VIEWS & REVIEWS

MRI characteristics of neuromyelitis optica

spectrum disorder
An international update

Ho Jin Kim, MD, PhD ABSTRACT

Friedemann Paul, MD Since its initial reports in the 19th century, neuromyelitis optica (NMO) had been thought to
Marco A. Lana-Peixoto, involve only the optic nerves and spinal cord. However, the discovery of highly specific anti–
MD, PhD aquaporin-4 antibody diagnostic biomarker for NMO enabled recognition of more diverse clinical
Silvia Tenembaum, MD spectrum of manifestations. Brain MRI abnormalities in patients seropositive for anti–aquaporin-4
Nasrin Asgari, MD, PhD antibody are common and some may be relatively unique by virtue of localization and configura-
Jacqueline Palace, DM, tion. Some seropositive patients present with brain involvement during their first attack and/or
FRCP continue to relapse in the same location without optic nerve and spinal cord involvement. Thus,
Eric C. Klawiter, MD characteristics of brain abnormalities in such patients have become of increased interest. In this
Douglas K. Sato, MD regard, MRI has an increasingly important role in the differential diagnosis of NMO and its spec-
Jérôme de Seze, MD, trum disorder (NMOSD), particularly from multiple sclerosis. Differentiating these conditions is of
PhD prime importance because early initiation of effective immunosuppressive therapy is the key to
Jens Wuerfel, MD preventing attack-related disability in NMOSD, whereas some disease-modifying drugs for multi-
Brenda L. Banwell, MD ple sclerosis may exacerbate the disease. Therefore, identifying the MRI features suggestive of
Pablo Villoslada, MD NMOSD has diagnostic and prognostic implications. We herein review the brain, optic nerve, and
Albert Saiz, MD spinal cord MRI findings of NMOSD. Neurology® 2015;84:1165–1173
Kazuo Fujihara, MD,
PhD GLOSSARY
Su-Hyun Kim, MD AQP4 5 aquaporin-4; IgG 5 immunoglobulin G; LETM 5 longitudinally extensive transverse myelitis; MOG 5 myelin-oligodendrocyte
With The Guthy-Jackson glycoprotein; MS 5 multiple sclerosis; NMO 5 neuromyelitis optica; NMOSD 5 neuromyelitis optica spectrum disorder; ON 5
optic neuritis.
Charitable Foundation
NMO International
Neuromyelitis optica (NMO) is an inflammatory disease of the CNS that is characterized by
Clinical Consortium &
Biorepository severe attacks of optic neuritis (ON) and longitudinally extensive transverse myelitis (LETM).1
The past decade has witnessed dramatic advances in our understanding of NMO. Such advances
were initiated by the discovery of the disease-specific autoantibody, NMO–immunoglobulin G
Correspondence to (NMO-IgG), and subsequent identification of the main target autoantigen, aquaporin-4
Dr. Ho Jin Kim:
[email protected] (AQP4), which has distinguished NMO as a distinct disease from multiple sclerosis (MS).2
Current diagnostic criteria, however, still require both ON and myelitis for an NMO diagno-
sis.3 Nevertheless, the identification of anti-AQP4 antibodies beyond the current diagnostic cri-
teria of NMO indicates a broader clinical phenotype of this disorder, so-called “NMO spectrum
disorder” (NMOSD).4,5 The NMOSD encompasses anti-AQP4 antibody seropositive patients
with limited or inaugural forms of NMO and with specific brain abnormalities. It also includes
anti-AQP4 antibody seropositive patients with other autoimmune disorders such as systemic
Supplemental data
at Neurology.org
From the Department of Neurology (H.J.K., S.-H.K.), Research Institute and Hospital of National Cancer Center, Goyang, Korea; NeuroCure
Clinical Research Center and Clinical and Experimental Multiple Sclerosis Research Center (F.P., J.W.), Department of Neurology, Charité
University Medicine, Berlin, Germany; CIEM MS Research Center (M.A.L.-P.), Federal University of Minas Gerais Medical School, Belo
Horizonte, Brazil; Department of Neurology (S.T.), National Paediatric Hospital Dr. Juan P. Garrahan, Buenos Aires, Argentina; Neurobiology
(N.A.), Institute of Molecular Medicine, University of Southern Denmark; Department of Neurology (N.A.), Vejle Hospital, Denmark;
Department of Clinical Neurology (J.P.), John Radcliffe Hospital, Oxford, UK; Department of Neurology, Massachusetts General Hospital
(E.C.K.), Harvard Medical School, Boston, MA; Department of Neurology (D.K.S.), Tohoku University School of Medicine, Sendai, Japan;
Neurology Department (J.d.S.), Hôpitaux Universitaires de Strasbourg, France; Institute of Neuroradiology (J.W.), University Medicine
Goettingen, Germany; Department of Pediatrics (B.L.B.), Division of Neurology, The Children’s Hospital of Philadelphia; Department of
Neurology (B.L.B.), The University of Pennsylvania; Center of Neuroimmunology (P.V., A.S.), Service of Neurology, Hospital Clinic and
Institute of Biomedical Research August Pi Sunyer, Barcelona, Spain; and Department of Multiple Sclerosis Therapeutics (K.F.), Tohoku
University Graduate School of Medicine, Sendai, Japan.
The Guthy-Jackson Charitable Foundation NMO International Clinical Consortium & Biorepository coinvestigators are listed on the Neurology®
Web site at Neurology.org.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

