytes) may be considered. Unfortunately, 17% of
patients with NMOSD continue to have relapses despite rituximab therapy.92 In
the retrospective review by Kim and colleagues,91 100 patients with NMOSD
were treated with rituximab; two regimens were used as induction treatment:
375 mg/m2 infused once weekly for 4 weeks and 1000 mg infused twice during
a 2-week interval. After induction therapy, a single infusion of rituximab
(375 mg/m2) was administered as maintenance therapy for at least 6 months.91
In this study, the FCGR3A-F allele among patients was associated with a risk of
relapse while receiving rituximab treatment and insufficient memory B-cell
depletion.91 Indeed, rituximab does not completely eliminate attacks, even when
treatment is tailored to deplete B-cells.93 Persistence of NMO-IgG–producing
plasmablasts, which do not express the CD20 antigen, may explain some of the
variability in clinical response among patients treated with rituximab.93 A subset
of patients, including those with a larger body surface area, may show early
repopulation of B cells, thus requiring more frequent dosing (eg, every
4 months). Furthermore, neutralizing antibodies and CNS compartmentalization
of pathogenic B cells may negatively affect treatment efficacy.
The discovery of AQP4-IgG and subsequent characterization of NMOSD as an
autoimmune astrocytopathy have led to the identification of key immunologic
therapeutic targets including the complement system, the IL-6 receptor, and
B cells.11 A large body of elegant work elucidating the immune pathobiology of
NMOSD led to the completion of four randomized placebo-controlled controlled
trials that demonstrated the efficacy of three new therapies, namely eculizumab,
satralizumab, and inebilizumab for patients with NMOSD.11,12 Although these
studies differed in design with respect to definition of relapse, use of other
immune therapies, and AQP4-IgG serostatus, all showed benefit in preventing

TABLE 7-4 Therapeutic Agents Used in the Treatment of Patients With Neuromyeltis
Optica Spectrum Disorders
Dosing options
(regimens may
Drug Mechanism vary) Adverse effects Indication
Off-label immunosuppressive (induction and maintenance) therapies
Rituximab Monoclonal antibody Suggested Late-onset neutropenia, Has been shown to be

that binds to CD20+ induction hypogammaglobulinemia, more effective at
B-lymphocyte surface therapies: reactivation of hepatitis B suppressing relapses
antigen and depletes B 375 mg/m2/ virus (leading to fulminant than many other
cells wk 4 weeks or liver failure), infections off-label agents
1000 mg 2 (upper respiratory tract including azathioprine
doses given over viral infections, and mycophenolate
2 weeks; nasopharyngitis, mofetil
followed by bronchitis, pneumonia,
maintenance and sepsis), severe
therapy of infusion reactions, tumor
375 mg/m2 every lysis syndrome, and
6 months mucocutaneous
reactions; rare cases of
progressive multifocal
leukoencephalopathy
have been reported
Azathioprine A purine analogue that Suggested Neutropenia, leukopenia, Has been shown to be
disrupts synthesis of dosing: 2 mg/kg/ pancytopenia, and severe inferior to rituximab and
DNA and RNA and d to 3 mg/kg/d myelosuppression; tocilizumab on relapses
induces T-cell apoptosis combined with opportunistic viral, and disability
oral prednisone bacterial, and fungal progression in
initially (30 mg/d infections neuromyelitis optica
which is tapered spectrum disorders
after 6-9 months) (NMOSD)
Mycophenolate An inhibitor of Suggested Neutropenia, leukopenia, Has been shown to be

mofetil inosine-5’- dosing: pancytopenia, and severe inferior to rituximab and
monophosphate 1000 mg/d to myelosuppression; tocilizumab on relapses
dehydrogenase, a key 3000 mg/d (can opportunistic viral, and disability
enzyme in the de novo be given in bacterial, and fungal progression in NMOSD
guanosine nucleotide divided doses) infections
synthesis combined with
prednisone
(30 mg/d tapered
after 6-9 months)
Methotrexate A folic acid analogue that Suggested Gastrointestinal Retrospective studies in

increases extracellular dosing: 15 mg/wk symptoms such as nausea NMOSD showed a
release of adenosine to to 25 mg/wk or diarrhea, bone marrow decrease of annual
mediate anti- depression, and an relapse rates between
inflammatory effect increase of liver enzymes 64% and 87%
1156 AUGUST 2022

