Neuromyelitis Optica Spectrum Disorders.15

Review Article
Neuromyelitis Optica
Address correspondence to
Dr Ilana Katz Sand,
Corinne Goldsmith Dickinson
Center for Multiple Sclerosis at
Mount Sinai, Box 1138,
5 E 98th St, New York, NY, 10029,
ilana.katzsand@mssm.edu.
Spectrum Disorders
Relationship Disclosure: Ilana Katz Sand, MD
Dr Katz Sand has received
research support from the
Guthy Jackson Charitable
Foundation, the National ABSTRACT
Multiple Sclerosis Society,
and the US Department Purpose of Review: This article provides a practical approach for providers caring
of Defense. for patients with neuromyelitis optica (NMO) spectrum disorders. Clinical and imaging
Unlabeled Use of features, diagnostic criteria, treatment of acute exacerbations, chronic preventive
Products/Investigational
Use Disclosure:
therapy, and symptom management in NMO spectrum disorders are discussed.
Dr Katz Sand discusses the Recent Findings: The rapid pace of research in NMO spectrum disorders has led to
unlabeled/investigational use many recent advances. A broader understanding of the clinical spectrum of the
of therapies for the chronic
management of neuromyelitis
disease as well as improvements in antiYaquaporin-4 antibody assays have led to
optica spectrum disorder, recent revision of the diagnostic criteria. Several recent studies have expanded the
none of which are approved knowledge base regarding the efficacy and safety of current therapies for NMO
for this indication by
the US Food and
spectrum disorders.
Drug Administration. Summary: An NMO spectrum disorder is an inflammatory disorder affecting the cen-
* 2016 American Academy tral nervous system, previously thought to be closely related to multiple sclerosis but
of Neurology. more recently demonstrated to represent a distinct clinical and pathophysiologic entity.
As NMO spectrum disorders carry significant morbidity and, at times, mortality, prompt
and accurate diagnosis followed by swift initiation of therapy for both treatment of
acute exacerbations and prevention of further relapses is critical. This article provides a
practical approach to the diagnosis and management of NMO spectrum disorders.
Continuum (Minneap Minn) 2016;22(3):864896.
INTRODUCTION prevention of further relapses is critical.

Neuromyelitis optica (NMO) is an in- The revised diagnostic criteria discussed
flammatory disorder affecting the cen- below suggest simplification of previous
tral nervous system (CNS) previously terminology such that all patients now
thought to be closely related to multiple fall under the umbrella term of NMO
sclerosis (MS) but more recently dem- spectrum disorders. The terms NMO
onstrated to represent a distinct clinical and NMO spectrum disorder will there-
and pathophysiologic entity. The iden- fore be used interchangeably here.
tification of antibodies to aquaporin-4,1 This article provides a practical ap-
a water channel present on astrocytic proach for providers caring for patients
foot processes heavily expressed in the with NMO spectrum disorders. It begins
optic nerves, brainstem, and spinal with clinical features and the diagnostic
cord, as well as the subsequent dem- process for patients presenting with
onstration that these antibodies are symptoms concerning for NMO spec-
pathogenic,2Y4 has greatly facilitated trum disorders, including consider-
this distinction. As NMO carries signif- ations for differential diagnosis. The
icant morbidity and, at times, mortality, management of acute disease exacer-
prompt and accurate diagnosis followed bations is then discussed. Finally, the
by swift initiation of therapy for both selection of an initial long-term preven-
treatment of acute exacerbations and tive therapy as well as strategies for
864 www.ContinuumJournal.com June 2016
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

KEY POINTS
managing breakthrough disease and typical clinical and MRI features of h The core clinical features
symptom management are reviewed. each of these clinical syndromes in of neuromyelitis optica
patients with NMO spectrum disorders spectrum disorders
DIAGNOSIS AND DIFFERENTIAL are reviewed here. include optic neuritis,
DIAGNOSIS OF NEUROMYELITIS Optic neuritis. Optic neuritis in acute myelitis, area
OPTICA SPECTRUM DISORDERS NMO spectrum disorder typically pre- postrema syndrome,
The diagnosis of neuromyelitis optica sents with visual loss accompanied by acute brainstem
spectrum disorders is based on the pain, with particular discomfort with syndrome, symptomatic
typical clinical and MRI features of the eye movements. Optic neuritis that is narcolepsy or acute
core clinical syndromes as well as lab- simultaneously bilateral or severe with diencephalic clinical
oratory evidence of the disease. poor recovery (acuity 20/200 or worse) syndrome, and
symptomatic cerebral
Clinical Features of despite treatment should raise suspi-
syndrome.
Neuromyelitis Optica cion for an NMO spectrum disorder,5,6
as should noncentral scotoma deficits h Optic neuritis that is
Spectrum Disorders simultaneously bilateral
The consideration of a potential diag- such as altitudinal field defects.7 Optic
or severe with poor
nosis of an NMO spectrum disorder nerve lesions are more likely to be recovery (acuity 20/200
begins with a patient who presents extensive in NMO spectrum disorders or worse) despite
with a suggestive clinical syndrome. than in MS.8 MRI may demonstrate treatment should
The core clinical features of NMO posterior optic nerve involvement; in raise suspicion for a
spectrum disorders include optic neu- particular, involvement of the chiasm is neuromyelitis optica
ritis, acute myelitis, area postrema highly suggestive of an NMO spectrum spectrum disorder.
syndrome, acute brainstem syndrome, disorder.9 Enhancement of the chiasm
symptomatic narcolepsy or acute di- in a patient with an NMO spectrum
encephalic clinical syndrome, and disorder with acute optic neuritis is
symptomatic cerebral syndrome. The demonstrated in Figure 10-1.
FIGURE 10-1 Optic neuritis involving the optic chiasm.

Postgadolinium T1-weighted MRI
demonstrating enhancement in the optic
chiasm in a patient with a neuromyelitis optica spectrum
disorder with optic neuritis.
Continuum (Minneap Minn) 2016;22(3):864896 www.ContinuumJournal.com 865

NMO Spectrum Disorders
cord syndrome dominated by sensory

symptoms.10 While pain may occur
with any etiology of myelitis, it is often
particularly prominent in an NMO spec-
trum disorder owing to central cord
involvement as well as the potential for
involvement that extends up into no-
ciceptive pathways in the medulla.11
Pruritus may be present as well.12
Myelitis in NMO spectrum disorder is
also frequently accompanied by parox-
ysmal tonic spasms,13 which may be
severe. As with optic neuritis in an NMO
spectrum disorder, recovery from mye-
litis may be poor despite treatment.
As described, MRI will typically
reveal a longitudinally extensive lesion
(Figure 10-2). At times, the lesion
may be quite extensive, involving the
entire length of the cord. Extension of
cervical lesions up into the medulla
(Figure 10-314) has been demonstrated
to have high predictive value for an
NMO spectrum disorder.15 However, it
is important to note that a minority of
patients may initially present with a
short-segment myelitis.16 NMO spectrum
disorder lesions tend to involve the
central cord (Figure 10-4),17 in con-
trast to MS lesions, which tend to
involve the dorsolateral cord.10 En-
hancement with gadolinium is usually,
FIGURE 10-2 Sagittal T2-weighted MRI demonstrating although not invariably, present, and
longitudinally extensive transverse myelitis ring enhancement may be seen.18 T1
in a patient with neuromyelitis optica
spectrum disorder. hypointensity may also be noted17; this
is an additional factor that differenti-
ates NMO spectrum disorders from MS.
KEY POINT Acute myelitis. The hallmark of Area postrema syndrome. An area
h The hallmark of myelitis myelitis in an NMO spectrum disorder postrema syndrome, characterized by
in a neuromyelitis is that it is typically longitudinally exten- intractable hiccups, nausea, and vom-
optica spectrum sive, spanning at least three vertebral iting, occurs in up to 43% of patients
disorder is that it is segments on MRI. Extensive involve- with NMO spectrum disorders.19Y21
typically longitudinally ment of the cord, which is frequently Hiccups may occur along with nausea
extensive, spanning at
swollen, often results in a complete and vomiting, or the patient may have
least three vertebral
spinal cord syndrome, with paralysis hiccups alone, nausea and vomiting with-
segments on MRI.
below the level of the lesion and loss out hiccups, or isolated nausea without
of sphincter control. This is in contrast vomiting or hiccups. Intractable hiccups,
to typical myelitis in MS, which most nausea, and vomiting may occur in iso-
commonly presents with a partial spinal lation or may herald the onset of another

KEY POINT
spectrum disorder. As such, the ini- h An area postrema
tial workup in an emergency depart- syndrome, characterized
ment or by a primary care physician by intractable hiccups,
is often gastrointestinal (Case 10-1). nausea, and vomiting,
This particular presentation tends to occurs in up to 43%
be quite responsive to treatment with of patients with
corticosteroids, as opposed to the fre- neuromyelitis optica
quently poor recovery seen with optic spectrum disorders.
neuritis and transverse myelitis.
Acute brainstem syndrome. Brain-
stem syndromes occur frequently in
NMO spectrum disorders. A multicen-
ter international study noted brain-
stem symptoms in 81 of 258 patients
(31.4%).23 Of these, vomiting (33.1%)
and hiccups (22.3%) were the most
common; oculomotor abnormalities
(19.8%) and pruritus (12.4%) were also
FIGURE 10-3 Sagittal T2-weighted
MRI demonstrating frequently reported. Less commonly
longitudinally extensive reported were hearing loss, facial palsy,
transverse myelitis extending upward into
the medulla. and trigeminal neuralgia (2.5% each);
Reprinted with permission from Kim HJ, et al,
vertigo or vestibular ataxia (1.7%); and
Neurology.14 www.neurology.org/content/84/11/ other cranial nerve abnormalities (3.3%).
1165.long. B 2015 American Academy of Neurology.
Excessive yawning has also been re-
ported.24 Lesions are typically periep-
focal neurologic deficit. The area po- endymal (Figure 10-5).
strema has been proposed as the initial Symptomatic narcolepsy/acute
site of entry for aquaporin-4YIgG22; it is diencephalic syndrome. An NMO
therefore not uncommon for intracta- spectrum disorder may involve dience-
ble hiccups, nausea, and vomiting to phalic structures with symptoms refer-
be the presenting symptom of an NMO able to the involved area. A syndrome
FIGURE 10-4 Axial T2-weighted MRI demonstrating

central cord involvement in the context of
longitudinally extensive myelitis.

