Neuromyelitis Optica Spectrum Disorder and Other.15

Neuromyelitis Optica REVIEW ARTICLE

Spectrum Disorder and 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
Other Non–Multiple
Sclerosis Central Nervous
System Inflammatory
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Diseases
By Eoin P. Flanagan, MBBCh
ABSTRACT
PURPOSE OF REVIEW: This article reviews the clinical features, diagnostic
approach, treatment, and prognosis of central nervous system
inflammatory diseases that mimic multiple sclerosis (MS), including those CITE AS:
defined by recently discovered autoantibody biomarkers. CONTINUUM (MINNEAP MINN)
2019;25(3, MULTIPLE SCLEROSIS
AND OTHER CNS INFLAMMATORY
RECENT FINDINGS: The discovery of autoantibody biomarkers of inflammatory DISEASES):815–844.
demyelinating diseases of the central nervous system (aquaporin-4 IgG
and myelin oligodendrocyte glycoprotein IgG) and the recognition that, Address correspondence to
Dr Eoin P. Flanagan, Mayo Clinic,
despite some overlap, their clinical phenotypes are distinct from MS have
Department of Neurology,
revolutionized this field of neurology. These autoantibody biomarkers 200 First St SW, Rochester,
assist in diagnosis and have improved our understanding of the underlying MN 55905,
flanagan.eoin@mayo.edu.
disease pathogenesis. This has allowed targeted treatments to be translated
into clinical trials, three of which are now under way in aquaporin-4 RELATIONSHIP DISCLOSURE:
IgG–seropositive neuromyelitis optica (NMO) spectrum disorder. Dr Flanagan receives
research/grant support from
MedImmune/Viela Bio.
SUMMARY: Knowledge of the clinical attributes, MRI findings, CSF
parameters, and accompanying autoantibody biomarkers can help UNLABELED USE OF
neurologists distinguish MS from its inflammatory mimics. These antibody PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
biomarkers provide critical diagnostic and prognostic information and Dr Flanagan discusses the
guide treatment decisions. Better recognition of the clinical, radiologic, unlabeled/investigational
use of azathioprine, cetirizine,
and laboratory features of other inflammatory MS mimics that lack
corticosteroids, eculizumab,
autoantibody biomarkers has allowed us to diagnose these disorders faster inebilizumab, IV immunoglobulin,
and initiate disease-specific treatments more expeditiously. methotrexate, mycophenolate
mofetil, plasma exchange,
rituximab, SA237, sivelestat, and
tocilizumab for the treatment of
INTRODUCTION neuromyelitis optica spectrum
D
disorder and other non–multiple
istinguishing multiple sclerosis (MS) from its central nervous
sclerosis central nervous system
system (CNS) inflammatory disease mimics has important inflammatory diseases.
therapeutic and prognostic implications. During the past
2 decades, advances in biomarker discovery and MRI © 2019 American Academy
characterization of CNS inflammatory disorders have aided our of Neurology.
CONTINUUMJOURNAL.COM 815
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

NMOSD AND OTHER NON-MS INFLAMMATORY DISEASES
ability to distinguish MS from its mimics. This article reviews the clinical,
laboratory, and radiologic clues that help distinguish MS from other
inflammatory CNS disorders and highlights the differences in the treatment
approach. The first section focuses on CNS inflammatory demyelinating
disease mimics of MS that are accompanied by specific serum biomarkers:
aquaporin-4 (AQP4)–IgG and myelin oligodendrocyte glycoprotein
(MOG)–IgG. These disorders are summarized and compared to MS in
TABLE 12-1. The second section reviews a variety of other nondemyelinating
TABLE 12-1 Comparison of Inflammatory Demyelinating Diseases of the Central

Nervous System
Attribute Multiple Sclerosis AQP4-IgG MOG-IgG

Antecedent Rare Rare Common
infection/
immunization
Ages affected Any (median age at onset in third Any (median age at onset in fourth Any (children and young adults
decade) decade) more predisposed)
Sex (female: 2:1 9:1 1.5:1

male)
Epidemiology Prevalence: common Prevalence: rare Prevalence: unknown
Ethnicity: whites more Ethnicity: African-Americans, Ethnicity: unknown

predisposed Afro-Caribbeans more
predisposed
Geographic: regions farthest Geographic: higher proportion of Geographic: unknown

from equator total demyelinating disease is
AQP4-IgG–positive neuromyelitis
optica spectrum disorder
(NMOSD) in regions where
multiple sclerosis prevalence is low
Most common Myelitis, optic neuritis, brainstem, NMOSD (any combination of Initial episode: optic neuritis,
manifestations cerebral episodes; myelopathy single/recurrent myelitis, optic acute disseminated
for progressive multiple sclerosis neuritis, area postrema syndrome) encephalomyelitis (ADEM),
NMOSD, myelitis
Relapse: optic neuritis
Course Relapsing-remitting from onset in Typically relapsing; usually no Monophasic or relapsing; no

85% (most later develop secondary progression reports of secondary progression
secondary progression); 10–15%
progressive from onset
Attack severity Usually mild to moderate Usually moderate to severe Usually moderate to severe
Recovery from Good Often incomplete Good

attacks
CONTINUED ON PAGE 817
816 JUNE 2019

inflammatory CNS diseases that can mimic MS and outlines how to
recognize them.
NEUROMYELITIS OPTICA SPECTRUM DISORDERS

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory
demyelinating disease of the CNS associated with episodes of optic neuritis,
transverse myelitis, and other neurologic manifestations that can mimic MS.
AQP4-IgG is a serum biomarker found in approximately 80% of patients with
CONTINUED FROM PAGE 816
Attribute Multiple Sclerosis AQP4-IgG MOG-IgG

CSF White blood cell count White blood cell count variable White blood cell count variable
<50/mm3 (lymphocytic) (usually lymphocytic but can be (lymphocytic); oligoclonal bands
or can be normal; neutrophilic or eosinophilic); in <15%
oligoclonal bands in 85% oligoclonal bands in 30%
Blood NA AQP4-IgG MOG-IgG

biomarker
Brain MRI Ovoid periventricular, Dawson Often normal/nonspecific; if ADEM-like fluffy white matter,
fingers, juxtacortical, cortical, present, area postrema, peri- deep gray matter, diffuse/
infratentorial peripheral, ring-/ third/fourth ventricle, splenium, confluent brainstem including
open ring-enhancing diffuse corpus callosum, pencil- cerebellar peduncles
thin ependymal or cloud
enhancement
Optic nerve Unilateral; enhancement of <50% Bilateral; enhancement of >50% of Bilateral; enhancement of >50% of
MRI of nerve affected; middle of optic nerve; posterior optic optic nerve; anterior optic
optic nerve pathway involving chiasm pathway (hence optic disc edema
common)
Spine MRI Multiple lesions; Single lesion (longitudinally Multiple lesions;

short lesions; periphery of cord extensive transverse myelitis 85%; (75% longitudinally extensive
(dorsal/lateral column); ring or short 15%); central on axial; ring or transverse myelitis; 25% short);
variable enhancement variable enhancement conus involved; central on axial;
enhancement variable
Acute IV steroids; plasma exchange IV steroids; plasma exchange IV steroids; plasma exchange
treatment (rarely required) (often required) (often required); IVIg (used in
children)
Maintenance Variety of approved None approved; steroid sparing None approved; none needed if
treatment immunomodulatory medications recommended: azathioprine, monophasic; steroid sparing for
mycophenolate mofetil, rituximab, relapsing disease (azathioprine,
eculizumab, tocilizumab, IVIg, mycophenolate mofetil,
methotrexate methotrexate, rituximab)
Prognosis Majority ambulatory after Attack-related accumulation of Most disability with first attack;
20 years; most disability occurs in disability; secondary progression transient seropositivity predicts
secondary progressive phase rarely if ever occurs monophasic course; persistent
seropositivity and high titer
predict relapsing disease
AQP4 = aquaporin-4; CSF = cerebrospinal fluid; IgG = immunoglobulin G; IV = intravenous; IVIg = intravenous immunoglobulin; MOG = myelin
oligodendrocyte glycoprotein; MRI = magnetic resonance imaging; NA = not applicable.

this syndrome, and a proportion of the remaining 20% may be accounted for by
another serum antibody biomarker, MOG-IgG.
History and Terminology