Dosing options
(regimens may
Mitoxantrone A type II topoisomerase Suggested Because of the side Has been associated
inhibitor that disrupts dosing: 12 mg/ effects (cardiotoxicity, with improved relapse
cellular DNA synthesis m2/mo for therapy-related acute rates and disability
and repair by 6 months, leukemia) and the limited
intercalation between followed by duration of the therapy,
DNA bases; inhibits monthly mitoxantrone use is
proliferation of maintenance generally not
macrophages, B and T dose of 6 mg/m2; recommended; the
cells; induces apoptosis total cumulative maximum cumulative dose
of B cells, monocytes, dose <120 mg/m2 should not exceed
and dendritic cells; and 100 mg/m2 body
decreases secretion of surface area
proinflammatory
cytokines
Cyclophosphamide An alkylating agent that The treatment Bladder cancer, gonadal Has been associated
forms DNA crosslinks, may be applied in toxicity, hemorrhagic with improved relapse
which is irreversible, and immune-ablative cystitis; alopecia, nausea/ rates and disability, but
causes cell apoptosis, doses (2000 mg/ vomiting, transient results are mixed82; it is
eliminates T regulatory d for 4 days) or at myelosuppression, and only recommended
cells, and induces T-cell a dose of 500 mg/ transient azoospermia when other
growth factors including m2 to 600 mg/m2 immunosuppressive
type I interferons body surface therapies fail or are not
area per available
administration;
the dose should
be adjusted
according to
changes in the
total leukocyte
count
Tocilizumab Anti–interleukin 6 (IL-6) Suggested Neutropenia, The TANGO trial83

receptor antagonist that dosing: 8 mg/kg lymphopenia, and demonstrated the safety
suppresses upregulated IV every 4 weeks pancytopenia; and efficacy of
IL-6, a main driver of opportunistic infections, tocilizumab and
aquaporin-4 (AQP4)- especially mycobacterial azathioprine in NMOSD;
antibody–producing infections, including time to relapse (primary
plasmablasts and other tuberculosis have been outcome) was longer in
pathogenic aspects of reported the tocilizumab than in
NMOSD the azathioprine group;
tocilizumab reduced the
relative risk of 24-week
confirmed disability
progression by 78%
compared with
azathioprine

CONTINUED
CONTINUED FROM FROM PAGE 1157
PAGE 1157
Dosing options
(regimens may
IV immunoglobulin Consists of polyclonal Suggested Fever and headache; Data are lacking; IVIg
(IVIg) IgG pooled from donors; dosing regimens aseptic meningitis, therapy is suggested as
the mechanism by which vary but include thrombosis, and an alternative for
it exerts its anti- IVIg treatment anaphylaxis patients with
inflammatory effect in 0.7 g/kg body contraindication to one
specific diseases is weight/d for of the other treatments
unknown but may stem 3 days, repeated or for children
from both functional at various
domains of the IgG intervals (monthly
molecule, the or otherwise)
antigen-binding
fragment (F[ab]2), and
the fragment
crystallizable region
Approved NMOSD maintenance therapies
Eculizumab Monoclonal antibody 900 mg/wk IV for Headaches, leukopenia, The PREVENT trial84
that binds to the 4 weeks, then and lymphopenia; showed that eculizumab
complement component 1200 mg IV on complement inhibition reduced the risk of
C5, inhibiting its cleavage week 5 and every increases the risk of relapse by 94%
and preventing the 2 weeks infection with compared with placebo,
generation of the thereafter encapsulated bacteria, and the risk reduction
terminal complement especially Neisseria persisted at 48 and
complex; inhibits AQP4 meningitidis 144 weeks
antibody formation of (meningococcal
the membrane attack vaccination is mandatory
complex before starting
treatment); upper/lower
respiratory tract
infections,
nasopharyngitis, influenza,
pharyngitis, and bronchitis
Inebilizumab A humanized, affinity- 300 mg IV Selective B-cell The N-MOmentum trial85

optimized, IgG1 2 weeks apart, lymphopenia, rare cases showed inebilizumab
monoclonal antibody then every of neutropenia and reduced relapses from
that binds to the B-cell 6 months leukopenia; a 15% 39% vs 12% in all patients
surface antigen CD19 reduction in regardless of AQP4
with subsequent B cell immunoglobulin levels (all serostatus
and plasmablast cell types); nasopharyngitis,
lymphocytolysis; this upper respiratory tract
effect decreases infection, influenza,
antibody production influenzalike illness, and
bronchitis
1158 AUGUST 2022