Case 10-1
A 28-year-old woman presented to the emergency department with nausea and vomiting. She denied
abdominal pain, diarrhea, fever, or other systemic symptoms. She was diagnosed with gastroenteritis,
given IV fluids, and discharged. Her symptoms persisted, and she returned to the emergency department
the following week. A head CT was read as normal. She was prescribed omeprazole for presumed
gastritis, given IV fluids, and again discharged. After three additional emergency department visits over
several weeks, she was admitted for a gastrointestinal workup, which suggested gastroparesis of
unknown etiology. She improved with antiemetics and was discharged. A few days later, she returned to
the emergency department with slurred speech, difficulty swallowing, drooling, and double vision. Brain
MRI showed a dorsal medullary/area postrema lesion (Figure 10-5). She was found to have positive
antiYaquaporin-4 antibodies and was diagnosed with a neuromyelitis optica (NMO) spectrum disorder.
FIGURE 10-5 Dorsal medullary/area postrema lesion (arrows) typical for neuromyelitis optica
spectrum disorder. AYC, Axial T2-weighted fluid-attenuated inversion recovery
(FLAIR) MRI. D, Postcontrast sagittal T1-weighted image showing an area of
T1 hypoattenuation within the lesion and a rim of gadolinium enhancement best seen along
the inferior margin of the lesion.
Comment. Persistent nausea and vomiting is a cardinal presenting feature of an NMO spectrum
disorder and often heralds the onset of other focal neurologic deficits. A patient with a single
episode consisting of at least one core clinical feature of an NMO spectrum disorder and positive
antiYaquaporin-4 antibodies meets the updated diagnostic criteria for NMO spectrum disorders.

KEY POINT
of hypersomnia/narcolepsy due to hy- h In symptomatic cerebral
pothalamic involvement is well de- syndrome, large
scribed in the literature; this can often hemispheric lesions may
be seen on imaging (Figure 10-625), cause encephalopathy
has been confirmed by pathologic as well as focal
study, and is associated with low CSF neurologic deficits,
orexin levels.25Y27 Disturbances of depending on the
temperature regulation, including hy- location involved.
pothermia, 28 hyperthemia, 29 and
poikilothermia30 have been reported.
Either anorexia31 or obesity28 may
occur. Syndrome of inappropriate se-
cretion of antidiuretic hormone
(SIADH) is possible32 as are other
endocrinologic abnormalities. Dif- FIGURE 10-7 Axial T2-weighted
fluid-attenuated
fuse anhidrosis has been described.33 inversion recovery (FLAIR)
Diencephalic lesions, particularly if MRI demonstrating thalamic lesion in a
thalamic involvement is present, may patient with neuromyelitis optica spectrum
disorder with acute confusional state.
also result in an altered level of
consciousness (Figure 10-7).
Symptomatic cerebral syndrome. ance following white matter tracts
Large hemispheric lesions may cause (Figure 10-9). Posterior reversible en-
encephalopathy as well as focal neuro- cephalopathy syndrome (PRES) has
logic deficits, depending on the location been described; dysregulation of water
involved. Lesions may have a tumefac- flux due to aquaporin disturbance may
tive appearance34 (Figure 10-8) or may be the culprit, or this may simply be a
demonstrate a spindlelike appear- PRES-like syndrome.35,36 One patient
FIGURE 10-6 Coronal T2-weighted

fluid-attenuated
inversion recovery FIGURE 10-8 Axial T2-weighted
(FLAIR) MRI demonstrating bilateral fluid-attenuated
hypothalamic lesions in a patient with inversion recovery
neuromyelitis optica spectrum disorder (FLAIR) MRI demonstrating a
with weight loss, sleepiness, tumefactive brain lesion in a patient
and hypothermia. with neuromyelitis optica
spectrum disorder.
Reprinted with permission from Viegas S, et al, J
Neurol Neurosurg Psychiatry.25 jnnp.bmj.com/ Reprinted with permission from Huh SY, et al,
content/80/6/679.abstract. B 2009 BMJ Mult Scler.34 msj.sagepub.com/content/20/6/
Publishing Group Ltd. 695.abstract. B 2013 SAGE Publications.

seen are periependymal lesions adja-

cent to the ventricular system, in-
cluding the diencephalic and dorsal
brainstem lesions described earlier in
this article. Lesions surrounding the
lateral ventricles are in this category as
well, including callosal lesions. Although
callosal lesions are also common in MS,
in MS the lesions are typically small and
discrete with an ovoid or flame-shaped
appearance and radially oriented to the
ventricles. This is in contrast to NMO
spectrum disorders, in which lesions
are often large and follow the epen-
FIGURE 10-9 Axial T2-weighted
fluid-attenuated inversion dymal lining (Figure 10-11).41 Acute
recovery (FLAIR) MRI callosal lesions may demonstrate sig-
demonstrating spindlelike hemispheric
lesions following white matter tracts in nificant edema with a heterogeneous
neuromyelitis optica spectrum disorder. marbled appearance (Figure 10-12).43
Reprinted with permission from Huh SY, et al, Involvement of the entire thickness of
Mult Scler.34 msj.sagepub.com/content/20/6/
695.abstract. B 2013 SAGE Publications. the corpus callosum may create an arch
bridge appearance (Figure 10-13).34
As described earlier, patients with
from our center with large hemispheric NMO spectrum disorders may develop
lesions developed hydrocephalus.37 large hemispheric lesions, resulting in
Other potential systemic symptoms encephalopathy or focal neurologic
of neuromyelitis optica spectrum deficits. Corticospinal tract lesions, which
disorders. Aquaporin-4 is ubiquitous, are often longitudinally extensive, may
leading to the possibility that further also be seen (Figure 10-1444).34,45
studies may reveal involvement of other
organ systems, although currently
this seems to occur only rarely. For ex-
ample, generalized fatigue/weakness
with high creatine kinase (CK)38Y40
has been reported.
Brain MRI in Neuromyelitis

Optica Spectrum Disorders
As the spectrum of clinical symptoms
of NMO spectrum disorders illustrates,
brain involvement is quite common,
contrary to prior conventional wisdom
about the disease. The most common
abnormality seen on brain MRI is FIGURE 10-10 Axial T2-weighted
fluid-attenuated
the presence of nonspecific deep inversion recovery
white matter T2 hyperintensities (FLAIR) MRI demonstrating nonspecific
T2 hyperintensities commonly occurring
(Figure 10-10).41 These are present in in neuromyelitis optica spectrum disorder.
the majority of patients with NMO Reprinted with permission from Kim W, et al, Mult
41
spectrum disorders and are typically Scler. msj.sagepub.com/content/16/10/1229.
abstract. B 2010 SAGE Publications.
asymptomatic. 14,42 Also frequently

Sagittal T2-weighted FIGURE 10-13 Axial T2-weighted
FIGURE 10-11 fluid-attenuated fluid-attenuated
inversion recovery (FLAIR) inversion recovery
image demonstrating diffuse involvement (FLAIR) image demonstrating involvement
of the corpus callosum following the of the entire thickness of the corpus
ependymal lining in a patient with callosum in neuromyelitis optica
neuromyelitis optica spectrum disorder. spectrum disorder, creating an arch
Reprinted with permission from Kim HJ, et al,
bridge appearance.
Neurology.14 www.neurology.org/content/84/ Reprinted with permission from Huh SY, et al,
11/1165.long. B 2015 American Academy 34
Mult Scler. msj.sagepub.com/content/20/6/
of Neurology. 695.abstract. B 2013 SAGE Publications.
FIGURE 10-12 Axial T2-weighted

fluid-attenuated Axial T1-weighted
inversion recovery
FIGURE 10-14
postgadolinium image
(FLAIR) MRI demonstrating marbled demonstrating cloudlike
appearance of acute callosal lesion in enhancement pattern in acute neuromyelitis
neuromyelitis optica spectrum disorder. optica spectrum disorder lesion.
Reprinted with permission from Kim HJ, et al, Reprinted with permission from Ito S, et al, Ann
14 44
Neurology. www.neurology.org/content/84/ Neurol. onlinelibrary.wiley.com/doi/10.1002/
11/1165.long. B 2015 American Academy ana.21753/abstract. B 2009 American
of Neurology. Neurological Association.