The eponym Devic disease arose from a 19th century report by Devic and his
student Gault describing the autopsy findings of a patient who died from an
episode of concurrent transverse myelitis and optic neuritis.1 Subsequently, the
term neuromyelitis optica (NMO) superseded Devic disease to account for its
most common clinical manifestations, namely optic neuritis and transverse
myelitis.2 In 2004, the discovery of AQP4-IgG as a specific biomarker of NMO
allowed its distinction from MS.3,4 This discovery led to the recognition that
patients can have more limited forms of the disease (eg, recurrent transverse
myelitis without optic neuritis) or symptoms beyond the optic nerve and spinal
cord (eg, area postrema syndrome), resulting in the current nosology of
NMOSDs.5 In Asia, it has long been recognized that a CNS demyelinating disease
existed that was different than the MS that occurred in whites; it was termed
opticospinal MS or Asian MS. It is now widely accepted that these diseases fall
under the category of NMOSD. Approximately 20% of patients with NMOSD are
seronegative for AQP4-IgG.6 A proportion of these patients are MOG-IgG
seropositive, which can lead to confusion as, in contrast to AQP4-IgG NMOSD
TABLE 12-2 Clinical Features of Neuromyelitis Optica Spectrum Disordera
Cardinal Clinical Features

◆ Transverse myelitis, typically longitudinally extensive (≥3 vertebral segments; often
followed by tonic spasms and occasionally accompanied by pain or pruritus)
◆ Optic neuritis (often severe; may be bilateral)
◆ Episodes of intractable nausea and vomiting or hiccups from area postrema involvement
Other Clinical Features
◆ Narcolepsy
◆ Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)
◆ Other hypothalamic presentations (eg, anorexia)
◆ Acute myopathy with hyperCKemia
◆ Brainstem syndromes (eg, ophthalmoplegia,b hearing loss [possibly related to inner ear
damage] opsoclonus/myoclonus)
◆ Myeloradiculitis
◆ Encephalopathyc (PRES-like; ADEM-like)
◆ Cognitive dysfunction (subcortical pattern [inattention, executive dysfunction, reduced
speed of processing])
◆ Hydrocephalus
ADEM = acute disseminated encephalomyelitis; CK = creatine kinase; PRES = posterior reversible

encephalopathy syndrome.
a
Reprinted with permission from Flanagan EP, Weinshenker BG, Curr Neurol Neurosci Rep.12
© 2014 Springer Science+Business Media.
b
Need to exclude coexisting myasthenia gravis as a cause.
c
Need to exclude coexisting N-methyl-D-aspartate (NMDA) receptor encephalitis as a cause.
818 JUNE 2019

(which is a disease of astrocytes), MOG-IgG NMOSD is a disease of KEY POINTS
oligodendrocytes. This has led to some debate and controversy in the field about
● Distinguishing multiple
whether to use syndrome-based (NMOSD) or biomarker-based (AQP4-IgG, sclerosis from its central
MOG-IgG) diagnostic criteria, although the syndrome-based NMOSD criteria nervous system
are currently used.5,7 inflammatory disease
mimics has important
therapeutic and prognostic
Epidemiology implications.
The prevalence of NMOSD in the United States (Olmsted County, Minnesota)
is 3.9 per 100,000, and similar results have been reported in Europe (Denmark) ● In 2004, the discovery of
at 4.4 per 100,000 and Asia (Japan) at 4.1 per 100,000.8–10 In contrast, the aquaporin-4 (AQP4)–IgG as a
specific biomarker of
prevalence is higher in populations of African descent (Afro-Caribbeans/African
neuromyelitis optica (NMO)
Americans), with a prevalence of 10 per 100,000.8 It is important to recognize allowed its distinction from
that in regions where MS prevalence is lower (eg, Asia and regions closer to the multiple sclerosis.
equator), NMOSD represents a larger proportion of CNS demyelinating diseases
and thus should be particularly considered in the differential in those regions. ● The discovery of
AQP4-IgG as a biomarker of
NMOSD is fivefold to tenfold more common in females than males.8,11 The NMO led to a recognition
disease can occur at any age, including in children and older adults. that patients can have
more limited forms of the
disease (eg, recurrent
Clinical Manifestations
transverse myelitis without
NMOSD has three cardinal manifestations: transverse myelitis, optic neuritis, optic neuritis) or symptoms
and area postrema syndrome (TABLE 12-212). The vast majority of patients follow beyond the optic nerve and
a relapsing course, and patients can have severe attacks resulting in permanent spinal cord (eg, area
deficits even after long periods of remission. A secondary progressive course is postrema syndrome),
resulting in the current
extremely rare with NMOSD, further highlighting its distinction from MS.13 The nosology of NMO spectrum
transverse myelitis episodes may present with typical findings of myelitis, with disorders (NMOSDs).
numbness, weakness, bowel/bladder impairment, and Lhermitte phenomenon,
typically reaching the nadir within days to a few weeks (progression beyond ● It is important to
recognize that in regions
1 month should raise concern for an alternative cause). In contrast to MS where multiple sclerosis
(TABLE 12-1), NMOSD myelitis attacks are often quite disabling (CASE 12-1). prevalence is lower (eg, Asia
Tonic spasms (involuntary painful episodes of flexion usually lasting less than and regions closer to the
1 minute and triggered by movement) may follow myelitis episodes and respond equator), NMOSD
represents a larger
well to low-dose carbamazepine (CASE 12-2). They are frequent in NMOSD
proportion of central
myelitis (up to 50%)14 and occur more frequently with NMOSD than with MS.15 nervous system
Optic neuritis episodes in NMOSD tend to be more severe, are associated with demyelinating diseases and
less recovery, and are more frequently bilateral than in MS.5 thus should be particularly
considered in the
The third cardinal manifestation in NMOSD is area postrema syndrome,
differential in those regions.
which results in intractable nausea and vomiting with or without hiccups.5,16
These may occur as the first manifestation and lead to initial evaluation by a ● NMOSD has three
gastroenterologist (CASE 12-2). The episodes may occur in isolation, have other cardinal manifestations:
accompanying brainstem features, or evolve into a myelitis episode.17 transverse myelitis, optic
neuritis, and area postrema
Occasionally, NMOSD is reported in a paraneoplastic context.18 A wide variety of syndrome.
other less common clinical manifestations of NMOSD are outlined in TABLE 12-2.
● Systemic autoimmune
Coexisting Autoimmunity disorders or their
Systemic autoimmune disorders or their autoantibody biomarkers frequently autoantibody biomarkers
frequently coexist with
coexist with NMOSD, including systemic lupus erythematosus, Sjögren NMOSD, including systemic
syndrome, and antiphospholipid antibody syndrome.19 The presence of optic lupus erythematosus,
neuritis, transverse myelitis, or intractable vomiting in a patient with one of Sjögren syndrome, and
these disorders should prompt AQP4-IgG testing; a positive result (given its antiphospholipid antibody
syndrome.
specificity of >99%) confirms a coexisting autoimmune neurologic disorder

rather than a neurologic manifestation of a rheumatologic disorder.19 Patients

with NMOSD with antiphospholipid antibodies or its syndrome may have an
increased risk of clotting disorders, including deep vein thrombosis and
miscarriage.20 Myasthenia gravis also coexists more frequently than expected,
with NMOSD usually occurring years to decades after myasthenia diagnosis.21
MRI Abnormalities
The MRI lesions in the optic nerve, brain, and spinal cord accompanying
AQP4-IgG–seropositive NMOSD have some notable differences from MS that
can help guide clinicians on when to order AQP4-IgG testing.
OPTIC NERVE. Optic nerve involvement is often bilateral and typically involves the
posterior optic pathway, including the optic chiasm (FIGURES 12-3A and 12-3B),
with enhancement usually extending more than half the length of the nerve.22
CASE 12-1 A 60-year-old man presented with subacute weakness and numbness in
his lower extremities and neurogenic bladder requiring intermittent
catheterization. At nadir, 2 weeks after onset, he was wheelchair
dependent.
His neurologic examination revealed severe upper motor neuron–
pattern weakness in the lower extremities and a T4 sensory level. Spine
MRI revealed a longitudinally extensive T2-hyperintense lesion
(FIGURE 12-1), and brain MRI showed no lesions suggestive of multiple
sclerosis (MS). A CSF study revealed a white blood cell count of
1727 cells/mm3 (64% lymphocytes; 16% eosinophils; 13% neutrophils),
protein of 322 mg/dL (normal, 0 to 35 mg/dL), and negative oligoclonal
bands. Serum aquaporin-4 (AQP4)–IgG was positive, and a diagnosis of
AQP4-IgG–seropositive neuromyelitis optica spectrum disorder
(NMOSD) was made.
Acute treatment with high-dose IV steroids was initiated. Because of a
lack of response, seven plasma exchanges were given, with resolution of
neurogenic bladder and a return to ambulating independently. Rituximab
was then prescribed as maintenance attack-prevention immunotherapy
along with transitional oral steroids for 1 month while rituximab took
effect.
COMMENT Longitudinally extensive transverse myelitis is a hallmark feature of NMOSD

and should prompt AQP4-IgG testing. In addition to the severity of the
episode and length of the spinal cord lesion, the presence of an elevated
CSF white blood cell count (>50 cells/mm3), absence of typical MS brain
lesions, and negative oligoclonal bands were red flags indicating a
diagnosis other than MS. This patient was African American and African
Americans are particularly predisposed to NMOSD. Clinicians should have a
low threshold to initiate plasma exchange in those with prominent residual
deficits after IV steroids. Long-term attack-prevention immunotherapy is
strongly recommended, as patients have a high risk of potentially disabling
relapses.
820 JUNE 2019