© 2015 American Academy of Neurology 1165

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 lupus erythematosus and Sjögren syndrome.4 Classification of brain MRI findings seen in NMOSD.
In this regard, MRI has an increasingly impor- Periependymal lesions surrounding the ventricular system.
Diencephalic lesions surrounding the third ventricles and cerebral
tant role in differentiating NMOSD from other
aqueduct. Diencephalic lesions surrounding the third
inflammatory disorders of the CNS, particu-
ventricles and cerebral aqueduct, which include the
larly from MS.6,7 Differentiating these condi-
thalamus, hypothalamus, and anterior border of the
tions is critical because treatments are distinct. midbrain have been reported in NMOSD
Furthermore, recent advanced MRI techniques (figure 1A).10,12 These lesions frequently are asymp-
are detecting additional specific markers and tomatic, but some patients may present with a syn-
help elucidate the underlying mechanisms of drome of inappropriate antidiuretic hormone
tissue damage in NMOSD. secretion,e6 narcolepsy,e7 hypothermia, hypotension,
We herein summarize the MRI findings of hypersomnia, obesity,e8 hypothyroidism, hyperpro-
NMOSD and discuss their diagnostic and lactinemia, secondary amenorrhea, galactorrhea, and
prognostic implications. behavioral changes.e9
Dorsal brainstem lesions adjacent to the fourth ventricle. One
of the most specific brain MRI abnormalities in pa-
BRAIN MRI FINDINGS IN NMOSD Since the early tients with NMOSD is a lesion in the dorsal brain-
8,9
studies using brain MRI in NMO, unexplained clin- stem adjacent to the fourth ventricle including the
ically silent and nonspecific white matter abnormalities area postrema and the nucleus tracts solitarius. Such
were found in some patients. With the advent of lesions are highly associated with intractable hiccups,
AQP4-IgG assays, it became clear that a high nausea, and vomiting,10,12,21 and have been reported
proportion of patients with NMOSD harbored brain in 7% to 46% of patients with NMOSD.12,15,e1,e10
MRI abnormalities, frequently located in areas This area, the emetic reflex center, has a less restrictive
associated with high AQP4 expression.10,11 However, blood-brain barrier, making it more accessible to
brain abnormalities also occurred in areas where AQP4-IgG attack. The MRI as well as clinical evi-
AQP4 expression is not particularly high.12 Although dence support the notion that area postrema is an
nonspecific small dots and patches of hyperintensity in important point of attack in patients with NMOSD
subcortical and deep white matter on T2-weighted or and further suggests that this area is a portal for entry
fluid-attenuated inversion recovery sequences are the of circulating IgG into the CNS.22,23 Pathologic
most common findings in NMOSD, certain lesions abnormalities were noted in this region in 40% of
have a location or appearance characteristic for patients with NMO, but there was no obvious neu-
NMOSD.6,7,11–15 ronal, axonal, or myelin loss.21 Medullary lesions are
Before the discovery of anti-AQP4 antibody, brain often contiguous with cervical cord lesion, usually
MRI abnormalities were reported in only 13% to 46% taking a linear shape (figure 1B.b). These lesions
of patients with NMO.1,8,16 However, when excluding may be associated with the first symptoms of the dis-
the brain MRI criteria, the incidence of brain MRI ease22,24 or herald acute exacerbation.25 Various symp-
abnormalities increased to 50% to 85% using the toms corresponding to a brainstem lesion may
revised 2006 NMO diagnostic criteria3,11,13,17,e1–e3 and develop, such as nystagmus, dysarthria, dysphagia,
to 51% to 89% in seropositive patients with ataxia, or ophthalmoplegia.15,20,e11,e12
NMOSD.5,12,18,19,e4,e5 Furthermore, brain MRI abnor- Periependymal lesions surrounding the lateral ventricles. Le-
malities at onset have been reported in 43% to 70% of sions in the corpus callosum have been described in
patients with NMOSD.5,7,11 One of the explanations 12% to 40% of patients with NMOSD.12,15,26
for discrepancies in frequency between studies may be Because both NMO and MS frequently have callosal
that brain MRI abnormalities become more frequent lesions, location by itself is not a unique finding that
with duration of disease. In a published series of differentiates NMOSD from MS. However, while
88 seropositive children, brain abnormalities were the callosal lesions in MS are discrete, ovoid, and
observed in 68% of the children with available MRI perpendicular to the ventricles and involve inferior
studies, and were predominantly located within peri- aspects of the corpus callosum (figure 2A),e13,e14
ventricular regions of the third (diencephalic) and NMOSD lesions are located immediately next to
fourth ventricles (brainstem), supratentorial and infra- the lateral ventricles, following the ependymal lining
tentorial white matter, midbrain, and cerebellum.20 (figure 1C.a).12 The acute callosal lesions in NMOSD
This is consistent with the observation that 45% to are often edematous and heterogeneous, creating a
55% of children with NMOSD show episodic cerebral “marbled pattern”26 and sometimes involving the
symptoms, including ophthalmoparesis, intractable complete thickness of splenium in a unique “arch
vomiting and hiccups, altered consciousness, severe bridge pattern” (figure 1, C.b and C.c).12 Sometimes,
behavioral changes, narcolepsy, ataxia, and seizures.20 the callosal lesions extend into the cerebral