KEY POINTS Laboratory Testing in

Acute brain lesions may enhance with
h Any patient for whom Suspected Neuromyelitis
the diagnosis of
gadolinium. The reported frequency
of gadolinium enhancement noted on Optica Spectrum Disorders
neuromyelitis optica
spectrum disorder is brain MRI varies,14 in part based on Any patient for whom the diagnosis of
suspected should have a whether the MRI was completed during an NMO spectrum disorder is suspected
serum sample evaluated a symptomatic episode with brain in- should have a serum sample evaluated
for the presence of volvement. The enhancement pattern for the presence of antiYaquaporin-4
antiYaquaporin-4 may be cloudlike (Figure 10-15),44 antibodies. Where available, a cell-
antibodies. Where although this is not invariably seen. based assay is preferred because of
available, a cell-based Other enhancement patterns that have higher sensitivity and specificity com-
assay is preferred been described include a thin rim of pared to alternative methods. A meta-
because of higher analysis examining 30 high-quality
enhancement lining the lateral ventri-
sensitivity and specificity
cles (pencil-thin enhancement)46 studies calculated a sensitivity of 76% for
compared to
alternative methods.
and, rarely, meningeal enhancement.41 cell-based assay, 59% for tissue-based
Of note, over time, many brain le- assay, and 65% for enzyme-linked immu-
h Whereas oligoclonal sions in NMO spectrum disorders de- nosorbent assay (ELISA). Specificity was
bands are seen in the
crease in size and may even disappear 99% for cell-based assay, 98% for tissue-
vast majority of patients
completely.43,45 However, when fol- based assay, and 97% for ELISA.48
with multiple sclerosis
(up to 90%), they are lowed longitudinally, close to half of While CSF evaluation is not a
much less common in acute NMO spectrum disorder brain required element of the diagnostic
neuromyelitis optica lesions display persistent T1 hypo- criteria for NMO spectrum disorders,
spectrum disorders, intensity, including some with cystic or it may be helpful in certain cases when
with studies reporting cavitary features.45 Cystic changes seem the diagnosis is not completely clear.
oligoclonal band to occur most commonly in callosal Results will be heavily dependent on
positivity rates of up to and corticospinal tract lesions.45,47 whether the patient is in the midst of
approximately 25%. an exacerbation, when CSF may appear
highly inflammatory, or whether the
patient is in remission, when CSF may
appear normal. Findings tend to be
more pronounced during an attack of
transverse myelitis as compared to
optic neuritis.49 Especially during an
acute attack, an elevated white blood
cell count is common and may be quite
impressive (up to 380 cells/2L in one
study).49 This is in contrast to MS, in
which more than 50 cells/2L is quite
rare. Also in contrast to MS, in which
lymphocytes make up the vast majority
of the differential, in NMO spectrum
disorders, neutrophils and eosinophils
FIGURE 10-15 Coronal T2-weighted are commonly seen,49 reflecting differ-
fluid-attenuated ences in the underlying pathogenesis
inversion recovery
(FLAIR) image demonstrating a long of the two diseases. Total protein may
corticospinal tract lesion in a be elevated regardless of current dis-
patient with neuromyelitis optica
spectrum disorder. ease activity status, although elevations
Reprinted with permission from Huh SY, et al,
of greater than 100 mg/dL seem to be
34
Mult Scler. msj.sagepub.com/content/20/6/ limited to those in the midst of a
695.abstract. B 2013 SAGE Publications.
relapse.49 The albumin quotient may

KEY POINT
be elevated, particularly during a when applying different categories of h The International Panel
relapse, indicating blood-brain barrier criteria, the diagnosis becomes NMO for Neuromyelitis Optica
disruption. Whereas oligoclonal bands spectrum disorder with aquaporin-4Y Diagnosis categories
are seen in the vast majority of pa- IgG, NMO spectrum disorder without (which include
tients with MS (up to 90%), they are aquaporin-4YIgG, or NMO spectrum neuromyelitis optica
much less common in NMO spectrum disorder with unknown aquaporin- spectrum disorder with
disorders, with studies reporting 4YIgG status. This allows for all aquaporin-4YIgG,
oligoclonal band positivity rates of up patients who exhibit typical NMO spec- neuromyelitis optica
to approximately 25%.50 Aquaporin- trum disorder clinical syndromes to spectrum disorder
4YIgG may be positive in the CSF; fall under the NMO spectrum disorder without aquaporin-
4YIgG, or neuromyelitis
occasionally this may improve the umbrella, with simple modification of
optica spectrum disorder
detection of aquaporin-4YIgG in a the diagnosis going forward should
with unknown
patient who is seronegative.51 Levels the patient later be demonstrated to aquaporin-4YIgG status)
of glial fibrillary acidic protein (GFAP) have positive aquaporin-4YIgG. It also allow for all patients who
have been shown to be significantly allows for simple modification in the exhibit typical
elevated during initial NMO spectrum event that future biomarkers prove neuromyelitis optica
disorder attacks to levels much higher clinically useful in patients who are spectrum disorder clinical
than in other CNS inflammatory dis- aquaporin-4YIgG negative. syndromes to fall under
eases, reflective of the prominent astro- Patients who are positive for the neuromyelitis optica
cytic damage unique to NMO spectrum aquaporin-4YIgG must have at least spectrum disorder
disorders.52,53 CSF interleukin 6 (IL-6) one core clinical characteristic for an umbrella, with simple
levels are also elevated during acute NMO spectrum disorder diagnosis. modification of the
diagnosis going forward
NMO spectrum disorder attacks.53,54 The only additional requirement is
should the patient later
the exclusion of alternative diagnoses.
be demonstrated to have
Applying Neuromyelitis The potential for an alternate etiology positive aquaporin-4YIgG.
Optica Spectrum Disorder is often raised because of the high pre-
Diagnostic Criteria valence of additional autoantibodies
Diagnostic criteria outlined in 2006 in patients with NMO spectrum disor-
were the first to incorporate the ders. These are generally regarded as
newly discovered antiYaquaporin-4 supportive of an NMO spectrum dis-
antibodies (aquaporin-4YIgG).55 These order rather than suggestive of an
criteria were validated in multiple set- alternative diagnosis and are further
tings and have been widely applied in discussed in the later section on
research and clinical practice since that differential diagnosis.
time. However, the subsequent rapid The diagnostic criteria are more strin-
accumulation of data regarding the clin- gent for patients who are negative for
ical and radiographic spectrum of NMO aquaporin-4YIgG or when aquaporin-
as well as improvements in laboratory 4YIgG status is unknown. These pa-
assays for antiYaquaporin-4 antibodies tients must have at least two core
as described necessitated reconsidera- clinical characteristics and meet the
tion of several points. The Interna- following requirements for an NMO
tional Panel for Neuromyelitis Optica spectrum disorder diagnosis: (1) at least
Diagnosis (IPND) convened in 2011 and one core clinical characteristic must
published updated consensus diag- be optic neuritis, acute myelitis with
nostic criteria incorporating relevant longitudinally extensive transverse my-
advances in 2015.56 elitis (LETM), or area postrema syn-
The diagnostic criteria stratify pa- drome; (2) dissemination in space (two
tients with suspected NMO spectrum or more different core clinical charac-
disorders by aquaporin-4YIgG status; teristics); (3) fulfillment of additional

KEY POINTS
h The most commonly MRI requirements, as applicable. MRI no additional diagnostic evaluation is
considered entity in the requirements reflect typical MRI fea- needed. Patients who are seronegative,
differential diagnosis of tures for NMO spectrum disorders particularly at the time of the initial
a neuromyelitis optica specific to the involved site. For optic episode or if atypical features are pres-
spectrum disorder is neuritis, the brain MRI must either be ent, often require additional diagnostic
multiple sclerosis. Optic normal/nonspecific or show a T2 hyper- evaluation. The workup of alternative
neuritis, myelitis, intensity or gadolinium-enhancing etiologies should be driven by the clin-
brainstem syndromes, lesion extending over half the optic ical presentation, taking into consider-
and abnormalities on nerve length or involving the chiasm. ation factors such as the characteristics
brain MRI are common For acute myelitis, spinal cord imag- of the clinical and imaging features and
to both disorders; at
ing must demonstrate an intra- the presence or absence of systemic
times, it may be difficult
medullary lesion extending over at symptoms. Red flags identified by the
to distinguish them.
least three contiguous segments. In pa- IPND are shown in Table 10-3.
h Most patients with tients with a prior history compatible The differential diagnosis of sus-
established rheumatologic
with acute myelitis, this may be sub- pected optic neuritis. Visual loss due
disease (eg, lupus,
stituted by focal cord atrophy that to suspected optic neuritis has many
Sjogren disease) with
longitudinally extensive
extends over at least three contiguous potential etiologies. These range from
transverse myelitis segments. An area postrema syndrome infectious to inflammatory to heredi-
previously attributed to requires typical dorsal medulla/area tary to neoplastic/paraneoplastic.57
their rheumatologic postrema lesions, and an acute brain- Features commonly seen with optic
condition are positive for stem syndrome requires associated neuritis due to an NMO spectrum dis-
aquaporin-4YIgG, and a periependymal brainstem lesions. Of order have been discussed earlier in
neuromyelitis optica note, the two required core clinical this article. Features that may prompt
spectrum disorder characteristics may be separated by an alternative explanation include the
provides a more any length of time or may occur within presence of fever or other systemic
accurate etiology of their a single clinical episode. The full IPND symptoms, subacute to chronic progres-
central nervous
2015 diagnostic criteria for NMO spec- sive course, and positive family history,
system pathology.
trum disorders in adult patients are among others. In patients who are
outlined in Table 10-1.56 aquaporin-4YIgG negative and have re-
current optic neuritis with a normal
The Differential Diagnosis brain MRI, a diagnosis of chronic relaps-
of Neuromyelitis Optica ing inflammatory optic neuropathy
Spectrum Disorders should be considered.58,59 Potential
The most commonly considered entity etiologies to consider in the differential
in the differential diagnosis of an NMO diagnosis of optic neuritis are outlined
spectrum disorder is MS. Optic neuritis, in Table 10-4.
myelitis, brainstem syndromes, and The differential diagnosis of longi-
abnormalities on brain MRI are com- tudinally extensive transverse myelitis.
mon to both disorders; at times, it may Most patients with established rheu-
be difficult to distinguish them. Fea- matologic disease (eg, lupus, Sjo gren
tures that help differentiate the two disease) with LETM previously attri-
disorders have been described in the buted to their rheumatologic condition
relevant sections discussing the clinical, are positive for aquaporin-4YIgG, and
imaging, and laboratory characteristics an NMO spectrum disorder provides a
of NMO spectrum disorders earlier and more accurate etiology of their CNS
are summarized in Table 10-2. pathology. However, although NMO
In a patient with a clinical presenta- spectrum disorder has become an in-
tion characteristic for an NMO spectrum creasingly recognized etiology of
disorder with positive aquaporin-4YIgG, LETM, not every patient with LETM