BRAIN. Most patients with NMOSD will not have typical MS lesions, and
only 10% to 20% will satisfy Barkhof MS criteria.23 Typical brain involvement
in NMOSD occurs around circumventricular organs where AQP4 expression
is highest, with lesions adjacent to the third and fourth ventricles
(dorsal medulla/area postrema) most typical (FIGURES 12-3C and 12-3D).23
Other lesions can be similar to acute disseminated encephalomyelitis (ADEM),
have a posterior reversible encephalopathy syndrome (PRES)–like appearance,
or involve the internal capsule (FIGURE 12-3E) or corpus callosum diffusely or
focally in the splenium in a “bridge-arch” pattern.23 Pencil-thin linear ependymal
enhancement (FIGURE 12-3F), leptomeningeal enhancement, and cloudlike
poorly marginated enhancement are also described.23
SPINAL CORD LESION LENGTH. Longitudinally extensive transverse myelitis

(LETM), with a T2-hyperintense lesion spanning three or more contiguous
FIGURE 12-1
Imaging of the patient in CASE 12-1. Sagittal T2-weighted cervical and thoracic spine MRIs
show a longitudinally extensive T2-hyperintense lesion extending from C3 to the conus
(A–C), with some scoliosis not allowing the lesion to be visible on a single thoracic sagittal
sequence.

vertebral segments on MRI, is characteristic of NMOSD (FIGURE 12-1) and

found in approximately 85% of patients.24 LETM is a useful discriminator
from MS myelitis, which is very rarely longitudinally extensive in adults;
however, up to 14% of MS myelitis events in children can be longitudinally
extensive.25 The timing of imaging can impact the lesion length; imaging
early can reveal a short lesion that later evolves into LETM, while imaging
late can reveal a discontinuous lesion that is no longer longitudinally
extensive.
Myelitis accompanied by short lesions (less than three vertebral segments)
occurs in 14% to 15% of AQP4-IgG myelitis attacks, and many of these patients
are initially diagnosed as having MS.24,26 Features that can help suggest those
at highest risk in whom AQP4-IgG should be tested include nonwhite race,
coexisting autoimmunity (eg, lupus), tonic spasms, central cord lesion location
on axial MRI, absence of typical MS brain lesions, and lack of CSF oligoclonal
bands.24 Despite an initial short myelitis, 90% of subsequent myelitis attacks are
associated with an LETM lesion in NMOSD.24
OTHER SPINAL CORD MRI FEATURES. Other reported spinal cord lesion features
include bright spotty (syrinxlike) regions within the T2 lesion, central
lesion T1 hypointensity, and a long segment of cord atrophy. Lesion
CASE 12-2 A 63-year-old right-handed woman developed an episode of intractable

nausea, vomiting, and hiccups lasting weeks. She was evaluated by a
gastroenterologist, but extensive investigations were unrevealing. A brain
MRI was performed and revealed an enhancing lesion in the dorsal
medulla (FIGURE 12-2A). CSF at that time revealed a white blood cell count
of 55 cells/mm3 (95% lymphocytes), protein of 50 mg/dL, and negative
oligoclonal bands. The patient was treated with IV steroids. She
subsequently developed subacute myelitis, and a second MRI showed
two short lesions extending less than three vertebral segments
(FIGURES 12-2B through 12-2E). The myelitis was followed by short-lived
episodic painful spasms in her right upper extremity, which responded
well to low-dose carbamazepine. Serum aquaporin-4 (AQP4)–IgG was
positive by cell-based assay and AQP4-IgG–seropositive neuromyelitis
optica spectrum disorder (NMOSD) was diagnosed.
COMMENT Intractable nausea and vomiting from an area postrema syndrome are
recognized as a cardinal manifestation of AQP4-IgG–seropositive
NMOSD. Patients with this syndrome are often evaluated first by
gastroenterologists. Tonic spasms commonly follow NMOSD myelitis and
respond to carbamazepine. Approximately 15% of patients will have a
myelitis accompanied by a short MRI lesion (<3 vertebral segments); thus,
its presence does not exclude NMOSD, despite being less typical than the
hallmark longitudinally extensive transverse myelitis episodes (CASE 12-1).
822 JUNE 2019

enhancement after gadolinium administration is usually patchy, but ringlike
or lens-shaped enhancement occurs in one-third of patients (FIGURES 12-2D
and 12-2E).23,27 Extension of cervical lesions to the dorsal medulla/area
postrema is suggestive of 28 but not specific for NMOSD and can be seen with
other myelopathies.29
Cerebrospinal Fluid Findings

The typical CSF findings in NMOSD are summarized in TABLE 12-1.
Aquaporin-4–IgG Testing
AQP4-IgG antibody testing is available commercially and is best tested in
blood, as CSF testing is less sensitive.30 Assay techniques have improved
over time, and cell-based assays are now recommended (using
fluorescence-activated cell sorting or direct immunofluorescence); they
yield a sensitivity of 75% to 80% and specificity of greater than 99%.5,6 The
older-generation enzyme-linked immunosorbent assay (ELISA) technique is
less sensitive and has a fivefold higher risk of false positives, particularly
when low titer, and additional diagnostic scrutiny is needed in such patients,
especially if NMOSD-atypical clinical manifestations or MRI findings
are detected.31,32
FIGURE 12-2
Imaging of the patient in CASE 12-2. A, Sagittal postcontrast T1-weighted MRI shows an
enhancing lesion in the area postrema (arrow) during an episode of intractable nausea
and vomiting. B, Sagittal T2-weighted MRI sequence taken during a subsequent myelitis
episode shows a short T2-hyperintense lesion in the cervical cord (arrows). The lesion is
central on axial T2-weighted sequences (C, arrow) and exhibits ring enhancement on
sagittal (D, arrow) and axial (E, arrow) postcontrast T1-weighted images.

FIGURE 12-3
Typical brain and optic nerve lesions in patients with aquaporin-4 IgG–seropositive
neuromyelitis optica spectrum disorder (NMOSD). Axial (A) and coronal (B) postcontrast
T1-weighted images with fat suppression show bilateral posterior optic nerve enhancement
extending to the optic chiasm (arrows). Axial fluid-attenuated inversion recovery (FLAIR) MRI
shows a T2-hyperintense lesion in the region of the area postrema (C, arrow). Coronal
T2-weighted MRI shows a characteristic lesion adjacent to the third ventricle (D, arrow). Axial
FLAIR MRI shows a left internal capsule NMOSD lesion (E, arrow). Coronal postcontrast
T1-weighted MRI with fat suppression shows pencil-thin linear ependymal enhancement
(F, arrows).
Diagnostic Criteria
Updated diagnostic criteria for NMOSD were published by the International
Panel for NMO Diagnosis in 2015 (TABLE 12-3).5 The criteria stratify the diagnosis
by those with AQP4-IgG and those without AQP4-IgG (including those for
whom testing is unavailable). The criteria use core clinical characteristics
focusing on the three cardinal manifestations of optic neuritis, myelitis, and
an area postrema syndrome, in addition to less common manifestations of
other brainstem attacks, diencephalic episodes, and cerebral episodes. The
presence of one of these core clinical characteristics in addition to AQP4-IgG
seropositivity and exclusion of other etiologies allows the diagnosis of NMOSD
with AQP4-IgG to be made. The criteria for patients who areAQP4-IgG
seronegative are more stringent, requiring additional characteristic radiologic
features be present to help avoid misdiagnosis.
824 JUNE 2019

Neuromyelitis Optica Spectrum Disorder Diagnostic Criteriaa TABLE 12-3
Diagnostic criteria for neuromyelitis optica (NMOSD) with aquaporin-4 (AQP4) IgG
1 At least one core clinical characteristic
2 Positive test for AQP4-IgG using best available detection method (cell-based assay
strongly recommended)
3 Exclusion of alternative diagnoses
Diagnostic criteria for NMO without AQP4-IgG or NMOSD with unknown AQP4-IgG status
1 At least two core clinical characteristics occurring as a result of one or more clinical attacks
and meeting all of the following requirements:
a At least one core clinical characteristic must be optic neuritis, acute myelitis with
longitudinally extensive transverse myelitis, or area postrema syndrome
b Dissemination in space (two or more different core clinical characteristics)
c Fulfillment of additional MRI requirements, as applicable
2 Negative tests for AQP4-IgG using best available detection method, or testing unavailable
3 Exclusion of alternative diagnoses
Core clinical characteristics
1 Optic neuritis
2 Acute myelitis
3 Area postrema syndrome: episode of otherwise unexplained hiccups or nausea and vomiting
4 Acute brainstem syndrome
5 Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical
diencephalic MRI lesions
6 Symptomatic cerebral syndrome with NMOSD-typical brain lesions
Additional MRI requirements for NMOSD without AQP4-IgG and NMOSD with unknown
AQP4-IgG status
1 Acute optic neuritis: requires brain MRI showing (a) normal findings or only nonspecific
white matter lesions, OR (b) optic nerve MRI with T2-hyperintense lesion or T1-weighted
gadolinium-enhancing lesion extending over more than half optic nerve length or involving
optic chiasm
2 Acute myelitis: requires associated intramedullary MRI lesion extending over ≥3 contiguous
segments (longitudinally extensive transverse myelitis) OR ≥3 contiguous segments of
focal spinal cord atrophy in patients with history compatible with acute myelitis
3 Area postrema syndrome: requires associated dorsal medulla/area postrema lesions
4 Acute brainstem syndrome: requires associated periependymal brainstem lesions
IgG = immunoglobulin G; MRI = magnetic resonance imaging.