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 hemisphere, forming an extensive and confluent
Figure 1 MRI lesions characteristic of neuromyelitis optica spectrum disorder
white matter lesion.12 In the chronic phase of
NMOSD, the callosal lesions tend to reduce in size
and intensity and may even disappear26; however,
cystic changes and atrophy of the corpus callosum
have been described.e15 Certain clinical symptoms,
such as dysfunctions of cognition and motor coordi-
nation, may be attributed to callosal lesions, but they
have not been well evaluated yet.
Hemispheric white matter lesions. Extensive and con-
fluent hemispheric white matter lesions are often tu-
mefactive (.3 cm in longest diameter) or have long
spindle-like or radial-shape following white matter
tracts (figure 1D).12 Mass effect is usually absent.e16
Increased lesion diffusivity on apparent diffusion
coefficient maps suggests vasogenic edema in associ-
ation with acute inflammation (figure 1D.c),12,27
occasionally mimicking posterior reversible encepha-
lopathy syndrome28 or Baló lesions.e17,e18 These
extensive lesions have been found more frequently
in anti-AQP4 antibody seropositive than seronegative
patients.29 In the chronic phase, these large lesions
tend to shrink and even disappear, but in some cases,
cystic-like or cavitary changes are revealed (figure 1D.
d).e19,e20 These lesions may cause various symptoms
such as hemiparesis, encephalopathy, and visual field
defects depending on the area they involve. Large
confluent hemispheric white matter lesions are not
uncommon in children with NMOSD. Tumefactive
lesions with a surrounding zone of edema and variable
mass effect may resemble acute disseminated enceph-
alomyelitis20,30 or CNS malignancies.31
Lesions involving corticospinal tracts. Lesions involving
the corticospinal tracts can be unilateral or bilateral,
and may extend from the deep white matter in the
cerebral hemisphere through the posterior limb of
the internal capsule to reach the cerebral peduncles
of the midbrain or the pons (figure 1E).12 These lesions
are contiguous and often longitudinally extensive, fol-
lowing the pyramidal tracts (figure 1E.c). Corticospinal
tract lesions have been found in 23% to 44% in some
cohorts of patients with NMOSD12,e2 and have occa-
sionally been reported in other cohorts.11,13 It is of
Diencephalic lesions surrounding (A.a) the third ventricles and cerebral aqueduct, (A.b) which interest that, unlike circumventricular areas, cortico-
include thalamus, hypothalamus, and (A.c) anterior border of the midbrain. (B.a) Dorsal brain- spinal tracts are not the areas where the AQP4 is highly
stem lesion adjacent to the fourth ventricle, (B.b) linear medullary lesion that is contiguous
with cervical cord lesion, (B.c) edematous and extensive dorsal brainstem lesion involving
expressed; it is unknown why these regions are also
the cerebellar peduncle. (C.a) Callosal lesion immediately next to the lateral ventricle, follow- frequently involved in NMOSD.
ing the ependymal lining, (C.b) “marbled pattern” callosal lesion, (C.c) “arch bridge pattern” Nonspecific lesions: Not unique, but most common. Non-
callosal lesion. (D.a) Tumefactive hemispheric white matter lesions, (D.b) a long spindle-like or
specific punctate or small (,3 mm) dots or patches of
radial-shape lesion following white matter tracts, (D.c) extensive and confluent hemispheric
lesions show increased diffusivity on apparent diffusion coefficient maps suggesting vaso- hyperintensities on T2-weighted or fluid-attenuated
genic edema, (D.d) hemispheric lesions in the chronic phase showing cystic-like cavitary inversion recovery sequences in the subcortical or
changes. (E.a) Corticospinal tract lesions involving the posterior limb of the internal capsule deep white matter have been described most fre-
and (E.b) cerebral peduncle of the midbrain, (E.c) longitudinally extensive lesion following the
quently on brain imaging studies of NMOSD
pyramidal tract. (F.a) Cloud-like enhancement, (F.b) linear enhancement of the ependymal
surface of the lateral ventricles, (F.c) meningeal enhancement. (35%–84%)11,12,17 and are usually asymptomatic.
Enhancing lesions. Although the exact frequency is
unclear, previous studies have described a variable