Dosing options
(regimens may
Satralizumab A monoclonal antibody Subcutaneous Leukopenia, In the SAkuraSky study
against the IL-6 satralizumab nasopharyngitis and (satralizumab plus
receptor; blocks the 120 mg at weeks 0 upper/lower respiratory background
IL-6R and B-cell antibody and 2 and every tract infections immunotherapy) 8 (20%) of
production 4 weeks 41 participants in the
thereafter, has treatment arm relapsed
been tested as over the course of the trial
monotherapy and compared with 18 (43%) of
as add-on 42 controls, resulting in a
therapy in two 62% reduction in
double- adjudicated relapse risk
blind placebo- over time; post hoc
controlled phase analysis by AQP4-Ig
3 trials serostatus revealed a
(SAkuraStar and greater effect in the
SAkuraSky)86,87 seropositive subgroup,
with a 79% reduction in
relapse risk compared
with seropositive
participants in the control
group; serum AQP4-IgG–
negative participants (n =
28; 14 in each arm) showed
no reduction in risk of
relapse with satralizumab
compared with placebo11
In the SAkuraStar study of

satralizumab, 19 (30%) of 63
participants in the
treatment arm relapsed
over the course of the trial
compared with 16 (50%) of
32 controls, resulting in a
55% reduction in
adjudicated relapse risk;
again, post hoc analysis by
serostatus revealed a 74%
reduction in relapse risk
among AQP4-IgG-positive
participants compared
with the placebo group;
serum AQP4-IgG–negative
participants (n = 31; 22 in
the satralizumab arm and 9
in the placebo arm) showed
no significant differences
with respect to relapses
between the treatment
and placebo groups11


Dosing options
(regimens may
NMOSD therapies under development
Aquaporumab A monoclonal antibody To be TBD Has been shown to be

that binds AQP4 with determined (TBD) effective in mouse
high affinity and is models of NMOSD
expected to block the
cell- and complement-
mediated cytotoxicity of
pathogenic AQP4
antibodies
Ravulizumab Next-generation TBD TBD Noninferiority to

antibody targeting C5 eculizumab has been
(complement inhibitor) proven by two large
designed to provide phase 3 trials in patients
prolonged therapy with paroxysmal
intervals nocturnal
hemoglobinuria
Results from the open-

label phase 3
CHAMPION-NMOSD trial
showed ravulizumab
treatment caused a
reduction in the risk of
relapse in adults with
anti-AQP4 antibody-
positive NMOSD
compared with the
external placebo arm
from the PREVENT
clinical trial88
Bortezomib A proteasome inhibitor Suggested Peripheral neuropathy can In NMOSD, bortezomib

that depletes plasma dosing: 1 mg/m2 occur with further effects was investigated as an
cells, approved for use in used TBD add-on medication in a
the treatment of subcutaneously small open-label phase 2
multiple myeloma in repeat cycles clinical trial in patients
who had NMOSD that
was refractory to other
drugs100,101; four of five
patients were
relapse-free during a
1-year follow-up
1160 AUGUST 2022

Dosing options
(regimens may
Ublituximab A third-generation Suggested Leukopenia with other Compared with
chimeric IgG1 dosing: single serious side effects TBD rituximab, ublituximab
monoclonal antibody dose of 450 mg IV permits less dosing and
with high affinity to the may have fewer adverse
Fcy receptor, an epitope events; a phase 1 clinical
on CD20+ B cells, which trial of ublituximab as an
is not targeted by add-on to steroids for
rituximab; causes the treatment of acute
depletion of CD20+ B NMOSD has shown that
cells 4 of 5 subjects achieved
an acute B-cell depletion
with at least 2 months of
durability89,100,101;
although not designed
for efficacy, this trial
demonstrated that
neurologic disability
improved in the three
subjects who achieved
immunologic remission
Cetirizine A second-generation TBD TBD A small open-label add-

histamine 1 (H1) on pilot study showed a
antagonist, stabilizes decrease in relapse rate
eosinophil degranulation in cetirizine–treated
patients with NMOSD
Cinryze A C1 esterase inhibitor 3 to 5 IV doses of TBD Shown to be safe as an

that prevents activation 1000 units to add-on therapy to
of the complement 2000 units steroids for
cascade management of acute
NMOSD relapses in an
open-label, phase 1b trial
Bevacizumab A monoclonal TBD TBD An open-label phase 1b

immunoglobulin that study showed a
targets vascular favorable safety profile
endothelial growth
factor (VEGF)
DNA = deoxyribonucleic acid; IgG = immunoglobulin; IV = intravenous; RNA = ribonucleic acid.