a
Reprinted with permission from Wingerchuk DM, et al, Neurology.5 © 2015 American Academy of Neurology

Aquaporin-4 IgG–Seronegative Neuromyelitis Optica Spectrum Disorder

Approximately 20% to 25% of patients with NMOSD are AQP4-IgG
seronegative. Up to 25% of patients with seronegative NMOSD will have
antibodies to MOG-IgG, as discussed below. The treatment approach to
AQP4-IgG–seronegative NMOSD is similar to AQP4-IgG–seropositive NMOSD.
Pathogenesis and Pathology

AQP4-IgG binds to AQP4, which is located on the end-feet of astrocytes,
initiating a cascade of immune-mediated inflammation resulting in secondary
demyelination.
A full discussion of the pathogenesis of NMOSD is beyond the scope of
this article but has been reviewed previously.33,34 Biopsy and autopsy studies
of patients with NMOSD show that lesions are associated with loss of
myelin, infiltration of inflammatory cells (macrophages, T cells and B cells,
neutrophils, eosinophils), and axonal and astrocyte loss.35 A rim-and-rosette
pattern of immunoglobulin deposition colocalized with complement is also
seen.35 AQP4 immunostaining is lost within NMOSD lesions, and cortical lesions
are not found, helping distinguish it from MS, in which AQP4 immunostaining is
preserved or increased and cortical lesions are common.36
Treatment
Treatment of NMOSD is divided into acute attack treatment and maintenance
(attack-prevention) treatment.
ATTACK TREATMENT. High-dose corticosteroids (1000 mg IV methylprednisolone

daily for 5 days) are used initially. The use of plasma exchange for five to
seven exchanges for severe, corticosteroid-refractory CNS inflammatory
demyelinating attacks is supported by data from a prospective randomized
sham-controlled crossover trial.37 The author recommends a low threshold to use
plasma exchange in those not improved or with incomplete recovery after
steroids (CASE 12-1), and a 2016 evaluation of more than 800 NMOSD attacks
highlighted its benefit.38
MAINTENANCE THERAPY. The importance of maintenance attack-prevention

immunotherapy in NMOSD is evidenced by the increasing recognition of this
disease as a relapsing disorder, compared to initial descriptions as a monophasic
disease. Despite the lack of completed randomized controlled trials in NMOSD,
preventive treatment is strongly recommended in all patients. This approach is
supported by the severity of attacks and incomplete recovery, leading to a risk of
accumulating disability with each attack, which differs from MS attacks
(TABLE 12-1). The goals of treatment are to prevent relapses while limiting side
effects. The three most commonly used medications are azathioprine,
mycophenolate mofetil, and rituximab; some observational data have suggested
that azathioprine may not be as effective as rituximab and mycophenolate
mofetil.33 Choice of treatment may depend on local availability, cost, patient
preference, and duration of concomitant oral steroids needed while the
immunosuppressant takes effect. The dosage recommendations for these
medications are outlined in TABLE 12-4. Because of its lower cost and more
widespread availability, methotrexate has also been used. Consideration for
switching maintenance immunotherapy arises if disease breakthrough occurs or
if intolerable severe side effects occur.
826 JUNE 2019

TREATMENT TRENDS IN NEUROMYELITIS OPTICA SPECTRUM DISORDER. AQP4-IgG KEY POINTS
is an IgG1 and thus can activate complement, which appears to play a role in
● In NMOSD, optic nerve
promoting the cascade of immune-mediated inflammation that follows involvement is often
AQP4-IgG binding; it is also notable that complement deposition is evident bilateral and typically
pathologically.33,35 The C5 complement inhibitor eculizumab showed possible involves the posterior optic
efficacy for attack prevention in a phase 2 open-label pilot study39 and is pathway, including the optic
chiasm, with enhancement
currently undergoing a phase 3 randomized clinical trial. After B-cell activation
usually extending more than
in lymph nodes, B cells (CD20+, CD19+) differentiate into plasmablasts half the length of the nerve.
(CD19+, CD20–) and plasma cells (CD19–, CD20–); the latter two B-cell subsets
account for the majority of antibody production. IL-6 is necessary for ● Typical brain involvement
plasmablast survival and appeared to be important in experimental studies of in NMOSD occurs around
circumventricular organs
NMOSD pathogenesis.12 Thus, there has been interest in treatments targeting where AQP4 expression is
CD19+ plasmablasts and IL-6. A randomized placebo-controlled study of highest, with lesions
inebilizumab (previously known as MEDI-551), a monoclonal antibody adjacent to the third and
targeting CD19 in attack prevention, is currently under way. Tocilizumab is an fourth ventricles (dorsal
medulla/area postrema)
antibody targeting IL-6 that has been repurposed from its use in rheumatoid most typical.
arthritis; retrospective studies suggest it may be a useful treatment in NMOSD,
with reductions in neuropathic pain a novel added benefit.40 Another IL-6 ● Longitudinally extensive
receptor monoclonal antibody, SA237, is currently being studied in a transverse myelitis, with a
T2-hyperintense lesion
randomized controlled clinical trial. Other approaches currently in
spanning three or more
development include AQP4 blocking antibodies in animal models, inhibitors contiguous vertebral
of neutrophils (sivelestat) or eosinophils (cetirizine), and studies of segments on MRI, is
immune tolerance.33 characteristic of NMOSD
and found in approximately
TREATMENT RISKS. Long-term immunosuppression is currently recommended 85% in patients.
in all patients with NMOSD, but the long-term risks have yet to be established.
● Assay techniques for
A single case of progressive multifocal leukoencephalopathy in NMOSD treated AQP4-IgG have improved
with azathioprine has thus far been reported.41 Opportunistic retinal infections over time, and cell-based
(toxoplasmosis, cytomegalovirus) from immunosuppression in NMOSD can assays are now
mimic optic neuritis attacks.42 Further studies are needed to determine whether, recommended (using
fluorescence-activated
in some patients, maintenance immunotherapy could be discontinued safely and
cell sorting or direct
thus reduce the risks associated with long-term immunosuppression. immunofluorescence); they
yield a sensitivity of 75% to
MYELIN OLIGODENDROCYTE GLYCOPROTEIN ANTIBODY DISEASE 80% and specificity of
MOG has been of interest to researchers for decades given its location on the greater than 99%.
surface of oligodendrocytes, making it a potential target for pathogenic
● Approximately 20% to
antibodies. Initial studies suggested that MOG-IgG was a biomarker of MS, 25% of patients with NMOSD
but these studies were hampered by older-generation techniques (ELISA, are AQP4-IgG seronegative.
Western blot) and failure to use MOG in its human conformational form.43
With the use of cell-based assays transfected with MOG in its conformational ● AQP4-IgG binds to AQP4,
which is located on the
form, the antibody has been shown to be a specific biomarker of a spectrum end-feet of astrocytes,
of CNS inflammatory demyelinating disease distinct from MS and initiating a cascade of
AQP4-IgG–seropositive NMOSD.43 The three disorders are compared in immune-mediated
TABLE 12-1. inflammation resulting in
secondary demyelination.
Nomenclature
No single term is widely accepted to describe this disease. Most recently, the term
MOG-antibody (MOG-IgG) disease has been suggested44; this term is used in
this article, although other terms used include MOG/MOG-IgG paired with the
relevant syndrome (encephalomyelitis, myelitis, NMOSD, optic neuritis, and
demyelinating disease).43,45