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 long-segment inflammation of the optic nerve,
Figure 2 MRI lesions characteristic of MS
particularly when simultaneous bilateral and
extending posteriorly into the optic chiasm, should
lead us to suspect the diagnosis of NMOSD in the
appropriate clinical context.

SPINAL CORD MRI FINDINGS IN NMOSD The

inflammatory process of NMOSD in spinal cord
MRI is characterized by hyperintensity on T2-
weighted sequences and by hypointensity on T1-
weighted sequences. These abnormalities in the
spinal cord MRI have been reported to be, in
general, more frequently present in the cervical and
the upper thoracic spinal cord segments than the
lower thoracic and lumbar regions23,34,e23 with a
preferential involvement in the central gray
matter.34,35 In the spinal cord, AQP4 is abundant in
the gray matter and in glial cell processes adjacent to
the ependymal cells of the central canal and to a lesser
degree in the white matter of the spinal cord.e24
The most distinct manifestation of NMO is
LETM, defined as a lesion that spans over 3 or more
contiguous vertebral segments and predominantly in-
volves central gray matter on the spinal cord MRI
(A) Contrasting MS periventricular and callosal lesions, which are discrete, ovoid, and perpen-
(figure 4).4 However, not all LETM is NMOSD
dicular to the ventricles. (B) Contrasting MS enhancing lesions, which are ovoid or open-ring and several studies of patients with LETM have
gadolinium-enhanced lesions with well-defined borders. MS 5 multiple sclerosis. observed significant differences in demographic and
clinical features between anti-AQP4 antibody
percentage of gadolinium-enhancing brain lesions positive compared with negative patients with
(9%–36%) in patients with NMOSD.12,15,e2,e3 Most LETM.19,36–38 LETM seems to be less specific for
of the enhancement was displayed in a poorly mar- NMO in children than in adults. LETM is frequently
ginated, subtle, and multiple patchy pattern, a so- observed in children with acute disseminated enceph-
called “cloud-like” enhancement (figure 1F.a).18 alomyelitis,39,40 but also in 17% of those with MS,e25
These cloud-like enhanced lesions differ from the and in 67% to 88% of children with monophasic
ovoid or ring/open-ring gadolinium-enhancing le- transverse myelitis.e26,e27 Therefore, it is important
sions with well-defined borders that are more typical to bear in mind that numerous other differential diag-
of MS (figure 2). A linear enhancement of the epen- noses than NMOSD need to be considered when a
dymal surface of the lateral ventricles (pencil-thin patient presents with LETM.
lesion) has also been described in NMOSD (figure Spinal cord lesions during follow-up of NMOSD. MRI
1F.b).e21 Rarely, well-marginated nodular enhance- changes of LETM have been observed over the course
ment or meningeal enhancement has been reported of NMOSD and MRI data indicate that LETM lesions
in NMOSD (figure 1F.c).12,e16 may evolve into multiple shorter lesions during remis-
sion or after treatment with high-dose steroids.23,41 In
OPTIC NERVE MRI FINDINGS IN NMOSD MRI addition, spinal cord atrophy as a consequence of
studies have reported nonspecific optic nerve sheath recurrent myelitis has been reported and may
thickening, optic nerve hyperintensities on T2- correlate with neurologic disability.23 Consequently,
weighted sequences, and gadolinium enhancement the timing of MRI may be important for the
on T1-weighted sequences in acute ON of demonstration of LETM.42
NMOSD.14,17 However, as similar findings also have
been described in ON of MS,e22 these findings are not COMPARING THE IMAGING OF NMOSD WITH
considered diagnostic of NMOSD. Recent studies MS In clinical practice, the main differential diagno-
have looked at the differential MRI features of the sis of NMO is MS, particularly disease limited to the
optic nerve lesion between MS and NMOSD.32,33 A optic nerves and spinal cord. Differentiating these
trend to more posterior involvement of the optic nerve conditions is of prime importance because of differen-
including chiasm, and simultaneous bilateral disease, ces in prognosis and therapy, as some MS therapies
has been observed in NMOSD (figure 3).32,33 Thus, can exacerbate NMO.43–45 Thus, it is important to