a
TABLE 10-1 Neuromyelitis Optica Spectrum Disorder Diagnostic Criteria for Adult Patients
Diagnostic Criteria for Neuromyelitis Optica (NMO) Spectrum Disorders With Aquaporin-4 Immunoglobulin G
(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 diagnosesb
Diagnostic Criteria for NMO Spectrum Disorders Without AQP4-IgG or NMO Spectrum Disorders 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 (LETM) lesions, 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 diagnosesb
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 NMO spectrum disorderYtypical
diencephalic MRI lesions
6. Symptomatic cerebral syndrome with NMO spectrum disorderYtypical brain lesions
Additional MRI Requirements for NMO Spectrum Disorders Without AQP4-IgG and NMO Spectrum
Disorders With Unknown AQP4-IgG Status
1. Acute optic neuritis: requires brain MRI showing normal findings or only nonspecific white matter
lesions OR optic nerve MRI with T2-hyperintense lesions or T1-weighted gadolinium-enhancing lesion
extending over 9 one-half optic nerve length or involving optic chiasm
2. Acute myelitis: requires associated intramedullary MRI lesion extending over Q three contiguous segments
(LETM) OR Q three contiguous segments of focal spinal cord atrophy in patients with prior 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
MRI = magnetic resonance imaging.
a
Reprinted with permission from Wingerchuk DM, et al, Neurology.56 www.neurology.org/content/85/2/177.full. B 2014 American
Academy of Neurology.
b
See Table 10-3 on serologic considerations for recommendations regarding interpretation of clinical and serologic testing.

TABLE 10-2 Features Differentiating Neuromyelitis Optica Spectrum Disorder From

Multiple Sclerosis
Features Spectrum Disorder Multiple Sclerosis
Epidemiology
Age Older mean age (40) at Younger mean age (30) at
diagnosis; onset over age diagnosis; onset over age
60 not uncommon 60 very rare
Race/ethnicity More common in nonwhite More common in whites
populations, particularly Asians and (although recent US studies
those of Afro-Caribbean descent show similar rates in blacks)
Female preponderance As high as 9:1 As high as 4:1
Myelitis
Length of lesion Typically longitudinally extensive Almost never longitudinally
(Q three vertebral segments) extensive (typically G three
vertebral segments)
Partial versus complete Complete spinal cord Partial spinal cord syndrome
syndrome common common
Location Central cord usually involved Dorsolateral cord usually
involved
Cord cross-sectional area More than one-half the cord Typically less than one-half
cross-sectional area often the cord cross-sectional area
involved involved
T1 hypointensity May be present Absent
Poor recovery Common Uncommon
Optic neuritis
Simultaneous bilateral involvement Common Very rare
High severity/poor recovery Common Uncommon
Posterior involvement, including Common Very rare
the optic chiasm
Long extensive lesion Common Very rare
Area postrema syndrome Common Almost never
Diencephalic syndrome Common Very rare
Progressive clinical course Extremely rare Common
Brain MRI
Lesions oriented perpendicularly Very rare Very common
to ventricles (Dawson fingers)
Juxtacortical lesions Uncommon Very common
Extensive hemispheric lesions Common Uncommon (can see in
tumefactive multiple sclerosis)
Continued on page 877

TABLE 10-2 Features Differentiating Neuromyelitis Optica Spectrum Disorder From
Multiple Sclerosis Continued from page 876
Features Spectrum Disorder Multiple Sclerosis
Laboratory findings
Aquaporin-4 immunoglobulin G Usually present Absent
CSF cell count Often very elevated, especially 950 white blood cells very rare
in the setting of relapse
CSF neutrophils and eosinophils Often present Usually absent
CSF protein Often very elevated, especially Usually normal, may be
in the setting of relapse mildly elevated
CSF oligoclonal bands Often absent (present in Usually present (in approximately
e25% of patients) 90% of patients)
CSF glial fibrillary acidic protein Often very elevated Normal or may be mildly elevated
during relapse
CSF = cerebrospinal fluid; MRI = magnetic resonance imaging.
has an NMO spectrum disorder. Po- Progressive course or persistent gado-

tential alternative etiologies to consider linium enhancement (longer than
are listed in Table 10-5.60 Certain 3 months) are not characteristic of an
features of spinal cord imaging may NMO spectrum disorder and should raise
help distinguish LETM caused by an suspicion for other etiologies, including
NMO spectrum disorder from that malignancy (eg, glioma, lymphoma), sar-
resulting from other etiologies, such as coidosis, histiocytosis, Behcet disease,
T1 hypointensity and lesions that oc- or chronic lymphocytic inflammation
cupy more than half the cross-sectional with pontine perivascular enhancement
area of the cord.61 Despite further diag- responsive to steroids (CLIPPERS).
nostic evaluation, some patients will Consideration of other autoimmune
have monophasic LETM with no diseases. During the initial diagnostic
etiology found. evaluation, patients with a suspected
The differential diagnosis of brain- NMO spectrum disorder are often
stem syndromes. Several features noted to have autoantibodies poten-
accompanying brainstem syndromes tially indicative of other autoimmune
are not consistent with NMO spec- diseases. Several questions often arise:
trum disorders and warrant additional
diagnostic evaluation. Fever, especially & Does the patient have an
if accompanied by encephalopathy, additional autoimmune disease?
could suggest entities such as listeria & Is the neurologic presentation
rhombencephalitis, viral infection related to an NMO spectrum
(eg, varicella), Whipple disease, or disorder or to the additional
tuberculosis. Syndromes that respect autoimmune disease?
a particular vascular territory, such as & What is the significance of the
a lateral medullary syndrome and autoantibodies in the absence of
those with hyperacute symptom onset, clinical symptoms of the associated
should prompt vascular evaluation. autoimmune disease?

a,b
TABLE 10-3 Findings Atypical for Neuromyelitis Optica Spectrum Disorder
b Clinical/Laboratory Red Flags

Clinical features and laboratory findings
Progressive overall clinical course (neurologic deterioration unrelated to attacks; consider multiple
sclerosis [MS])
Atypical time to attack nadir; less than 4 hours (consider cord ischemia/infarction); continual
worsening for more than 4 weeks from attack onset (consider sarcoidosis or neoplasm)
Partial transverse myelitis, especially when not associated with longitudinally extensive transverse
myelitis MRI lesion (consider MS)
Presence of CSF oligoclonal bands (oligoclonal bands occur in G20% of cases of neuromyelitis optica
[NMO] versus 980% of MS)
Comorbidities associated with neurologic syndromes that mimic NMO spectrum disorder
Sarcoidosis, established or suggestive clinical, radiologic, or laboratory findings thereof (eg,
mediastinal adenopathy, fever and night sweats, elevated serum angiotensin-converting enzyme, or
interleukin-2 receptor levels)
Cancer, established or with suggestive clinical, radiologic, or laboratory findings thereof; consider
lymphoma or paraneoplastic disease (eg, collapsin response mediator protein-5 [CRMP-5]Yassociated
optic neuropathy and myelopathy or anti-MaYassociated diencephalic syndrome)
Chronic infection, established or with suggestive clinical, radiologic, or laboratory findings thereof
(eg, human immunodeficiency virus [HIV], syphilis)
b Conventional Neuroimaging Red Flags
Brain
Imaging features (T2-weighted MRI) suggestive of MS (MS-typical)
Lesions with orientation perpendicular to a lateral ventricular surface (Dawson fingers)
Lesions adjacent to lateral ventricle in the inferior temporal lobe
Juxtacortical lesions involving subcortical U fibers
Cortical lesions
Imaging characteristics suggestive of diseases other than MS and NMO spectrum disorders
Lesions with persistent (93 months) gadolinium enhancement
Spinal cord
Characteristics more suggestive of MS than NMO spectrum disorders
Lesions G3 complete vertebral segments on sagittal T2-weighted sequences
Lesions located predominantly (970%) in the peripheral cord on axial T2-weighted sequences
Diffuse indistinct signal change on T2-weighted sequences (as sometimes seen with long-standing or
progressive MS)
CSF = cerebrospinal fluid; MRI = magnetic resonance imaging.
a
Reprinted with permission from Wingerchuk DM, et al, Neurology.56 www.neurology.org/content/85/2/177.full. B 2014 American
Academy of Neurology.
b
These are some common or key findings that should prompt thorough investigation for competing differential diagnoses before
making a diagnosis of NMO spectrum disorders.

a
TABLE 10-4 Differential Diagnoses and Mimics of Acute Optic Neuritis
Etiology Features Differential Diagnoses Paraclinical Tests