relapses.11 Eculizumab is a C5 inhibitor. In the PREVENT (Prevention of Relapses

in Neuromyelitis Optica) trial,84 an international phase 3 study, 3% of
participants (3 of 96) in the eculizumab treatment arm (eculizumab plus
background immunotherapy) relapsed compared with 43% of participants (20 of
47) in the control arm (placebo plus background immunotherapy), resulting in a
94% reduction in adjudicated relapse risk (hazard ratio, 0.06; 95% CI, 0·02 to
0·20; P < 0.001).11,84 At 48 weeks, 98% of participants (94 of 96) who started on
eculizumab were relapse free compared with 63% of participants (30 of 47) in the
control group; at 96 weeks, 96% of participants (93 of 96) were relapse free in the
eculizumab group versus 52% of participants (24 of 47) in the control group.11,84
Eculizumab has a relatively rapid onset of action and may have utility for acute
attacks.12 It has a reasonable safety profile, although the risk of meningococcal
disease is increased.11,12 This agent may not need to be used in combination with
other immunotherapies for full effect.11,12 The main challenges with this drug
pertain to administration (the current formulation requires twice-monthly
infusions) and cost.
Satralizumab is a monoclonal antibody that blocks the IL-6 receptor and
has been trialed in two international phase 3 studies called SAkuraStar and
SAkuraSky.11,86,87 In the SAkuraSky study of satralizumab plus background
immunotherapy, 20% of participants (8 of 41) in the treatment arm had relapses
compared with 43% of controls (18 of 42), resulting in a 62% reduction in
adjudicated relapse risk (hazard ratio, 0.38; 95% CI, 0.16 to 0.88; P = 0.02). The
proportion of participants using satralizumab who were relapse free was 89%
(36 of 41) at 48 weeks (versus 66% [28 of 44] for the control group) and 78%
(31 of 41) at 96 weeks (versus 59% [25 of 42] for the control group). In the
SAkuraStar study of satralizumab, 30% of participants (19 of 63) in the treatment
arm had relapses compared with 50% of controls (16 of 32). This resulted in a 55%
reduction in adjudicated relapse risk (hazard ratio, 0.45; 95% CI, 0.23 to 0.89;
P = 0.018). The proportion of participants using satralizumab who were relapse
free was 76% (48 of 63) (versus 62% [20 of 32] for the control group) at 48 weeks
and 72% (45 of 63) (versus 50% [16 of 32] for the control group) at 96 weeks. One
potential disadvantage of satralizumab is its relatively slow onset of action.11,12 The
advantages of this agent include its subcutaneous formulation and compatibility
with other therapies.11,12 Moreover, no routine monitoring is necessary.
Inebilizumab is a monoclonal antibody to the B lymphocyte antigen CD19,
which, like rituximab, depletes B cells.11,12 This agent also removes B-cell
precursors from the circulation.11 In the N-MOmentum study,85 12% of participants
(21 of 174) in the treatment arm had relapses over the course of the trial compared
with 39% (22 of 56) in the control (placebo alone) arm, resulting in a 73% reduction
in adjudicated relapse risk (hazard ratio, 0.27; 95% CI, 0.15 to 0.50; P < 0.001).11,85
Inebilizumab eliminates plasmablasts and B cells, thus causing immunosuppression
and impeding immunosurveillance. This therapy may, therefore, pose a higher risk
for certain cancers and progressive multifocal leukoencephalopathy similar to
ocrelizumab.11 A 6% incidence of hypogammaglobulinemia associated with the
drug, owing to immunosuppressive effects, has also been reported.11 Inebilizumab
requires two infusions at induction 2 weeks apart, followed by two infusions per
year. This schedule parallels that of rituximab, which has been effective for
patients with NMOSD.11
Tailoring treatment with these new agents to the specific needs of a given
patient with NMOSD requires consideration of relapse history, immunosurveillance
1162 AUGUST 2022