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 differ in sensitivity and are confounded by differences
Figure 3 Optic nerve MRI lesions characteristic of neuromyelitis optica
spectrum disorder
in the duration of follow-up.
As previously described, the most important imag-
ing hallmark of NMO is the LETM, but a few pa-
tients may have centrally located short myelitis.46
Other MRI features of the spinal cord lesion that
appear to differ between NMOSD and MS are sum-
marized in the table.
The 2006 NMO diagnostic criteria include a
brain MRI that is nondiagnostic for MS (using the
Paty criteria) at onset as support for NMO. However,
it is now known that MS-like lesions may appear in
10% to 12.5% of cases,11,e3 and 5% to 42% of pa-
tients with NMO fulfill the Barkhof criteria.6,14,15,47 A
recent report showed that 13% and 9% of patients
with NMOSD, respectively, met Barkhof and the
(A) Dense gadolinium-enhancing lesion at the posterior part of the right optic nerve. (B) Exten-
sive gadolinium-enhancing lesion at the bilateral posterior part of the optic nerve/chiasm. European Magnetic Imaging in MS diagnostic criteria
for MS on brain MRI at onset.7 Lesion probability
maps have not found statistically significant lesion
improve the methods and analysis by which to dis-
locations in patients positive for anti-AQP4 antibody
tinguish these conditions to facilitate early and accu-
over those with MS.6 However, distinguishing
rate diagnosis. Contrasting features between the 2
features were identified on MS brain MRI that were
conditions may further improve our understanding
sensitive and specific, such as the presence of a lateral
of the different pathogenic processes.
ventricle and inferior temporal lobe lesion, Dawson
Whereas it is possible to select patients with
fingers, or an S-shaped U-fiber lesion, to classify the
NMOSD using the specific marker (serum anti-
patient as MS. Imaging sensitive to cortical lesions
AQP4 antibodies), there is no corresponding specific
has revealed their absence in NMO (excluding one
biomarker for MS. Studies contrasting NMO and
Japanese study of NMO pathology48), whereas they
MS have often used different selection criteria, partic-
are seen in the majority of patients with MS.49,50
ularly whether they have restricted the NMO inclu-
Characteristic MS brain lesions surround central ven-
sion criteria to patients positive for anti-AQP4
ule in .80% on high-strength MRI.50,51 In NMO
antibody or not, and this may influence the results.
lesions, this is less frequent, reported in 9% to 35% of
Conflicting data may also be partly explained by the
cases50,52 and likely indicates the different pathogenic
use of various assays for anti-AQP4 antibodies, which
mechanisms of the disease.
The frequency of silent lesion formation appears
Figure 4 Spinal cord MRI lesions characteristic of neuromyelitis optica
to differ between the 2 diseases. Patients with
spectrum disorder NMOSD are less likely to develop clinically silent
MRI lesions than patients with MS. However, new
silent MRI lesions do occur in a small proportion of
patients with NMOSD. In addition, most studies
show that nonlesional tissue damage as measured on
nonconventional imaging such as diffusion tensor
imaging is well recognized in MS and may not occur
in NMO except in the connecting tracts up and
downstream of lesions.53,54 Collectively, these find-
ings support the clinical observation that NMO, in
contrast to MS, may be a lesion-dependent disease
that produces relapses without more generalized neu-
rodegenerative pathology, and hence the lack of a
progressive phase.
The differences noted between NMO and MS
may relate to the CNS-specific antibody-mediated
pathology against astrocytes rather than a T-cell–
predominant inflammatory condition targeting
(A) Longitudinally extensive cord lesion involving thoracic cord. (B) Exclusive involvement of myelin. In support of this possibility, a marker of
gray matter (H-shaped cord lesion). astrocytic function, myo-inositol was reduced in

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 Table Comparison of characteristic MRI findings between NMOSD and MS

NMOSD MS

Spinal Longitudinally extensive lesion ($3 vertebral segments) Short, often multiple lesions
cord

Central/gray matter involvement Peripheral/asymmetrical/often posterior

T1 hypointensity common on acute lesions T1 hypointensity rare

Optic Long-length/posterior-chiasmal lesions Short-length lesions

nerve

Brain Periependymal lesions surrounding the ventricular system (wide-based Dawson fingers (perpendicular to ventricles)/S-shaped U-fiber lesions,
along the ependymal lining) inferior lateral ventricle and temporal lobe lesions