Infectious Subacute or progressive visual loss Spirochetes Serology, polymerase chain
following exposure to infectious (eg, syphilis, Lyme) reaction (PCR), CSF, MRI
agent; frequently with broader
Human immunodeficiency MRI, serology
cellular reaction in the eye
virus (HIV)
Bartonella henselae, Chest radiography, serology,
neurocysticercosis, CSF, MRI
tuberculosis
Sinus pain Viral sinusitisb MRI
c
Reactive Bilateral and simultaneous; Postinfectious Serology, CSF
often in childhood and then
Postvaccination Optical coherence
mostly good prognosis. In
tomography (OCT),
contrast, in adults
electroretinogram (ERG)
the outcome is more
frequently poor Acute disseminated MRI
encephalomyelitis (ADEM)
Neuroretinitis Macular stard
Vascular Sudden-onset visual loss, mostly Anterior ischemic Erythrocyte sedimentation rate,
painless (except giant cell arteritis optic neuropathy C-reactive protein, glucose
[GCA]); acutely swollen optic
PION Coagulation tests
disc (except posterior ischemic
optic neuropathy [PION]); GCA Temporal artery biopsy
cardiovascular risk factors
Diabetic papillopathy ECG, Doppler ultrasound
Frequent episodes, migraine Retinal vasospasm ECG, Doppler ultrasound
Hearing loss, encephalitis Susac syndrome Audiogram, OCT, visual fields
Proptosis, chemosis, orbital Carotid cavernous Orbital bruit, computed
venous congestion, fistula tomography angiography
diplopia (intermittent) (CTA)/magnetic resonance
angiography (MRA)
Seizures, neurologic signs Vascular malformations CTA/MRA, digital subtraction
angiography, CSF
Nutritional Bilateral, painless, progressive; Vitamin B12 deficiency Vitamin B12, methylmalonic
and toxic evidence is emerging that cobalt acid
toxicity may also be relevant to
Tobacco-alcohol, toxic Complete blood cell count,
(hip) joint implants containing
cobalt levels
cobalt. Pale discs, poor prognosis
Endemice OCT, visual fields
Methanol, ethambutol, Plasma osmolar gap, ethylene
ethylene glycol glycol, glycolic acid, formate
Compressive Painless, progressive, pale disc Primary tumors, CT or MRI of orbits and
at presentation, cilioretinal shunt metastases, tuberculoma, brain with contrast, MRA, OCT,
vessels, history of cancer; sinus mucoceles, Graves biopsy, antithyroid antibodies
proptosis, lid lag, diplopia, disease (Graves disease only)
history of thyroid disease
Continued on page 880

a
TABLE 10-4 Differential Diagnoses and Mimics of Acute Optic Neuritis Continued from page 879
Etiology Features Differential Diagnoses Paraclinical Tests

Systemic Painful, progressive and often All diagnoses Brain and orbits
disease bilateral, more frequent in with contrast
nonwhites, subacute visual
Sarcoidosis Angiotensin-converting
loss, history of migraine
enzyme, CSF, biopsy (sarcoid)
Behet disease OCT, chest radiography, MRI
Systemic lupus Coagulation tests; if antinuclear
erythematosus antibodyYpositive, search for
specific antibodies
Cancer Paraneoplastic antibodies
Persistent migrainous Further tests not part of
visual aura routine workup
Ocular Pain Posterior scleritis OCT, ultrasound,
antineutrophil
cytoplasmic antibodies
Painless, metamorphopsia Maculopathies OCT, ERG
Preserved color vision Retinopathies Fluorescein angiogram
Visual field loss, photopsias Big blind spot Visual fields, OCT
syndromes
Preserved color vision Acute zonal occult outer ERG
retinopathy
Hereditary Family history; bilateral, painless Leber hereditary optic Genetic testing
neuropathy; OPA1 and
OPA3 mutations
CSF = cerebrospinal fluid; CT = computed tomography; ECG = electrocardiogram; MRI = magnetic resonance imaging.
a
Reprinted with permission from Petzold A, et al, Nat Rev Neurol.57 www.nature.com/nrneurol/journal/v10/n8/abs/nrneurol.2014.108.
html. B 2014 Rights Managed by Nature Publishing Group.
b
Sinusitis was high up in the differential diagnosis in the past but has almost disappeared over the past few decades.
c
It is mandatory to obtain a good history, including recent travels to high-risk areas for certain infections (eg, malaria, dengue virus, West
Nile virus, cysticercosis) or other forms of exposure.
d
A macular star is suggestive of neuroretinitis and can be associated with peripheral retinal hemorrhages and speckled appearance of the
pigment epithelium.
e
Endemic optic neuropathies have been described in Cuba and Tanzania.
If the neurologic presentation is con- thritis, Sjo

gren disease, autoimmune
sistent with one of the core clinical thyroid disease, myasthenia gravis,
presentations of NMO spectrum disor- autoimmune encephalitis, and several
ders, that is likely to be the best expla- others have all been described in pa-
nation for the symptoms, especially if tients with NMO spectrum disorders.62
the patient is positive for aquaporin- In addition, approximately 40% of
4YIgG. Other autoimmune diseases do patients with NMO spectrum disor-
commonly coexist with NMO spectrum ders have been noted to have positive
disorders; these should only be diag- autoantibodies without clear clinical
nosed if the patient exhibits the char- symptoms of the associated autoim-
acteristic clinical symptoms. Systemic mune disease.63 The clinical signifi-
lupus erythematosus, rheumatoid ar- cance of these is not entirely clear. In

a
TABLE 10-5 Causes of Longitudinally Extensive Transverse Myelitis and Potential Mimics
Cause Clinical Radiology Laboratory

Spinal infarction Sudden onset; Anterior gray matter
history of vascular disease involvement; pencil-like
longitudinal lesion
Spinal dural Usually elderly men; Flow voids on MRI spine; T2

arteriovenous thoracolumbar location; hyperintensity on MRI extends
fistulas symptoms worsen with erect into conus; spinal angiogram may
posture or Valsalva maneuver demonstrate feeding vessel
Compressive lesions Gradual onset symptoms; Pancakelike enhancement at
may have a history of neck the point of maximal stenosis;
pain or radicular symptoms associated degenerative
disk disease
Metabolic (vitamin Possible history of gastric Selective involvement of Low serum B12 or
B12 deficiency, bypass or malabsorption the dorsal columns copper levels;
copper deficiency) syndrome macrocytosis;
associated neuropathy
on nerve conduction
studies
Alexander disease Autosomal dominant; Ventricular garlands on Rosenthal fibers on
progressive bulbar and MRI brain; usually associated brain biopsy;
spinal dysfunction with spinal cord atrophy, GFAP mutation
but can be associated with
longitudinal high signal
lesions in the cervical cord
Primary spinal cord Gradual symptom onset Positron emission Demonstration of
neoplasm without remissions tomography (PET) scan malignancy on
demonstrating malignancy; spinal cord biopsy;
syrinx may be associated neoplastic cells in
with ependymoma spinal fluid
or hemangioblastoma
Paraneoplastic Systemic symptoms or Tract-specific involvement; Detection of
signs of malignancy enhancement following paraneoplastic
gadolinium administration antibody in serum
or spinal fluid
Acute disseminated Associated encephalopathy; Cerebral white Leukocytosis on
encephalomyelitis more common in children matter changes spinal fluid analysis
(ADEM)
Multiple sclerosis May have Lhermitte Eccentric lesions on Oligoclonal bands;
symptom; associated with axial spinal cord images leukocytosis on spinal
other features of multiple fluid analysis
sclerosis (eg, history of optic
neuritis or internuclear
ophthalmoplegia) Continued on page 882

TABLE 10-5 Causes aof Longitudinally Extensive Transverse Myelitis and Potential
Mimics Continued from page 881
Cause Clinical Radiology Laboratory

Infectious Signs of systemic infection Diffuse cord edema; Detection of
(eg, fever, herpetic rash); root involvement infectious agent in
prominent residual amyotrophy (syphilis); gray matter the spinal fluid;
(enterovirus and flavivirus); involvement (enterovirus leukocytosis in spinal
travel to endemic region and flavivirus) fluid analysis
(schistosomiasis, other
parasitic infections)
MRI = magnetic resonance imaging.
a
Modified with permission from Tobin WO, et al, Curr Opin Neurol.60 journals.lww.com/co-neurology/pages/articleviewer.aspx?year=
2014&issue=06000&article=00006&type=Abstract. B 2014 Wolters Kluwer Health.
KEY POINTS
some cases, the patient may later go data related to MS and other inflam-
h Approximately 40%
on to develop that autoimmune dis- matory conditions, and expected pos-
of patients with
neuromyelitis optica ease, but much of the time will not. sible adverse events are assumed to
spectrum disorders have Some patients will have multiple positive be similar. In contrast to MS, in NMO
been noted to have antibodies; this pattern is supportive spectrum disorders IV methylprednis-
positive autoantibodies of an NMO spectrum disorder diagno- olone should be followed by a pro-
without clear clinical sis. Rheumatology input may be help- longed prednisone taper, usually in the
symptoms of the ful in select cases. range of 2 to 6 months. The length of
associated autoimmune the taper will vary based on individual
disease. The clinical TREATMENT OF ACUTE factors, such as choice and timing of
significance of these is EXACERBATIONS OF disease-modifying agent, medical his-
not entirely clear. In NEUROMYELITIS OPTICA tory and comorbidities, the patients
some cases, the patient SPECTRUM DISORDERS prior experiences with prolonged ste-
may later go on to
Corticosteroids and plasma exchange roid use, and adverse reactions.
develop that autoimmune
disease, but much of are the most commonly employed
therapies for acute NMO spectrum Plasma Exchange
the time will not.
disorder attacks. IV immunoglobulin Because of the proposed underlying
h Acute exacerbations of
(IVIg) may also be used. When a pa- disease pathophysiology, the severity
neuromyelitis optica
spectrum disorders are tient fails to improve from a rel- of many NMO spectrum disorder re-
nearly universally treated apse, some clinicians may consider IV lapses, and clinical experience and avail-
with corticosteroids, cyclophosphamide, although few data able data suggesting a benefit, many
typically IV exist to support this strategy. Because clinicians treat NMO spectrum dis-
methylprednisolone recovery is often incomplete despite order relapses with plasma exchange.
1 g/d for 5 days. treatment, several agents are also cur- Practice patterns vary regarding whether
rently being explored in early-stage plasma exchange is offered as first-
clinical trials. line therapy or only after a suboptimal
response to IV steroids is noted. Clini-
Corticosteroids cians tend to offer plasma exchange as
Acute exacerbations of NMO spectrum first-line therapy in particular if a pa-
disorders are nearly universally treated tient has previously responded well to
with corticosteroids, typically IV meth- plasma exchange, especially if that
ylprednisolone 1 g/d for 5 days. This patient has previously responded
practice is extrapolated from available poorly to corticosteroids.