Demographics
In contrast to AQP4-IgG–seropositive NMOSD and MS, which have a female
predominance, the sex distribution with MOG-IgG disease appears to be more
equal, although a slight female predominance was reported in the largest clinical
series to date.44 MOG-IgG disease appears to have a particular predilection for
children and young adults, but any age can be impacted.44,46 The incidence and
prevalence of this disease have not yet been well elucidated, and population-
based epidemiologic studies are lacking. In the only population-based study of
autoimmune encephalitis including ADEM, MOG-IgG was the most frequent
antibody detected.47
Clinical Features
Preceding prodromal symptoms are commonly encountered and can include fever,
rhinorrhea, malaise, and cough, which can sometimes lead to the suspicion of an
infectious rather than immune-mediated disorder. The major clinical manifestations
include optic neuritis, ADEM, NMOSD (seronegative for AQP4-IgG), transverse
myelitis, and brainstem demyelinating episodes.43 The clinical presentation is in the
form of attacks that are subacute in onset similar to other CNS inflammatory
demyelinating diseases, with optic neuritis being the most common and accounting
TABLE 12-4 Common Maintenance Immunotherapy Regimens for Neuromyelitis Optica

Spectrum Disordera
Medication/Dose/Regimen (Adults) Precautions/Monitoring/Prophylaxis Common/Important Side Effects

Corticosteroids: prednisone/
methylprednisolone
1 mg/kg prednisone orally once daily Precautions/monitoring: assess for Infection, osteoporosis,
initially hyperglycemia if diabetic/at risk, baseline avascular necrosis of the hip,
bone density scan in those at risk cushingoid appearance, skin
If adding rituximab, use prednisone
thinning and easy bruising,
concurrently for 1 month and then taper Prophylaxis: calcium 1500 mg/d
insomnia, psychosis, depression,
and vitamin D 800 IU/d, trimethoprim-
If adding azathioprine or mycophenolate cataracts, hypertension, weight
sulfamethoxazole one double-strength
mofetil, use prednisone concurrently for gain and edema; addisonian crisis
tablet (800 mg/160 mg) 3 times per
6 months and taper over next 6 months; with abrupt discontinuation
week, proton pump inhibitor/histamine-2
consider low doses (10–20 mg) in
receptor blocker in those at high risk for
addition to azathioprine or
gastrointestinal ulceration
mycophenolate mofetil to maintain
remission if necessary
Induction therapy of 1 g IV
methylprednisolone daily for 5 days may
be used before starting oral prednisone
Azathioprine
Target dose: 2.5–3 mg/kg/d orally in Precautions/monitoringb: measure Infection, malignancy (lymphoma,
divided doses thiopurine S-methyltransferase enzyme skin cancers and others), nausea,
activity before startingc; complete blood macrocytic anemia, skin rash,
cell count,d renal function, and liver hypersensitivity reaction, drug
function at baseline, then weekly for fever, pancreatitis, elevated liver
1 month, every other week for 2 months function tests
and monthly thereafter
828 JUNE 2019

for the majority of relapses. The clinical presentation and radiologic appearance of
MOG-IgG myelitis may mimic that of the acute flaccid myelitis associated with
enterovirus infections.45 The episodes tend to be more severe than with MS
(CASE 12-3) but have better recovery than AQP4-IgG–seropositive NMOSD.43
MOG-IgG–related optic neuritis is associated with optic disc edema in
approximately 86% of patients, and 30% to 50% may be bilateral, distinguishing
it from MS optic neuritis in which both of these features are rare.48 MOG-IgG is
found in 15% of patients with recurrent optic neuritis without other nervous
system involvement, similar to the 13% frequency of AQP4-IgG in these patients.49
In contrast, MOG-IgG is rarely encountered (2%) with recurrent LETM, in which
AQP4-IgG accounts for up to 90% of cases.50 Bowel and bladder disturbance and
erectile dysfunction in men are common with MOG-IgG myelitis, likely due to the
frequent conus involvement.44 Episodes of intractable nausea and vomiting have
been reported, although much less frequently than with AQP4-IgG.44 Rare cases of
hemi-encephalitis and seizures have been reported with MOG-IgG.51,52
Clinical Course and Prognosis

Some patients have a monophasic course, while others go on to develop relapsing
disease. Higher titers and persistent MOG-IgG positivity over time predict a higher
Medication/Dose/Regimen (Adults) Precautions/Monitoring/Prophylaxis Common/Important Side Effects

Mycophenolate mofetil
Target dose: 1000 mg 2 times a day Monitoringb: complete blood cell count, Infection, increased risk of
orally (start at 500 mg 2 times a day renal function, and liver function at malignancy (lymphoma, skin
for 1–2 weeks, then increase to baseline, then weekly for 1 month, every cancers, and others), diarrhea,
maintenance dose of 1000 mg other week for 2 months, and monthly hypertension, hepatitis,
2 times a day) thereafter myelosuppression, renal failure
Rituximab
Initial dosee: two doses of 1000 mg Monitoringb: complete blood cell count Infusion reactions, infection
IV, 2 weeks apart monthly; CD 19+ and CD27+ counts are (opportunistic infections
monitored by somef including progressive multifocal
Redosingf every 6 months: two doses
leukoencephalopathy [risk 1/
of 1000 mg IV, 2 weeks apart
20,000]), myelosuppression,
human antichimeric antibodies,
hepatitis B reactivation,
tuberculosis reactivation
IV = intravenous.
a
Modified with permission from Flanagan EP, Weinshenker BG, Curr Neurol Neurosci Rep.12 © 2014 Springer Science+Business Media.
b
Trimethoprim-sulfamethoxazole one double-strength tablet (800 mg/160 mg) 3 times a week may be considered for Pneumocystis jiroveci
prophylaxis, but evidence for its use in this context is limited and guidelines are lacking.
c
Low activity (heterozygote for TPMT gene) increases risk for drug toxicity and may require slower titration and increased monitoring/use of
alternative agent. If no activity (homozygote for TPMT gene), use alternative agent.
d
Consider monitoring mean corpuscular volume; increases of >5 femtoliters may be associated with improved efficacy.
e
Some use an alternative dosing strategy of four weekly doses of 375 mg/m2.
f
Monitoring of CD19+ counts is done by some with redosing when CD19+ cells begin to return, although many prefer to redose every 6 months
(1000 mg repeated in 2 weeks) regardless of B-cell counts because rapid B-cell repopulation may occur that may be missed by monthly
monitoring and patients are vulnerable to relapse during repopulation periods.

risk of relapse in children and adults, as illustrated by CASE 12-3.46,53 Those with
transient seropositivity are likely to follow a monophasic course.46,53 Some may have
corticosteroid-dependent optic nerve involvement, termed chronic relapsing
inflammatory optic neuropathy.48 Relapses are dominated by optic neuritis, and
most permanent disability appears to arise from the initial episode. In contrast to
MS, a secondary progressive course has not been reported.
Radiologic Accompaniments
The MRI features of MOG-IgG disease have notable differences from AQP4-
IgG–seropositive NMOSD and MS that can help suggest those at highest risk in
whom MOG-IgG should be tested.
CASE 12-3 A 47-year-old man was admitted to the hospital with a rapidly progressive
quadriparesis and encephalopathy following a viral prodrome. At his nadir
2 weeks from onset, he required mechanical ventilation, and his examination
revealed quadriplegia, hyperreflexia, spasticity, and extensor plantar
responses bilaterally. MRI of the brain and cervical spine were abnormal,
showing multifocal white matter lesions and a myelitis lesion (FIGURE 12-4). CSF
analysis revealed a white blood cell count of 139/mm3 (75% lymphocytes),
protein of 74 mg/dL, and negative oligoclonal bands. Serum aquaporin-4
(AQP4)–IgG was negative. He underwent a brain biopsy after having no
response to high-dose IV corticosteroids, which showed myelin loss,
perivascular macrophage infiltrate, and relatively preserved axons consistent
with acute disseminated encephalomyelitis (ADEM). Myelin oligodendrocyte
glycoprotein (MOG) IgG was tested and returned positive by live cell-based
assay at high titer, confirming a MOG-IgG disease diagnosis. He completed
seven plasma exchange treatments and received oral prednisone with a
slow taper.
Three months later, his neurologic examination was normal and his MRI
lesions had resolved. During prednisone tapering, he developed right
optic neuritis, which was treated with IV methylprednisolone, a slower
taper of oral prednisone, and azathioprine as maintenance steroid-
sparing immunotherapy. Serum MOG-IgG remained persistently positive
2.5 years after onset.
COMMENT ADEM is a hallmark episode of MOG-IgG–related disease. The preceding

viral prodrome, severity of the episode, longitudinally extensive spinal cord
lesion, CSF white cell count of greater than 50/mm3, and absence of
oligoclonal bands were all atypical for multiple sclerosis. Despite severe
attacks, patients often have excellent recovery after acute treatment, as
was seen in this patient. High titers of MOG-IgG at onset and persistent
seropositivity over time predict relapsing disease. Relapses in MOG-IgG
disease are dominated by optic neuritis. Steroid-sparing immunosuppressants
are often used for attack prevention, particularly in relapsing disease,
although randomized controlled trials have not yet been undertaken.
830 JUNE 2019

OPTIC NERVE. Enhancement involves more than half of the length of the optic
nerve in 80% of patients and may involve the optic nerve sheath (FIGURE 12-5A)
or extend into the orbital fat.48 Bilateral anterior pathway optic nerve
enhancement without extension to the optic chiasm (FIGURE 12-5B) is more
typical of MOG-IgG than AQP4-IgG.54
BRAIN. Multifocal white matter T2 hyperintensities (FIGURE 12-4A) with

involvement of the deep gray matter (FIGURE 12-5C) are typical of MOG-IgG
disease, particularly with ADEM-like presentations. Infratentorial lesions tend
to be more diffuse than with MS (TABLE 12-1). However, in contrast to MS, ovoid
periventricular, inferior temporal pole, and Dawson finger lesions are typically not
FIGURE 12-4
Imaging of the patient in CASE 12-3. A, Axial fluid-attenuated inversion recovery (FLAIR) MRI
shows multifocal fluffy T2 hyperintensities that are typical of acute disseminated
encephalomyelitis (ADEM) and that did not have accompanying enhancement (not shown).
B, Sagittal T2-weighted cervical spine MRI shows an accompanying slightly discontinuous
longitudinally extensive T2-hyperintense spinal cord lesion (arrow) that also lacked
enhancement (not shown).