Hemispheric tumefactive lesions Cortical lesions

Lesions involving corticospinal tracts Perivenous lesions

“Cloud-like” enhancing lesions Ovoid or ring/open-ring enhancing lesions

Others Normal-appearing tissue involvement may be limited to lesional tracts Normal-appearing white matter manifests tissue damage using special
and associated cortex MRI techniques

Lesional myo-inositol reduced on MRS Lesional N-acetyl-aspartate reduced on MRS

Abbreviations: MRS 5 magnetic resonance spectroscopy; MS 5 multiple sclerosis; NMOSD 5 neuromyelitis optica spectrum disorder.

cervical cord lesions of patients positive for anti- imaging findings may be proportional to the amount
AQP4 antibody, but not in patients with MS. In of astrocyte damage and have potential prognostic im-
contrast, N-acetyl-aspartate, a marker of myelin- plications.e29 The presence of extensive brain lesions
and neurofilament-specific injury, was significantly might predict a higher rate of relapse and increased
reduced in patients with MS compared with controls disability at follow-up.e30 Longitudinal follow-up
and nonsignificantly reduced in the patients positive studies are required to confirm whether patients with
for anti-AQP4 antibody.55 brain lesions have a worse prognosis than those with-
Important comparisons between NMOSD and out brain lesions. At this point, there are no individ-
MS scans are summarized in the table. Because ual MRI parameters that can predict the prognosis of
long-term systematic imaging studies in NMO have NMO.
not yet been performed, the reported cross-sectional More recently, antibodies against myelin-
differences compared with MS require further confir- oligodendrocyte glycoprotein (MOG) have been
mation. Developing algorithms using the brain crite- found in some patients with clinical features of
ria described by Matthews et al.6 in combination with NMOSD, but who lack anti-AQP4 antibodies.58 Pa-
spinal cord and optic nerve imaging features and pos- tients exhibiting the anti-MOG–positive and anti-
sibly nonconventional imaging may further improve AQP4–negative serotype have been suggested to have
the sensitivity and specificity. fewer attacks, bilateral ON, more caudal myelitis, and
recover better than patients with anti-AQP4 antibod-
PROGNOSTIC IMPLICATION OF MRI ies and those who are seronegative for both antibod-
ABNORMALITIES Anti-AQP4 antibody positivity is
ies.59,60 Therefore, patients presenting with an
established as a prognostic marker, and its positivity NMOSD phenotype with anti-MOG antibodies
indicates a high risk of further relapses of ON and may have a distinct underlying disease mechanism
myelitis.56,57 Because of the presence of many imaging presumably with a better prognosis than those with
features suggesting severe damage of spinal cord, such anti-AQP4 antibodies, although this needs to be con-
as T1 hypointensity with edema or cavitation and firmed by further studies.
atrophy, patients with NMOSD are more likely to
have a poor recovery, refractory pain,e28 and a high OUTLOOK: MRI FINDINGS IN THE CONTEXT OF
risk of permanent disability. In addition, patients NMO DIAGNOSTIC CRITERIA The notion that
with NMOSD who have lesions in the upper cervical brain MRI abnormalities are frequent in patients with
region extending to the brainstem may be at risk of NMOSD refutes the older doctrine that a normal
respiratory failure. brain MRI is a prerequisite for a diagnosis of
High levels of glial fibrillary acidic protein in the NMO. Herein, we have reviewed the advances in
CSF of patients with NMOSD during acute attacks our knowledge on the spectrum of imaging findings
correlated with length of MRI spinal cord lesion in NMOSD. However, sensitivity and specificity of
and Expanded Disability Status Scale score 6 months these imaging features for NMOSD have not been
after those attacks. This correlation suggests that systematically investigated in a prospective manner,