KEY POINTS
Although large prospective studies The suggested dose is 0.4 g/kg/d h Because of the proposed
are lacking, available data suggest for 5 days, for a total dose of 2 g/kg. underlying disease
plasma exchange is effective at treat- Potential adverse events include head- pathophysiology, the
ing NMO spectrum disorder exacerba- ache (rarely, due to aseptic meningi- severity of many
tions.64 One 2015 study retrospectively tis), malaise, fever, rash, thrombotic neuromyelitis optica
examined the records of 83 admissions events, renal insufficiency, and, quite spectrum disorder
to Johns Hopkins Hospital for NMO rarely, anaphylaxis.68 Most side effects relapses, and clinical
spectrum disorder relapses and con- are self-limited and do not require experience and available
cluded those treated with plasma discontinuation of therapy. data suggesting a
exchange after a course of IV methyl- benefit, many clinicians
DISEASE-MODIFYING THERAPY treat neuromyelitis optica
prednisolone were more likely to im-
FOR NEUROMYELITIS OPTICA spectrum disorder
prove on a standardized version of the
relapses with
neurologic examination than those who SPECTRUM DISORDERS
plasma exchange.
received IV methylprednisolone alone.65 Unlike in MS, where much of the
The typical protocol is an exchange disability is driven by progressive h IV immunoglobulin has
also been suggested as
of 1 to 1.5 volumes of plasma every disease, nearly all of the disability in
a potential treatment
other day for a total of five treatments, NMO spectrum disorders is driven by for acute relapses in
although some clinicians recommend relapses. Relapses are often severe, neuromyelitis optica
up to seven treatments. Adverse events with poor recovery despite aggressive spectrum disorders,
are relatively uncommon in centers treatment. A single attack may leave particularly when
experienced in plasma exchange. Po- a patient blind or paraplegic or may response to steroids is
tential adverse events include compli- result in death due to respiratory com- suboptimal and a
cations related to central venous promise. Effective preventive therapy is contraindication to
catheter use (eg, bleeding, infection) therefore of utmost importance, and plasma exchange exists.
and citrate-induced hypocalcemia or therapy initiation should be viewed h A single attack of
metabolic alkalosis. Depletion of coag- as urgent. neuromyelitis optica
ulation factors may occur when Owing to multiple factors, includ- spectrum disorder may
nonplasma replacement fluids are ing the rarity and severity of the leave a patient blind or
used; coagulation factors must be disease, no prospective randomized paraplegic or may
monitored. Plasma-based replacement double-blind placebo-controlled trials result in death due to
respiratory compromise.
fluids carry risks of donor products, exist to support current treatment
Effective preventive
such as anaphylaxis, transfusion- recommendations; therefore, none of
therapy is therefore of
related acute lung injury, and trans- the recommended treatments are US utmost importance, and
mission of infections. Food and Drug Administration (FDA)- therapy initiation should
approved for an NMO spectrum dis- be viewed as urgent.
Intravenous Immunoglobulin order indication. Studies have either
IVIg has also been suggested as a been retrospective or open-label, and
potential treatment for acute relapses all have been relatively small. They
in NMO spectrum disorders, particu- suffer from biases introduced by the
larly when response to steroids is limitations of their designs, most no-
suboptimal and a contraindication to tably the lack of appropriate control
plasma exchange exists. The rationale groups. In addition, studies tend to
stems from efficacy in other humorally enroll at or near the time of recent
mediated neurologic diseases, such as exacerbation. Since NMO exacerbations
myasthenia gravis.66 One small retro- tend to cluster, some regression to the
spective series of 11 episodes found mean is likely inherent in study obser-
improvement with IVIg in 5 of 11, vations. Recommendations are based
with the remainder showing no fur- on this (limited) data and expert con-
ther worsening.67 sensus regarding clinical experience.

KEY POINT
h Decreased activity Choosing an Initial Preventive extrapolated from the transplant and
of thiopurine Therapy for Neuromyelitis rheumatoid arthritis literature. In con-
methyltransferase, an Optica Spectrum Disorders trast to patients with NMO spectrum
enzyme that participates The most commonly prescribed therapies disorders, who are typically treated
in the metabolic include azathioprine, mycophenolate, with azathioprine as monotherapy
pathway of azathioprine, and rituximab. Other therapies, such (although at times with concomitant
predisposes patients to as methotrexate, mitoxantrone, cyclo- corticosteroids), transplant and rheu-
adverse effects, some phosphamide, and cyclosporine, are matologic patients are often treated
of which may be with multiple immunosuppressants
less commonly used. The data for
severe. Thiopurine simultaneously. Reported potentially
these therapies are extremely limited;
methyltransferase
a full discussion of their potential use serious adverse effects include lym-
activity levels are
is beyond the scope of this review. phoma and other malignancies, hepa-
decreased in
approximately 11% of Azathioprine. Azathioprine is an totoxicity, bone marrow suppression,
the US population and antimetabolite that interferes with and infections, including progressive
should therefore ideally lymphocyte proliferation. It was the multifocal leukoencephalopathy
be tested prior to therapy first therapy to be formally studied in (PML).75 Azathioprine also carries sig-
initiation to avoid patients with NMO, in a small study of nificant tolerability issues, including
overt toxicity. seven patients in which azathioprine gastrointestinal upset, hair thinning,
(2 mg/kg/d) was given along with oral and fatigue. One retrospective study
prednisone after a pulse of IV methyl- in the United Kingdom found that of
prednisolone. 69 The primary end 103 patients started on azathioprine
point, Expanded Disability Status Scale for NMO, 29 had discontinued it be-
(EDSS) score, improved from an aver- cause of tolerability issues at a median
age of 8.2 at baseline to 4.0 after 18 follow-up interval of 18 months.74
months of follow-up. In a retrospective Decreased activity of thiopurine
study of 99 patients with a median of methyltransferase (TPMT), an enzyme
22 months of follow-up, the annualized that participates in the metabolic path-
relapse rate fell from 2.09 before way of azathioprine, predisposes pa-
azathioprine to 0.82 after azathioprine tients to adverse effects, some of which
(dose of less than 2 mg/kg/d) and from may be severe. TPMT activity levels
2.20 to 0.52 (dose of 2 mg/kg/d or are decreased in approximately 11%
more), both with PG.0001.70 Reductions of the US population76 and should
were significant in patients receiving therefore ideally be tested prior to
azathioprine both with and without therapy initiation to avoid overt toxicity.
concomitant steroids. Both studies, as Depending on the level of TPMT ac-
well as other retrospective studies tivity, azathioprine should be initi-
that have looked at azathioprine effi- ated at a reduced dose or avoided
cacy,71Y74 are limited by the nature of altogether. Azathioprine carries an FDA
their designs and potential regression pregnancy Category D rating and is
to the mean, as discussed above. therefore not recommended for use
Several issues have limited the adop- during pregnancy. Despite these issues,
tion of azathioprine as a first-line agent azathioprine may still be the preferred
for NMO spectrum disorders. Compa- therapy in areas where access to the
rative efficacy studies suggest it may other agents is limited or in situations
not be as effective as the other agents. where costs of the other agents are
It is difficult to estimate the true risk of prohibitive.
adverse events in the NMO spectrum For NMO spectrum disorders, aza-
disorder population given the size and thioprine can be started at 25 mg/d
design of completed studies; risks are (recommended if TPMT activity testing