FIGURE 12-5
Typical optic nerve and brain lesions in patients with myelin oligodendrocyte glycoprotein
antibody (MOG-IgG) disease. A, Coronal postcontrast T1-weighted orbital MRI shows
enhancement of the optic nerve and its surrounding sheath (arrow). B, Axial postcontrast
T1-weighted orbital MRI shows bilateral anterior optic nerve enhancement (arrows). C, Axial
fluid-attenuated inversion recovery (FLAIR) MRI shows a T2-hyperintense lesion in the right
thalamus (arrow), typical of the deep gray matter involvement of MOG-IgG.
FIGURE 12-6
Typical spinal cord lesions in patients with myelin oligodendrocyte glycoprotein antibody
(MOG-IgG) disease. A, Sagittal thoracic T2-weighted sequence shows a longitudinally
extensive hyperintense lesion extending for four and a half vertebral segments (arrows).
B, Sagittal T2-weighted cervical spine MRI shows a short T2-hyperintense lesion extending
two vertebral segments and forming a sagittal line (arrow). C, Sagittal T2-weighted thoracic
MRI shows a short hyperintense lesion extending one vertebral segment and involving the
conus (arrow). D, The T2 hyperintensity is central on axial sequences and highly confined
to the gray matter, forming an H pattern (arrow). E, The lesion is again confined to the gray
matter, forming an H pattern on axial view (arrow).
832 JUNE 2019

present.55 The brain MRI is more difficult to distinguish from NMOSD than MS.55
Cortical lesions and leptomeningeal enhancement have also been reported.52
SPINAL CORD. Longitudinally extensive lesions (FIGURE 12-6A) occur in the
majority (60% to 80%), while the remainder may be short (FIGURE 12-6B), although
both may be present simultaneously. In contrast to AQP4-IgG (in which a
solitary LETM is typical), with MOG-IgG, it is not uncommon to have two
separate lesions with the conus often involved (FIGURE 12-6C).45 Lesions are
usually central on axial sequences, which differs from MS (TABLE 12-1).56 The
T2-signal abnormality can be restricted to gray matter, forming a sagittal line
(FIGURE 12-6B) and axial H sign (FIGURES 12-6D and 12-6E) in approximately
one-third of patients, differing from central lesions of AQP4-IgG, which
typically involve both gray and white matter.45
Cerebrospinal Fluid Findings in Myelin Oligodendrocyte Glycoprotein IgG

Positive oligoclonal bands are found in less than 15% of patients with
MOG-IgG.44,52 The other CSF findings are reviewed and compared to
AQP4-IgG and MS in TABLE 12-1.
Myelin Oligodendrocyte Glycoprotein–IgG Testing

A 2018 consensus article outlined patients in whom MOG-IgG should be tested
and recommended against testing MOG-IgG in all patients with MS, given the
risk of false positives when testing in low-probability situations.57 In general,
testing should be reserved for those with one of the classic phenotypes of
MOG-IgG disease (TABLE 12-1) that lacks characteristic features of MS.
Testing with a cell-based assay (with direct visual immunofluorescence or
fluorescence-activated cell sorting) is strongly recommended.57 Blood testing is
recommended for MOG-IgG, and the role of CSF MOG-IgG is uncertain.57
Detection with ELISA, Western blot, or assays using the nonconformational
MOG epitope should be avoided.57
Some patients with MOG-IgG, particularly children with an ADEM phenotype,
appear to have a monophasic course. In these patients, MOG-IgG elevation is often
transient, and follow-up testing after 6 to 12 months is often negative. Some
studies have shown that higher MOG-IgG titers at onset are associated with an
increased risk of relapse, but this requires further study.46 In addition, persistent
seropositivity may predict relapse.46,53 The author generally recommends repeat
testing 6 months after the initial episode to assist prognostication.
Pathogenesis and Pathology

Pathology case reports have shown overlap with pattern II MS (demyelinating
lesions with an inflammatory infiltrate of T cells and macrophages with
accompanying complement deposition).58 A full discussion of the potential
pathogenesis of MOG-IgG is beyond the scope of this article but has been
reviewed elsewhere.59
Treatment
No randomized clinical trial data are available to guide clinicians in treating
MOG-IgG disease. Acute treatments for MOG-IgG are very similar to those for
NMOSD. A major area of study is determining which patients may have a
monophasic disorder and not require treatment. For patients with relapsing disease,
the maintenance treatment approach is almost identical to that of acute and

maintenance therapy for NMOSD (outlined above), although IV

immunoglobulin (IVIg) appears to be useful in children acutely and as a
maintenance treatment.60
ACUTE DISSEMINATED ENCEPHALOMYELITIS AND OTHER CNS

INFLAMMATORY DEMYELINATING DISEASES
Despite the discovery of neural antibody biomarkers of CNS inflammatory
demyelinating diseases, many diseases in this category lack antibody biomarkers.
At the author’s facility, testing AQP4-IgG and MOG-IgG is recommended in
all patients with ADEM, but more than 50% will be seronegative for both. ADEM
is most common in children, and the presentation often follows vaccination or an
infectious prodrome. The MRI findings include multifocal white matter T2
hyperintensities, deep gray matter lesions, and longitudinally extensive spinal cord
lesions. Acute treatment is similar to the approach outlined with NMOSD above.
Many patients with ADEM have a monophasic course, but some can go on to
develop typical MS or further non-MS relapsing course (eg, multiphasic ADEM),
and, although many of this latter group will be MOG-IgG seropositive, some are
seronegative. Other patients can have recurrent attacks of CNS demyelination
restricted to one site (eg, recurrent optic neuritis or recurrent transverse myelitis)
that do not meet criteria for MS and are seronegative for AQP4-IgG and
MOG-IgG.49,50 This subset of patients represents an important focus for research
to determine if antibody biomarkers that define those diseases exist. Treatment
for these disorders is similar to the approach for NMOSD.
OTHER INFLAMMATORY CNS DISORDERS

A wide variety of other inflammatory CNS diseases can mimic MS, which practicing
neurologists should be aware of; these are
discussed in the following sections.
Autoimmune Glial Fibrillary Acidic

Protein Astrocytopathy
In 2016, an antibody to glial fibrillary acidic
protein (GFAP-IgG) was reported
that, when detected in CSF, appeared to be
specific for an inflammatory
meningoencephalomyelitis, termed
autoimmune GFAP astrocytopathy.61 Patients
of any age can be impacted (median age of
44 years), and the frequency is similar in
males and females.62 Clinical manifestations
include subacute to chronic meningitis
(headache, neck stiffness, photophobia),
encephalitis (memory loss, tremor, ataxia),
and myelitis (urinary retention, numbness,
weakness), and thus some of its features
can mimic MS.62,63 Bilateral optic disc FIGURE 12-7
edema is a helpful clue, but intracranial Axial postcontrast T1-weighted MRI
reveals the typical radial enhancement
pressure is typically normal and thus does
accompanying antibodies to
not reflect papilledema.64 The myelitis autoimmune glial fibrillary acidic
features tend to be mild and occur in protein (GFAP) astrocytopathy.
834 JUNE 2019