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 and none of the findings can be considered pathogno- approved the final manuscript. Dr. P. Villoslada critically reviewed and
revised the manuscript, and approved the final manuscript. Dr. A. Saiz crit-
monic or evidentiary for NMOSD. Therefore, as
ically reviewed and revised the manuscript, and approved the final manu-
with other inflammatory CNS conditions, imaging script. Dr. K. Fujihara critically reviewed and revised the manuscript, and
findings should prompt broad differential diagnostic approved the final manuscript. Dr. S.-H. Kim analyzed the literature, wrote
consideration—a topic that is beyond the scope of the manuscript, critically reviewed and revised the manuscript, and approved
the final manuscript.
this review. The actual utility of lesion probability
maps to distinguish NMO and MS is limited by an
ACKNOWLEDGMENT
unclear definition of some traditional criteria for MS- The authors thank The Guthy-Jackson Charitable Foundation for its
suggestive findings, such as “Dawson fingers.”e31 The support in organizing the NMO International Clinical Consortium &
picture is further complicated by recent observations of Biorepository. The authors thank Drs. Brian Weinshenker and Jack Simon
for their comments and Dr. Valerie Pasquetto for her assistance.
patients with anti-MOG antibodies that some, but not
all, have considered part of the NMO spectrum.58,59
STUDY FUNDING
Some commonalities but also differences in clinical No targeted funding reported.
presentation, epidemiology, and imaging have been
reported between these 2 conditions, suggesting that DISCLOSURE
NMOSD may not be a homogeneous nosologic H. Kim has given talks, consulted, and received honoraria and/or research sup-
entity. In addition, because NMOSD can coexist port from Bayer Schering Pharma, Biogen Idec, Genzyme, Kael-GemVax,
Merck Serono, Novartis, Teva-Handok, and UCB. He serves on a steer-
with other autoimmune diseases and antibodies to ing committee for MedImmune. F. Paul has received funding from
other CNS antigens such as anti-NMDA receptor German Research Council, German Ministry of Education and Research
antibodies may be present in patients seropositive (Competence Network Multiple Sclerosis “KKNMS”), and The Guthy-
Jackson Charitable Foundation. He has received travel compensation,
for anti-AQP4 antibody, it is possible that
speaker honoraria, and research support from Biogen, Bayer, Teva,
autoimmunity against multiple CNS autoantigens Merck, Novartis, and Sanofi, and has served as steering committee mem-
may participate in the formation of inflammatory ber of the OCTIMS Study sponsored by Novartis. M. Lana-Peixoto
lesions of NMOSD.e32,e33 The emerging heterogeneity reports no disclosures relevant to the manuscript. S. Tenembaum has
provided consulting services to Genzyme Corporation and Biogen Idec
of NMOSD is mirrored by the broad range of
and received lecture fees from Merck Serono. N. Asgari reports no dis-
neuroimaging findings summarized in this article. closures relevant to the manuscript. J. Palace is partly funded by highly
Areas for improved imaging that may facilitate more specialized services to run a national congenital myasthenia service and a
specific diagnostic, prognostic, therapeutic efficacy or neuromyelitis service. She has received support for scientific meetings and
honorariums for advisory work from Merck Serono, Biogen Idec, No-
other patient care benefit include higher-resolution vartis, Teva, Chugai Pharma, and Bayer Schering, and unrestricted grants
imaging methods, 3-dimensional imaging of site- from Merck Serono, Novartis, Biogen Idec, and Bayer Schering. Her
specific lesions, and potential computationally guided hospital trust receives funds for her role as clinical lead for the RSS,
and she has received grants from the MS Society and Guthy-Jackson
analysis of images for quantitative comparisons.
Foundation for unrelated research studies. E. Klawiter has received
International collaborative efforts are now under way research funding from Roche. He has received consulting fees and/or
that will permit accrual of sufficiently large, carefully speaking honoraria from Biogen Idec, Bayer Healthcare, Genzyme Cor-
characterized NMO/NMOSD patients to better poration, and Teva Neuroscience. D. Sato receives scholarship funds
from the Ministry of Education, Culture, Sports, Science and Technol-
understand the frequency of brain involvement and to
ogy (MEXT) of Japan and has received research support from Ichiro
more thoroughly appreciate the implications of MRI Kanehara Foundation. J. de Seze has received honoraria from Bayer
abnormalities in clinical diagnosis and prognosis. Schering, Biogen Idec, LFB, Merck Serono, Novartis, Sanofi-Aventis,
and Teva. He serves as a consultant for Alexion and Chugai. J. Wuerfel
serves on advisory boards for Novartis and Biogen Idec. He received a
AUTHOR CONTRIBUTIONS research grant from Novartis, and speaker honoraria from Bayer, Novar-
Dr. H.J. Kim conceived and designed the work, analyzed the literature, tis, and Biogen Idec. He is supported by the German Ministry of Science
wrote the manuscript, critically reviewed and revised the manuscript, (BMBF/KKNMS). B. Banwell serves as a senior editor for Multiple Scle-
and approved the final manuscript. Dr. F. Paul conceived the work, analyzed rosis and Related Disorders and on the editorial board of Neurology®. She
the literature, wrote the manuscript, critically reviewed and revised the man- serves as a consultant for Biogen Idec, Novartis, Teva Neuroscience, and
uscript, and approved the final manuscript. Dr. M.A. Lana-Peixoto analyzed Merck Serono. She has been funded by the Canadian MS Research
the literature, wrote the manuscript, critically reviewed and revised the Foundation, the Canadian MS Society, and CIHR. P. Villoslada serves
manuscript, and approved the final manuscript. Dr. N. Asgari analyzed as a board member for Roche, Novartis, Neurotec Pharma, Bionure
the literature, wrote the manuscript, critically reviewed and revised the Farma, and as a consultant for Novartis, Roche, TFS, Heidelberg Engi-
manuscript, and approved the final manuscript. Dr. S. Tenembaum analyzed neering, MedImmune, Digna Biotech, and Neurotec Pharma. He has
the literature, wrote the manuscript, critically reviewed and revised the received research support from European Commission, Instituto Salud
manuscript, and approved the final manuscript. Dr. J. Palace analyzed the Carlos III, Marato TV3, Novartis, and Roche and travel expenses from
literature, wrote the manuscript, critically reviewed and revised the manu- Novartis. He holds patents with Digna Biotech, Bionure Farma, and
script, and approved the final manuscript. Dr. E.C. Klawiter analyzed the stock/stock options of Bionure Farma. A. Saiz has received compensation
literature, wrote the manuscript, critically reviewed and revised the manu- for consulting services and speaking from Bayer Schering, Merck Serono,
script, and approved the final manuscript. Dr. D.K. Sato analyzed the liter- Biogen Idec, Sanofi-Aventis, Teva Pharmaceutical Industries, and Novar-
ature, wrote the manuscript, critically reviewed and revised the manuscript, tis. K. Fujihara serves on scientific advisory boards for Bayer Schering
and approved the final manuscript. Dr. J. de Seze critically reviewed and Pharma, Biogen Idec, Mitsubishi Tanabe Pharma Corporation, Novartis
revised the manuscript, and approved the final manuscript. Dr. J. Wuerfel Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharma-
critically reviewed and revised the manuscript, and approved the final man- ceutical, Merck Serono, Alexion Pharmaceuticals, MedImmune, and
uscript. Dr. B.L. Banwell critically reviewed and revised the manuscript, and Medical Review; has received funding for travel and speaker honoraria