KEY POINT
is not available) or 50 mg/d with plan for As with azathioprine, it is somewhat h Mycophenolate is a
laboratory check after 1 week. It can difficult to estimate true expected rates known teratogen;
then be increased up to a target dose of of relatively rare adverse effects of exposure during
2 mg/kg/d to 2.5 mg/kg/d over the next mycophenolate in NMO spectrum dis- pregnancy increases
few weeks if tolerated and no major orders, as mycophenolate is most often the risk of first-trimester
disturbances in laboratory testing oc- used as monotherapy in NMO spec- loss as well as the risk
cur. Weekly laboratory testing is trum disorders, whereas polytherapy is of congenital fetal
recommended for the first month of commonly employed in transplant and malformations, including
therapy, followed by 2 times a month rheumatologic patients. Mycophenolate ear abnormalities, cleft
for months 2 and 3, and monthly carries a risk of unusual/opportunistic lip/palate, and
other abnormalities.
thereafter for the remainder of the first infections, including PML, which has
year.75 Because of its delayed onset of not been reported in NMO spectrum
action, azathioprine is typically disorders but has been reported in
overlapped with oral corticosteroids, transplant and rheumatologic patients.
the dose and tapering schedule of It can cause bone marrow suppression,
which will depend somewhat on requiring frequent monitoring particu-
whether it is being started in the larly during the initiation phase of the
context of a recent relapse or whether drug, although this seems to occur at
the patient is in remission. Corticoste- lower rates than with azathioprine. It is
roids are typically tapered over approx- rarely associated with lymphoproli-
imately 6 months. ferative disorders and dermatologic ma-
Mycophenolate mofetil. Mycophe- lignancies. Mycophenolate is a known
nolate inhibits guanosine nucleotide teratogen (current FDA pregnancy Cat-
biosynthesis, thereby suppressing lym- egory D); exposure during pregnancy
phocyte proliferation. To date, no pro- increases the risk of first-trimester loss
spective studies have been conducted as well as the risk of congenital fetal
on the use of mycophenolate in NMO malformations, including ear abnormal-
spectrum disorders. The largest ret- ities, cleft lip/palate, and other abnor-
rospective study to date looked at 58 malities. The Risk Evaluation and
Korean patients from three centers Mitigation Strategy (REMS) program
treated with a median dose of myco- mandated by the FDA requires pro-
phenolate 2000 mg/d.77 With a me- viders to discuss this risk and to require
dian follow-up interval of approximately women of childbearing potential to use
20 months, median annualized relapse reliable contraception while taking
rate decreased from 1.5 to 0 (PG.001) mycophenolate and for 6 weeks after
and 35 patients (60%) were relapse- its discontinuation. Mycophenolate is
free. Of the 23 who relapsed, 11 were generally better tolerated than azathio-
determined to be inadequately treated prine, although gastrointestinal distur-
at the time of relapse (poor adher- bance may occur.
ence or during the first month of The starting regimen for myco-
therapy), while 12 relapsed despite phenolate varies by individual and
adequate treatment. A prior retrospec- institutional practice preferences. This
tive study of 24 patients also treated author begins patients on 500 mg/d,
with a median dose of 2000 mg/d with then increases each week by 500 mg to
median follow-up interval of 27 reach the typical maintenance dose of
months found a reduction in annual- 2 g/d (usually in two divided doses of
ized relapse rate among those patients 1 g) by the end of the first month
who continued the drug (19 of 24), pending normal laboratory values
from 1.28 to 0.09.78 prior to each weeks increase. The dose

KEY POINT
h Rituximab is often the may be further increased (up to 3 g/d) treatment to 0.3 at 2 years of follow-up
preferred therapy for to achieve the target absolute lympho- (PG.001). In an additional study of
neuromyelitis optica cyte count of less than 1500/2L.79 The 21 patients with a longer follow-up in-
spectrum disorders prescribing information recommends terval (mean 48 months) in which
because of relatively laboratory tests be monitored weekly patients were treated on a standard
rapid onset and efficacy. for the first month, 2 times a month schedule every 6 months, annualized
during the second and third months, relapse rate fell similarly, from 2.0 to
and then monthly for the remainder of 0.16 (PG.01).83
the first year, after which spacing may Several retrospective studies have
be increased.80 It also recommends also suggested rituximab efficacy in
pregnancy testing prior to beginning NMO spectrum disorders. The first
therapy as well as follow-up testing at such study, published in 2008, looked
routine visits. at 25 patients followed at seven cen-
Rituximab. Rituximab is a chimeric ters treated with different variations
monoclonal antibody directed against on the above regimens for a median
CD20, a marker expressed by B cells, of 19 months.84 Median annualized
although notably absent from plasma relapse rate fell from 1.7 pretreatment
cells. The earliest evidence for benefit to 0 posttreatment (PG.001), with 20
in NMO spectrum disorders comes of 25 patients achieving stability or
from an open-label study conducted improvement in neurologic disability.
in eight patients published in 2005.81 The remaining five patients included a
Subjects were treated with rituximab patient who died of a brainstem re-
375 mg/m2 weekly for 4 weeks, then lapse, although this was 9 months after
retreated with two infusions of 1000 mg the last rituximab infusion. A similar
2 weeks apart upon reemergence study of 23 patients found similar
of CD19+ B cells, with an average results; at a median follow-up of
follow-up of 1 year. Median annualized 32.5 months, the median annualized
relapse rate fell from 2.6 to 0 (P=.0078). relapse rate decreased from 1.87 pre-
Six of the eight patients remained treatment to 0 posttreatment and 17
relapse-free during the year after of 23 patients remained relapse-free.85
rituximab initiation. Of the two who An additional study looked at the
experienced a relapse, one was in the cohort from the prospective study of
setting of not receiving a follow-up 30 patients described earlier in this
course of rituximab because of in- article by analyzing response to ritux-
surance issues. In an additional open- imab retrospectively after 5 years of
label study published in 2011, 30 follow-up.86 Patients were continued
subjects were similarly treated with on the described protocol with retreat-
rituximab, either 375 mg/m2 weekly for ment with a single infusion of rituxi-
4 weeks or 1000 mg twice, 2 weeks mab at a dose of 375 mg/m2 upon
apart. 82 They were subsequently reemergence of CD27+ memory B cells.
retreated with a single dose of 375 Again, nearly all patients (26 of 30)
mg/m 2 upon detection of CD27 + exhibited a reduction in relapse rate,
memory B cells at 0.05% of peripheral with 18 of 30 (60%) remaining relapse-
blood mononuclear cells, which were free. Another study analyzed 32 patients
checked every 6 to 8 weeks. Nearly all who had received rituximab as first-line
patients (28 of 30) experienced a therapy and, after a mean follow-up of
reduction in relapse rate, and 21 of 30 28.7 months, noted 27 of 32 (83.4%)
(70%) were relapse-free. Mean annual- were relapse-free and annualized re-
ized relapse rate fell from 2.4 prior to lapse rate was reduced by 97%.87

Rituximab is often the preferred for NMO spectrum disorder worsen-
therapy for NMO spectrum disorders ing in the early days after its adminis-
because of relatively rapid onset and tration. Rituximab induces production
efficacy. As evidenced by variations in of the tumor necrosis factor family
the studies described earlier in this cytokine B-cell activating factor (BAFF),
article, the dosing regimen differs by which is necessary for B-cell differenti-
institutional and individual practice ation and survival. A study of seven
preferences. A starting regimen com- patients with NMO spectrum disorders
monly employed is an initial dose of demonstrated an increase in BAFF
1000 mg, followed by a second dose levels after rituximab administration,
of 1000 mg 2 weeks later, a regimen with a peak at approximately 2 weeks.91
originally based on the rheumatology An association existed between the rise
literature.88 Alternatively, 375 mg/m2 in BAFF titer and increase in aquaporin-
can be given weekly for 4 weeks, a 4YIgG, with the largest increases in
regimen originally based on the aquaporin-4YIgG correlated to the larg-
hematology/oncology literature.89 est increases in BAFF. Because of this
Practice differences also exist regard- concern coupled with clinical experi-
ing maintenance therapy. The most ences, it is this authors practice to
commonly used strategies are to repeat administer the initial dose of rituximab
rituximab dosing using the same regi- 1000 mg along with 1000 mg IV meth-
men as the starting dose either at the ylprednisolone the day prior to as well
time of CD19+ B-cell reemergence (1% as the day of the infusion, followed by
or more) or at 6 months, whichever prednisone 20 mg/d until the second
comes first. For those who seem to infusion. At the second infusion, the
have early B-cell reemergence, it is this patient receives an additional 1000 mg
authors practice to switch to a single of methylprednisolone, after which the
infusion of 1000 mg every 3 months to patient returns to prednisone 20 mg/d.
avoid the constant concern that a Prednisone taper is initiated 2 weeks
relapse will occur during the period of after the second infusion. If a patient is
reemergence. At least one group follows already taking daily prednisone because
the strategy of dosing maintenance of a recent relapse or because he or
rituximab as a single dose of 375 mg/m2 she is being transitioned from an oral
when reemergence of CD27+ memory regimen, as long as the current predni-
cells is detected.86 A small study in five sone dose exceeds 20 mg, the IV
Chinese patients suggests that an even methylprednisolone is administered
lower dose of rituximab may be suffi- only on infusion days. In a patient being
cient to treat NMO spectrum disorders. retreated, the high-dose IV methylpred-
Patients were treated with rituximab nisolone (in excess of the 100 mg to
100 mg weekly (50 mg/m2 to 59 mg/m2) 250 mg typically administered to pre-
for 3 weeks, then retreated with a single vent infusion reactions) is not neces-
infusion of 100 mg when CD19+ B sarily needed if B cells have not
cells reached 1%.90 This regimen was reemerged. If B cells have begun to
sufficient to deplete B cells, and none reemerge, consideration may be given
of the five patients experienced a re- to concomitant corticosteroid adminis-
lapse during the 1-year follow-up period. tration depending on the extent of the
The cost per patient was about 20% of B-cell presence. If the B cells have
the cost of the 375 mg/m2 regimen. returned to the normal range, repeat-
Some concern exists that rituximab ing the above steroid regimen used for
administration may increase the risk treatment initiation may be considered.