risks, and long-term costs and feasibility. Currently, these agents are approved for KEY POINTS
seropositive patients, which means that seronegative patients with NMOSD still
● A large body of elegant
have limited options. Eculizumab acts quickly but requires frequent dosing. work elucidating the
Inebilizumab is more easily administered but impedes immunosurveillance, thus immune pathobiology of
requiring more careful safety monitoring. Satralizumab has immunomodulatory NMOSD has led to the
effects without impeding immunosurveillance, yet this agent has delayed onset of discovery of three new
approved therapies, namely
action and requires continued administration throughout the disease course. All
eculizumab, satralizumab,
three agents, unfortunately, currently come at considerable cost, which may and inebilizumab, which
ultimately limit their use. have all shown robust
Autologous hematopoietic stem cell bone marrow transplantation is an immune benefits in preventing
relapses.
reconstitution therapy that has also been used successfully to treat patients with
NMOSD.94-98 Small studies using transplantation techniques have shown clinical ● Immune reconstitution
benefit, radiologic remission, improved disability, and suppression of therapy may serve as an
AQP4-IgG antibody production.94-98 The European Group for Blood and Marrow induction strategy in
Transplantation Autoimmune Diseases Working Party95 reported that 3 of 16 patients with NMOSD with
severe refractory disease
NMOSD cases demonstrated resolution of disease progression and required no before the initiation of
additional immunosuppressive treatment after a median follow-up period of long-term
47 months. Burton and colleagues96 used an autologous hematopoietic stem cell immunomodulation.
transplantation protocol in three patients with NMOSD who were followed for a
minimum of 5 years. The primary outcome in this study was relapse-free status at
3 years.96 One patient had no evidence of disease activity over 10 years, a second
patient demonstrated improvement in relapse rate and EDSS but experienced clinical
and radiologic breakthrough events requiring rituximab at 5 years, and the third
patient died at 3.5 years because of uncontrollable NMOSD relapses and accumulation
of marked disability.96 The evidence to date suggests that autologous hematopoietic
stem cell transplantation may be used as salvage therapy for severe breakthrough
disease to reconstitute the immune system. This treatment may also serve as an
induction therapy for severe initial presentations of NMOSD before the initiation of
long-term immunomodulation.94-99 In the short term, immune reconstitution
therapies have advantages over immunosuppressive agents by providing long-term
efficacy with minimal risk for opportunistic infections and malignancy.94 Moreover,
the estimated cost of autologous hematopoietic stem cell transplantation has
been less than $4700 per quality-adjusted life-year in patients with MS.94,99
New agents that act on different critical points of the immunopathologic
cascade are being explored in patients with NMOSD. Collectively, these therapies
target B cells, AQP4 antibodies, the blood-brain barrier, the complement system,
and granulocyte production.100-102 Several anti-CD20 monoclonal antibodies, for
example, including ocrelizumab, ofatumumab, obinutuzumab, and ublituximab
are under investigation.100,101 Bortezomib, a proteasome inhibitor, has been
shown to decrease relapses, AQP4 antibody titers, and B-cell counts in patients
with NMOSD (TABLE 7-4).100,101 Aquaporumab is a recombinant monoclonal
antibody that codes for effector Fc IgG function (thus abolishing complement
and cell-based cytotoxicity) and prevents formation of new NMOSD lesions,
likely by competing with pathologic AQP4 antibodies (TABLE 7-4).100,101
Vascular endothelial growth factor (VEGF)–neutralizing antibodies may restore
blood-brain barrier integrity in patients with NMOSD, prompting speculation
that bevacizumab, a monoclonal immunoglobulin that targets VEGF, may be
beneficial in this patient population (TABLE 7-4).101 Furthermore, cetirizine, a
second-generation histamine 1 (H1) antagonist that stabilizes eosinophil
degranulation may also ameliorate NMOSD relapses (TABLE 7-4).101