conjunction with encephalitis; an isolated myelitis generally does not occur.65 KEY POINTS
Coexisting neoplasms, particularly teratoma, may be seen.62 N-Methyl-D-aspartate
● The use of plasma
(NMDA) receptor autoantibodies and AQP4-IgG may coexist.62 Samples are best exchange for five to seven
tested in CSF for optimal sensitivity and specificity; dual testing is recommended exchanges for severe,
using tissue immunofluorescence and cell-based assay confirmation of GFAP corticosteroid-refractory
central nervous system
(GFAPα appears to be the most sensitive isoform).62 Care is needed with serum
inflammatory demyelinating
positivity alone because of a high attacks is supported by data
risk of false positives. Brain MRI from a prospective
may reveal a characteristic radial randomized sham-controlled
crossover trial.
perivascular enhancement
perpendicular to the ventricles ● Despite the lack of
(FIGURE 12-7),62 although a similar completed randomized
pattern can be seen with controlled trials in NMOSD,
preventive treatment is
intravascular lymphoma, strongly recommended in
neurosarcoid, and CNS vasculitis. all patients.
Leptomeningeal enhancement is
also common. In the spinal cord, a ● With the use of
cell-based assays
longitudinally extensive faint T2 transfected with myelin
hyperintensity may be seen with oligodendrocyte
central canal or punctate glycoprotein (MOG) in its
parenchymal enhancement.65 The conformational form, the
antibody has been shown to
vast majority (>85%) of patients be a specific biomarker of a
with autoimmune GFAP spectrum of central nervous
astrocytopathy will have an system inflammatory
demyelinating disease
elevated CSF white cell count,
distinct from multiple
and oligoclonal bands are sclerosis and AQP4-
detected in half.62 Response to IgG–seropositive NMOSD.
steroids is generally brisk,
● The major clinical
although a less corticosteroid-
manifestations of MOG-IgG
responsive phenotype was noted disease include optic
in an Asian cohort.66 Prolonged neuritis, acute disseminated
oral corticosteroids are the most encephalomyelitis, NMOSD
(seronegative for AQP4-IgG),
frequent treatment used, and transverse myelitis, and
relapse is frequent during steroid brainstem demyelinating
tapering.62 Corticosteroid-sparing episodes.
agents are often prescribed to try
● Some patients with
to maintain remission, although MOG-IgG disease have a
randomized controlled trials monophasic course, while
are lacking.62 others go on to develop
relapsing disease.
Diagnostic Pearls With FIGURE 12-8

● Radiologic findings in
Inflammatory/Autoimmune Imaging of a patient with paraneoplastic myelitis.
MOG-IgG disease include
Sagittal T2-weighted cervical spine MRI shows a
Disorders Associated With longitudinally extensive hyperintensity (A,
enhancement that involves
Other Autoantibody Biomarkers more than half of the length
arrows). Sagittal (B) and axial (C) postcontrast
of the optic nerve in 80% of
Neurologic syndromes associated T1-weighted images of the same patient show
patients and may involve the
with collapsin response mediator enhancement in a characteristic tract-specific
optic nerve sheath or extend
pattern extending along both lateral columns
protein-5 (CRMP-5) autoantibody on axial sequences (C, arrows).
into the orbital fat.
(CRMP-5-IgG/anti-CV2) include Reprinted with permission from Flanagan EP et al,
optic neuropathy, retinitis, and Neurology.67 © 2016 American Academy of Neurology.

FIGURE 12-9
Axial postcontrast T1-weighted MRI shows
punctate foci of enhancement that are pontine
predominant (arrow) but also involve the
cerebellum (arrowhead) in a patient with chronic
lymphocytic inflammation with pontine
perivascular enhancement responsive to
steroids (CLIPPERS).
FIGURE 12-11
Sagittal T2-weighted cervical spine MRI of a
patient with spinal cord sarcoidosis shows a
longitudinally extensive T2-hyperintense lesion
(A, arrow) accompanied, on postcontrast
T1-weighted sagittal image, by hallmark dorsal
subpial enhancement (B, arrows) and central canal
enhancement (B, arrowheads), which on axial
postcontrast T1-weighted images form a trident
appearance (C, arrow).
Reprinted with permission from Zalewski NL, et al,
Neurology.71 © 2016 American Academy of Neurology
FIGURE 12-10
Axial T2-weighted MRI shows a hyperintense left
midbrain lesion in a patient with Behçet syndrome.
836 JUNE 2019

myelitis and thus can mimic MS KEY POINTS
or NMOSD.67 Spinal cord
● Multifocal white matter
T2-hyperintense lesions tend to T2 hyperintensities with
be longitudinally extensive and involvement of the deep
involve lateral or dorsal columns, gray matter are typical in
with a characteristic symmetric MOG-IgG disease,
particularly with acute
tract-specific enhancement
disseminated
sometimes seen (FIGURE 12-8).67 encephalomyelitis–like
The myelopathy may mimic presentations.
primary progressive MS.67 The
oncologic associations include ● Positive oligoclonal bands
are found in less than 15%
small cell lung cancer and of patients with MOG-IgG.
thymoma. γ-Aminobutyric acid
(GABA)A receptor autoantibodies ● A 2018 consensus article
can mimic MS on MRI with outlined patients in whom
MOG-IgG should be tested
multifocal white matter and and recommended against
cortical lesions.68 The disease testing MOG-IgG in all
has a particular predilection for patients with multiple
children and can occur as a sclerosis, given the risk of
FIGURE 12-12 false positives when testing
Sagittal fluid-attenuated inversion recovery postinfectious phenomenon
in low-probability situations.
(FLAIR) MRI of a patient with Susac syndrome after viral encephalitis or In general, testing for
shows snowball-like T2-hyperintense lesions may be paraneoplastic MOG-IgG should be
predominating in the corpus callosum (arrows).
(eg, thymoma).68 reserved for those with one
of the classic phenotypes
that lacks characteristic
Chronic Lymphocytic Inflammation With Pontine Perivascular features of multiple
Enhancement Responsive to Steroids sclerosis.
Chronic lymphocytic inflammation with pontine perivascular enhancement
responsive to steroids (CLIPPERS) is an inflammatory disorder of uncertain ● A major area of study in
MOG-IgG disease is
cause that may mimic MS. The presentation is that of a progressive brainstem determining which patients
syndrome with accompanying ataxia. The hallmark MRI finding is a may have a monophasic
disorder and not require
treatment.
● For patients with

relapsing MOG-IgG disease,
the treatment approach is
almost identical to that of
acute and maintenance
therapy for NMOSD,
although IV immunoglobulin
appears to be useful in
children acutely and as a
maintenance treatment.
● In 2016, an antibody to
glial fibrillary acidic protein
(GFAP) was reported that,
when detected in CSF,
appeared to be specific
for an inflammatory
FIGURE 12-13
meningoencephalomyelitis,
Imaging of a patient with primary angiitis of the central nervous system. Axial
termed autoimmune GFAP
susceptibility-weighted imaging (SWI) shows parenchymal microhemorrhages (A, arrowhead)
astrocytopathy.
and sulcal superficial siderosis, noted as dark regions with accompanying leptomeningeal
enhancement (B, arrows).

multifocal bilateral punctate (<3 mm) enhancement pattern that is centered on

the pons and often extends to the cerebellum (FIGURE 12-9).69 The absence of
mass effect is an important feature.70 CSF shows an elevated white cell count in
one-third of patients, but oligoclonal bands are infrequent (<10%). Pathology
shows dense perivascular inflammation with a T-cell predominance.70
Diagnostic criteria have been proposed and should be stringently adhered to as,
in addition to MS, lymphoma and neurosarcoid can mimic this disorder.70
Biopsy to exclude lymphoma is important if atypical features are present.70 Oral
corticosteroids and corticosteroid-sparing immunosuppressants are the mainstay
of treatment.
Neuro-Behçet Disease
Neuro-Behçet disease characteristically involves the brainstem (FIGURE 12-10),
although myelitis and cerebral venous sinus thrombosis are also reported.
Individuals from the old Silk Road (Middle East and Asia) are predisposed.
The presence of oral and genital ulcers, pathergy (exaggerated skin injury to
TABLE 12-5 Noninflammatory Diseases With Features That Mimic Central Nervous
System Inflammation
Mimic of Central Clinical MRI Discriminators