Neurology 84 March 17, 2015 1171

ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 from Bayer Schering Pharma, Biogen Idec, Eisai Inc., Mitsubishi Tanabe 15. Chan KH, Tse CT, Chung CP, et al. Brain involvement
Pharma Corporation, Novartis Pharma, Astellas Pharma Inc., Takeda in neuromyelitis optica spectrum disorders. Arch Neurol
Pharmaceutical Company Limited, Asahi Kasei Medical Co., Daiichi 2011;68:1432–1439.
Sankyo, and Nihon Pharmaceutical; serves as an editorial board member
16. Ghezzi A, Bergamaschi R, Martinelli V, et al. Clinical
of Clinical and Experimental Neuroimmunology (2009–present) and an
characteristics, course and prognosis of relapsing Devic’s
advisory board member of Sri Lanka Journal of Neurology; has received
research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi neuromyelitis optica. J Neurol 2004;251:47–52.
Kasei Medical, The Chemo-Sero-Therapeutic Research Institute, Teva 17. Cabrera-Gomez JA, Quevedo-Sotolongo L, Gonzalez-
Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma, Chugai Quevedo A, et al. Brain magnetic resonance imaging find-
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Genzyme Japan; and is funded as the secondary investigator 186–192.
(22229008, 2010–2015) by the Grants-in-Aid for Scientific Research 18. Ito S, Mori M, Makino T, Hayakawa S, Kuwabara S.
from the Ministry of Education, Science and Technology of Japan and as “Cloud-like enhancement” is a magnetic resonance imag-
the secondary investigator by the Grants-in-Aid for Scientific Research from
ing abnormality specific to neuromyelitis optica. Ann
the Ministry of Health, Welfare and Labor of Japan (2010–present). S. Kim
Neurol 2009;66:425–428.
reports no disclosures relevant to the manuscript. Go to Neurology.org for
full disclosures. 19. Jarius S, Ruprecht K, Wildemann B, et al. Contrasting
disease patterns in seropositive and seronegative neuromy-
Received June 29, 2014. Accepted in final form November 18, 2014. elitis optica: a multicentre study of 175 patients.
J Neuroinflammation 2012;9:14.
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 MRI characteristics of neuromyelitis optica spectrum disorder: An international
update
Ho Jin Kim, Friedemann Paul, Marco A. Lana-Peixoto, et al.
Neurology 2015;84;1165-1173 Published Online before print February 18, 2015
DOI 10.1212/WNL.0000000000001367

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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since
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rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.