Going forward, drug sequencing combinations may have to be tailored to the

needs of a given patient with NMOSD to optimize disease management. As
mentioned, autologous hematopoietic stem cell transplantation has been
suggested as an induction or rescue therapy, used to reconstitute the immune
system after severe attacks. Immunosuppressive therapies may be selected with
the goal of controlling the complement system (eculizumab), transitioning to
immunomodulation (satralizumab), and providing longer-term
immunosuppression (inebilizumab), as needed.12 In addition to bolstering the
effectiveness of relapse management, future agents will be needed to restore and
regenerate neurologic function in patients with NMOSD with chronic neurologic
injury. Finally, concerted efforts will be required to promote access to newly
approved NMOSD agents, as the current costs of these therapies will ultimately
limit their benefits to a select few patients.
SPECIAL CIRCUMSTANCES
NMOSD co-associates with numerous other pathologic states including
infections, systemic inflammatory conditions, cancers, and immune-mediated
connective tissue diseases.10 With respect to the association between connective
tissue diseases and NMOSD, the aforementioned international panel concluded
that the presence of SLE and Sjögren syndrome in NMOSD should be viewed as a
coexistence, rather than a complication.9,15 Indeed, the presence of SLE and
Sjögren syndrome in the context of an NMOSD core clinical syndrome such as
optic neuritis or transverse myelitis lends support for the diagnosis of NMOSD.9,15
This co-association has clinical implications that require consideration. Positive
AQP4-IgG antibodies can occur in asymptomatic patients with connective tissue
diseases; moreover, positive antinuclear antibodies, anti–double-stranded DNA
antibodies, anti–Sjögren syndrome A (SSA)/Ro antibodies, and anti-SSB/La
antibodies are also found in patients with NMOSD without clinically apparent
systemic autoimmune diseases.15 For this reason, patients with NMOSD should
be asked about systemic symptoms and undergo a rheumatologic workup if an
underlying connective tissue disease is suspected. Similarly, neurologic
manifestations such as area postrema syndrome, optic neuritis, or transverse
myelitis in a patient with a known connective tissue disease should prompt
evaluation for NMOSD, including an MRI of the brain with and without contrast,
as well as serum antibody testing for AQP4-IgG and MOG-IgG.15 Acutely, these
patients may be treated with high-dose corticosteroids; yet, deciding on the
appropriate long-term immunosuppressive therapy may be challenging and
require multidisciplinary collaboration. Rituximab, and to a lesser extent
mycophenolate mofetil, have been used to treat patients with both connective
tissue diseases and NMOSD.15 Importantly, therapies that interfere with tumor
necrosis factor-alpha such as infliximab, adalimumab, or etanercept would best
be avoided because these agents have been associated with causing and
exacerbating CNS inflammatory disorders.15
Pediatric Neuromyelitis Optica Spectrum Disorders

The diagnosis of NMOSD is uncommon in children, such that pediatric-onset
NMOSD accounts for 3% to 5% of all NMOSD cases.103 Children with
seropositive NMOSD generally have similar imaging features to adults with this
disease, but it can be challenging to distinguish these cases from potential clinical
mimics.32 Children with NMOSD, for example, may be more likely than adults to
1164 AUGUST 2022