Nervous System Discriminators From From Multiple Other Helpful
Category/Disease Inflammation Multiple Sclerosis Sclerosis Investigations
Neoplastic
Primary central Increased CSF cells, Older age, Deep gray matter CSF cytology/
nervous system multifocal enhancing risk factors involvement; flow abnormal
lymphoma lesions, steroid- (immunosuppression persistent
responsive [HIV, transplant]) enhancement
(>3 months)
Erdheim-Chester Brainstem/ Bone pain, Persistent X-ray/bone scan

disease cerebellar older age enhancement for showing
enhancing lesions; more than 3 months osteosclerosis of long
inflammatory CSF bones; BRAF genetic
may occur testing or staining on
pathology
Genetic
Alexander disease Enhancing brainstem Family history Tadpole sign GFAP mutation
lesions and (autosomal (normal-sized pons,
multifocal brainstem dominant); with atrophic
signal abnormality progressive medulla), spinal
course cord atrophy
Adrenoleukodystrophy/ Enhancement at Family history Diffuse cord atrophy Long chain fatty
Adrenomyeloneuropathy edge of diffuse (X-linked); male; without spinal cord acids; ABCD1 gene
white matter T2 adrenal failure lesions
hyperintensity
838 JUNE 2019

minor trauma), and uveitis are useful clinical clues. The CSF is often
neutrophilic, helping to distinguish Behçet disease from MS, and HLA-B51
may be positive.
Neurosarcoidosis
Neurosarcoidosis should be included among the differential diagnosis of MS as
it can manifest with multifocal involvement of the CNS, including the optic
nerve, brain, or spinal cord. An elevated CSF white cell count and enhancing
lesions overlap with MS, but oligoclonal bands are usually absent; basilar
leptomeningeal enhancement and spinal cord linear dorsal subpial enhancement
extending two or more vertebral segments are suggestive.14 Occasionally, dorsal
subpial enhancement is accompanied by central canal enhancement, forming a
hallmark trident appearance on axial images (FIGURE 12-11).71 Clinical and
radiologic recurrence is frequent when IV steroids are discontinued, and
persistence of enhancement beyond 3 months helps distinguish from MS, where
enhancement is typically transient, resolving within 2 months. Prolonged
Mimic of Central Clinical MRI Discriminators

Nervous System Discriminators From From Multiple Other Helpful
Category/Disease Inflammation Multiple Sclerosis Sclerosis Investigations
Vascular
Spinal cord infarct May have Acute onset (time to Restricted diffusion; Lacks confirmatory
enhancement, nadir <12 hours), axial anterior horn tests
occasional mild severe deficit, cell T2 signal (owl
CSF pleocytosis vascular risk factors eye, snake eye);
vertebral body
infarct; adjacent
dissection
Dural arteriovenous 50–60% have Stepwise worsening Thoracic cord with Formal spinal
fistula parenchymal with exercise/ conus involved; angiogram
enhancement Valsalva; worse with flow voids; missing necessary for
steroids piece sign with diagnosis
section lacking
enhancement
Structural
Cervical spondylotic Enhancement (7%); Progressive course, Pancakelike Flexion/extension

myelopathy occasional CSF neck pain, coexisting enhancement MRI can help
inflammation radiculopathies (FIGURES 12-14A, highlight;
12-14B, and 12-14C), improvement after
axial circumferential surgery
pattern sparing gray
matter, persistent
enhancement for
more than 3 months
CSF = cerebrospinal fluid; HIV = human immunodeficiency virus; MRI = magnetic resonance imaging.

high-dose oral corticosteroid

treatment is usually required for
neurosarcoid with or without
corticosteroid-sparing
medications.
Central Nervous System

Inflammatory Vascular
Mimics of Multiple
Sclerosis
Some of the inflammatory
vascular diseases of the brain
can mimic MS. Susac syndrome
is an inflammatory
endotheliopathy that is
characterized by a triad of
branched retinal artery
occlusions, hearing loss, and
dementia/encephalopathy.
Ophthalmologic examination
can show branched retinal
artery occlusions, Gass plaques
(yellow plaques within
mid-arterioles on funduscopy),
or arterial wall hyperfluorescence
on fluorescein angiogram.72
Low-frequency hearing loss is
typical on audiogram. MRI can
mimic MS with corpus callosum
lesions, but these tend to
predominate in the center of the
corpus callosum and may have a
FIGURE 12-14 snowball-type appearance
Imaging of a patient with spondylotic myelopathy
(FIGURE 12-12), rather than the
mimicking multiple sclerosis. A, Sagittal
T2-weighted cervical spine MRI shows a short Dawson finger appearance seen
T2-hyperintense lesion (arrow) adjacent to a with MS. A “string of pearls”
region of moderate to severe stenosis appearance of beaded
(arrowheads). Sagittal (B) and axial (C) microinfarcts along the internal
postcontrast T1-weighted sequences show a
“pancakelike” transverse band of enhancement capsule is suggestive.73 Primary
(B, arrow) in a circumferential pattern sparing gray angiitis of the CNS can mimic
matter (C, arrows) characteristic of cervical MS with inflammatory-
spondylotic myelopathy with enhancement. appearing lesions, but the
presence of diffusion restriction
in defined arterial territories, microhemorrhages, and leptomeningeal
enhancement is an important discriminating feature (FIGURE 12-13).
PARACLINICAL FINDINGS MIMICKING INFLAMMATION IN

NONINFLAMMATORY CENTRAL NERVOUS SYSTEM DISORDERS
A variety of noninflammatory CNS diseases are accompanied by findings that
mimic a primary inflammatory cause; a list of common examples with clues to
840 JUNE 2019

discriminate them from MS are outlined in TABLE 12-5, with an example of KEY POINTS
spondylotic myelopathy with enhancement mimicking MS shown in
● In autoimmune GFAP
FIGURE 12-14.
74
astrocyopathy, brain MRI
may reveal a characteristic
radial perivascular
CONCLUSION enhancement perpendicular
The field of inflammatory demyelinating diseases of the CNS is evolving rapidly. to the ventricles, although
a similar pattern can be
Assays for the novel antibody biomarkers AQP4-IgG and MOG-IgG are seen with intravascular
commercially available and useful in diagnosis and distinction from MS. lymphoma, neurosarcoidosis,
Furthermore, these biomarkers have given insight into the pathogenesis of these and central nervous
diseases, allowing specific targeted treatments to be developed and translated to system vasculitis.
clinical practice, as evidenced by the three clinical trials currently under way in ● Susac syndrome is an
AQP4-IgG–seropositive NMOSD. Improved recognition of the clinical, inflammatory endotheliopathy
radiologic, and laboratory features of other CNS inflammatory mimics of MS has that is characterized by a triad
allowed clinicians to better distinguish these disorders from MS despite the of branched retinal artery
occlusions, hearing loss, and
absence of a serum biomarker in many. All these developments are leading to
dementia/encephalopathy.
improvements in diagnosis and treatment. Indeed, the future for patients
afflicted by these disorders has never been brighter.
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TABLE 12-1 Comparison of Inflammatory Demyelinating Diseases of the Central

Attribute Multiple Sclerosis AQP4-IgG MOG-IgG

Sex (female: 2:1 9:1 1.5:1

Epidemiology Prevalence: common Prevalence: rare Prevalence: unknown

Ethnicity: whites more Ethnicity: African-Americans, Ethnicity: unknown

Geographic: regions farthest Geographic: higher proportion of Geographic: unknown

Course Relapsing-remitting from onset in Typically relapsing; usually no Monophasic or relapsing; no

Recovery from Good Often incomplete Good

CONTINUED ON PAGE 817

816 JUNE 2019

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NEUROMYELITIS OPTICA SPECTRUM DISORDERS

CONTINUED FROM PAGE 816

Attribute Multiple Sclerosis AQP4-IgG MOG-IgG

Blood NA AQP4-IgG MOG-IgG

Spine MRI Multiple lesions; Single lesion (longitudinally Multiple lesions;

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History and Terminology

TABLE 12-2 Clinical Features of Neuromyelitis Optica Spectrum Disordera

Cardinal Clinical Features

ADEM = acute disseminated encephalomyelitis; CK = creatine kinase; PRES = posterior reversible

818 JUNE 2019

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rather than a neurologic manifestation of a rheumatologic disorder.19 Patients

COMMENT Longitudinally extensive transverse myelitis is a hallmark feature of NMOSD

820 JUNE 2019

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SPINAL CORD LESION LENGTH. Longitudinally extensive transverse myelitis

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vertebral segments on MRI, is characteristic of NMOSD (FIGURE 12-1) and

CASE 12-2 A 63-year-old right-handed woman developed an episode of intractable

822 JUNE 2019

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Cerebrospinal Fluid Findings

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824 JUNE 2019

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IgG = immunoglobulin G; MRI = magnetic resonance imaging.

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Aquaporin-4 IgG–Seronegative Neuromyelitis Optica Spectrum Disorder

Pathogenesis and Pathology

ATTACK TREATMENT. High-dose corticosteroids (1000 mg IV methylprednisolone

MAINTENANCE THERAPY. The importance of maintenance attack-prevention

826 JUNE 2019

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TABLE 12-4 Common Maintenance Immunotherapy Regimens for Neuromyelitis Optica

Medication/Dose/Regimen (Adults) Precautions/Monitoring/Prophylaxis Common/Important Side Effects

CONTINUED ON PAGE 829

828 JUNE 2019

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Clinical Course and Prognosis

CONTINUED FROM PAGE 828

Medication/Dose/Regimen (Adults) Precautions/Monitoring/Prophylaxis Common/Important Side Effects

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COMMENT ADEM is a hallmark episode of MOG-IgG–related disease. The preceding

830 JUNE 2019

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BRAIN. Multifocal white matter T2 hyperintensities (FIGURE 12-4A) with

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