have cerebral lesions, and these radiologic lesions may have a poorly demarcated, KEY POINTS
“fluffy” appearance.32 Thalamic and internal capsule lesions are more common in
● Patients with NMOSD can
ADEM than NMOSD, which can help distinguish these diagnoses in pediatric have connective tissue
patients.32 LETM is a common feature on spinal imaging among pediatric patients disorders such as systemic
with NMOSD, but this finding may also be caused by MOG-associated disease and lupus erythematosus and
monophasic transverse myelitis.32 Evaluation of suspected NMOSD cases in the Sjögren syndrome.
Management approaches
pediatric population often implicates MOG-associated disorders, given the
should be multidisciplinary
significant clinical overlap of these conditions. In fact, the majority of pediatric to optimize clinical
patients with an NMOSD phenotype have antibodies to MOG-IgG, highlighting outcomes.
the need for new trials evaluating therapies for this subgroup of patients.103
As with adults, detection of AQP4-IgG predicts relapses, including transverse ● Pregnancy and the
postpartum state are
myelitis and optic neuritis in children with NMOSD, with imminent threat of vulnerable phases for
disability.103 Accordingly, chronic immunosuppression is needed. Commonly patients with NMOSD
used treatment regimens include rituximab, mycophenolate mofetil, and because relapses are more
azathioprine.103 The role of newer agents including eculizumab, satralizumab, likely to occur and patients
may experience miscarriage.
tocilizumab, and inebilizumab needs to be determined in this patient population. Accordingly, pregnant
women with NMOSD should
Neuromyelitis Optica Spectrum Disorder in Pregnancy be considered high risk, and
The diagnosis of NMOSD is of significant concern for pregnant patients because a multidisciplinary approach
to care should be
pregnancy may precipitate disease onset for some women and exacerbate disease implemented.
activity for those with an established diagnosis. The third trimester and
peripartum period are vulnerable states for relapses among women with
NMOSD.10,104 The risks related to pregnancy may be caused in part by the high
expression of AQP4 in the placenta. Notably, women with NMOSD are more
likely to experience miscarriage.104 Studies to date have shown that azathioprine,
rituximab, eculizumab, and glucocorticoid therapy are relatively safe in
pregnancy; moreover, tocilizumab can be considered for women with more
severe NMOSD.104 Mycophenolate mofetil has a 45% probability of spontaneous
abortion and 26% incidence of major fetal malformations and, therefore, is
contraindicated during pregnancy.104 The pregnancy risks of eculizumab,
inebilizumab, and satralizumab need to be further investigated. Pregnant
women with NMOSD should be considered relatively high risk, and a
multidisciplinary approach to care is needed.104
CONCLUSION
Over the past decade, scientific understanding regarding the clinical
manifestations, relapse-related risk factors, and therapeutic approach to NMOSD
has rapidly evolved. In many respects, the path of scientific discovery has been
an affirmation of a “bench-to-beside” model that started with the identification
of key immunologic therapeutic targets and culminated in the approval of three
new therapies for NMOSD in 2019. Currently, NMOSD poses not only a
diagnostic conundrum but also treatment challenges. The role of MOG-IgG
antibodies in the diagnostic criteria for NMOSD needs to be fully elucidated.
Better biomarkers are needed to predict relapses, and better treatments are
needed to prevent them. Areas of clinical priority in the management of patients
with NMOSD include the need for regenerative therapies to ameliorate the
effects of attack-dependent disability. In the modern treatment era, scientific
exploration, clinical rigor, and patient-oriented advocacy will be needed to
ensure safe and effective therapies are accessible to all patients with NMOSD.

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Neuromyelitis Optica REVIEW ARTICLE

RECENT FINDINGS: The discovery of the pathogenic aquaporin-4 (AQP4)-IgG

three new NMOSD therapies, namely eculizumab, satralizumab, and

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1132 AUGUST 2022

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causing an astrocytopathy, followed by secondary oligodendrogliopathy and

1134 AUGUST 2022

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RED FLAGS FOR MISDIAGNOSIS

u Acute symptom onset (less than 4 hours)

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TABLE 7-1 Clinical Features of Neuromyelitis Optic Spectrum Disorders

Neurologic, systemic, and

Cerebral syndromes Encephalopathy (acute disseminated encephalomyelitis [ADEM]-like), posterior reversible

Myeloradiculopathy Clinical features of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) including

IgG = immunoglobulin G; MRI = magnetic resonance imaging.

1136 AUGUST 2022

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IgG = immunoglobulin G; MRI = magnetic resonance imaging.

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been reported with chronic infections (tuberculosis, syphilis), neoplasms, SLE,

ANTIBODY STATUS, DIAGNOSIS, AND DISEASE COURSE

1138 AUGUST 2022

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immunologic, radiologic, and clinical characterization of patients affected by

EVERY RELAPSE MATTERS

1140 AUGUST 2022

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Relapses Versus Pseudorelapses

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and not otherwise explained by mitigating circumstances such as fever or

Predicting and Managing Neuromyelitis Optica Spectrum Disorder Relapses

1142 AUGUST 2022

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CASE 7-2 A 42-year-old woman presented with a history of painless, subacute-

1144 AUGUST 2022

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unresponsive to IV methylprednisolone and plasma exchange, immunosuppression

ESTABLISHED AND EMERGING BIOMARKERS

1146 AUGUST 2022

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Optical Coherence Tomography

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TABLE 7-3 Established and Emerging Biomarkers in Neuromyelitis Optic Spectrum

Biomarker Findings Role Key points

Aquaporin-4 80% of patients with neuromyelitis Diagnostic Cell-based assay preferred

Optical coherence tomography

CONTINUED ON PAGE 1149

1148 AUGUST 2022

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Biomarker Findings Role Key points

CONTINUED ON PAGE 1150

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CONTINUED FROM PAGE 1149