KEY POINT
h To reduce infusion If B cells are only barely present, Regarding the potential for infusion
reactions, it is consideration may be given to use of a reactions, it is recommended that all
recommended that lesser corticosteroid dose, such as patients be premedicated with an
all patients with prednisone 20 mg orally until 2 weeks antihistamine and acetaminophen as
neuromyelitis optica after the second infusion followed by well as corticosteroids, the dose of
spectrum disorders taper to off. Wide variation in clinical which is dependent on the condition.
who are to be treated practice exists regarding this issue, As discussed, practice patterns for
with rituximab be and some clinicians do not administer NMO spectrum disorders vary, but it
premedicated with an any steroids to patients receiving is recommended that all patients be
antihistamine and rituximab for NMO spectrum disorders given at least 100 mg of methylpred-
acetaminophen as well
other than what is required as prophy- nisolone. Patients with NMO spectrum
as corticosteroids.
laxis against infusion reactions. disorders should theoretically be at
As with the other therapies, poten- reduced risk for severe infusion re-
tial adverse effects and monitoring actions because NMO spectrum disor-
recommendations are extrapolated ders have no tumor lysis syndrome
from data gathered from clinical trials component, although anaphylactic-
and postmarketing data obtained in type reactions may still occur. Regard-
patients with other illnesses. This is ing the potential for hepatitis B
perhaps an even more difficult issue reactivation, all patients should be
for rituximab than for the oral thera- screened prior to the first infusion. It
pies as patients exposed to rituximab is recommended that any patient with
for other illnesses are often being evidence of current or prior hepatitis
treated simultaneously with multiple B infection be evaluated by a physician
chemotherapeutic agents in addition with experience in treating infectious
to having an underlying hematologic hepatitis for discussion about whether
malignancy. The indication for rheu- antiviral treatment should be consid-
matoid arthritis includes combination ered or whether treatment with
therapy with methotrexate. Many of rituximab is contraindicated. PML is
the potential adverse effects are there- exceedingly rare with rituximab, even
fore less likely to occur in patients in patients with underlying malignan-
with NMO spectrum disorders who cies who are treated with multiple
are being treated with rituximab chemotherapies. To date, PML has
monotherapy, and, indeed, this is never been reported as a complication
what has been noted in the limited of rituximab in a patient with an NMO
small studies that have been done in spectrum disorder (or MS). It is there-
NMO spectrum disorders, in which fore this authors practice not to
serious adverse effects have been quite routinely screen for the presence of
rare. Rituximab carries a boxed warning serum JC virus antibody prior to
for the possibility of severe infusion rituximab administration as JC virus
reactions (especially during the first antibody positivity will not affect the
infusion, including fatal reactions); hep- .management decision.
atitis B reactivation, which can rarely Comparative efficacy and failure
result in fulminant hepatitis; severe rates. A retrospective study of 138
mucocutaneous reactions; and PML.92 Korean patients with NMO spectrum
It may also be associated with other disorders compared the efficacy of
unusual infections and carries a warning azathioprine (n = 49), mycophenolate
about the potential for cardiac arrhyth- (n = 34), and rituximab (n = 55).93
mias with heightened monitoring for Using a multivariate model to adjust for
any patient with a cardiac history. baseline characteristics, the investigators

KEY POINTS
noted the azathioprine group had a therapy. Because of the potential se- h Because of the potential
higher risk of relapse based on annual- verity of exacerbations, a single relapse severity of exacerbations
ized relapse rate compared to the is often enough to encourage the in neuromyelitis optica
rituximab group (hazard ratio 1.82, practitioner to attempt to change the spectrum disorders, a
P=.03). The difference between preventive strategy. In the event of a single relapse is often
mycophenolate and rituximab was not relapse, the first step is to determine enough to encourage
statistically significant for this end point. whether the patient was optimally treated the practitioner to
For severe relapse as compared to with the current preventive therapy. In attempt to change the
rituximab, the azathioprine and the case of rituximab, if the relapse preventive strategy. In
mycophenolate groups had hazard ra- occurred in the setting of B-cell the event of a relapse,
the first step is to
tios of 11.66 (P=.001) and 5.96 reemergence, the practitioner should
determine whether the
(P=.048), respectively. Significant dif- consider more frequent rituximab dos-
patient was optimally
ferences in the time to first relapse and ing with close B-cell monitoring. In the treated with the current
time to first severe relapse were also case of mycophenolate, the practitioner preventive therapy.
observed, favoring rituximab. Of should consider whether the lym-
h When the
note, no patients discontinued either phocyte count was at target (less than
disease-modifying
rituximab or mycophenolate because 1500/2L) and, if not, then consider a therapy has already
of adverse drug reactions; however, dose increase unless the maximum been optimized and
in the azathioprine group, four pa- dosage of 3 g/d has already been a relapse of
tients discontinued because of ele- reached. The length of time on therapy neuromyelitis optica
vated liver enzymes, two because of is also important to consider; if a spectrum disorder
leukopenia, one because of pancyto- relapse occurs in the first few months occurs, an alternate
penia, and one because of gastrointes- following therapy initiation, this may strategy should
tinal disturbance. An additional two not represent a true therapy failure. The be considered.
patients developed avascular necrosis same holds true for consideration of
attributed to significantly higher rates azathioprine failure, although the time
of concurrent use of prednisolone by to reach effectiveness may be a bit
patients taking azathioprine as com- longer for azathioprine. Whether or not
pared to the other therapies. the target dose of at least 2 mg/kg/d
An additional multicenter study of to 2.5 mg/kg/d was reached should
comparative efficacy found similar re- also be considered.
sults favoring rituximab.79 Patients When the therapy has already been
who were optimally treated had lower optimized and a relapse occurs, an
failure rates than those with subopti- alternate strategy should be consid-
mal treatment. However, even opti- ered. If the patient is on an oral
mally treated patients showed failure therapy, rituximab should be consid-
rates of 25% for mycophenolate and ered. Several potential strategies may
17% for rituximab (optimal treatment be considered when rituximab is
for azathioprine was not uniformly deemed to have failed for a patient
established). One study has demon- despite optimal management; however,
strated the presence of genetic poly- these are based on even less evidence
morphism in the fragment c gamma than what is available for the standard
receptor 3A as a risk factor for lack initial therapies. To date, no published
of response to rituximab in NMO spec- studies have examined potential regi-
trum disorders.94 This and other poten- mens for rituximab failure outside of
tial biomarkers to predict treatment pilot studies forming the basis for
response require further exploration. clinical trials. Some patients respond
Management of breakthrough well to the addition of low-dose corti-
disease while on disease-modifying costeroids, although this comes with a

KEY POINT
h Tonic spasms occur known set of potential adverse effects. plasmablasts and is increased in NMO
more frequently in Other combination therapies, such as spectrum disorders. SA237 is similar
neuromyelitis optica simultaneous use of rituximab and one to tocilizumab, which also demon-
spectrum disorders as of the oral immunosuppressants may strated potentially promising pilot
compared to multiple be considered, although this strategy data.99,100 Each of these agents carries
sclerosis and other will certainly be accompanied by addi- a host of potential adverse effects,
causes of transverse tional risks, and whether additional and each trial has different inclusion
myelitis, and may benefit will result is unknown. Some criteria and design rendering it ap-
be severe. patients respond to the institution of a propriate only for a select group of
regimen of monthly maintenance plas- patients. The details of these trials are
ma exchange; this strategy is currently beyond the scope of this review;
being studied in an observational man- potentially interested patients should
ner in a small cohort of subjects.95 At be referred to a center with expertise
the point these strategies are being in managing NMO spectrum disor-
deliberated, consultation with an NMO ders that participates in clinical trials.
spectrum disorder expert should be
strongly considered if this has not SYMPTOM MANAGEMENT IN
already been done. NEUROMYELITIS OPTICA
SPECTRUM DISORDERS
Consideration of Clinical Trial Many symptoms of NMO spectrum
Participation disorders overlap with symptoms of
One option to consider for all patients MS and therefore can be managed
with NMO spectrum disorders, per- similarly. Recommendations for inter-
haps in particular for those with ventions, such as physical and occu-
breakthrough disease, is clinical trial pational therapy to help improve
participation. In addition to the issues weakness, incoordination, and gait
mentioned earlier regarding the rarity disturbances, and the management of
and severity of NMO spectrum disor- spasticity and bladder and bowel is-
ders, a multitude of additional consid- sues, are relatively similar to manage-
erations have complicated the design ment of these issues in patients with
of clinical trials. The scientific commu- MS, although, as described, patients
nity has debated issues, including with NMO spectrum disorders may be
optimal study end points, the ethics more severely affected. For more
of placebo-controlled versus active information on symptom manage-
comparator trials, the use of bio- ment in MS, refer to the article
markers, and appropriate inclusion Symptom Management and Lifestyle
criteria, among others.96 Phase 3 clin- Modifications in Multiple Sclerosis by
ical trials are currently under way to Patricia K. Coyle, MD, FAAN,101 in this
study several potential molecules of issue of Continuum. However, certain
interest.97 MEDI-551 is an anti-CD19 symptoms occur with higher fre-
monoclonal antibody with a potential quency or are managed differently in
advantage over rituximab owing to NMO spectrum disorders and there-
additional depletion of plasmablasts. fore warrant particular attention.
Eculizumab is a complement inhibitor As described, tonic spasms occur
with promising pilot data98 and can more frequently in NMO spectrum
potentially be used as an add-on disorders as compared to MS and
therapy. SA237 is an anti-IL-6 receptor other causes of transverse myelitis,
monoclonal antibody; IL-6 promotes and may be severe. These generally
the survival and differentiation of respond well to carbamazepine, often

at relatively low doses. This author and characterized by specific clinical,
suggests a starting dose of 100 mg imaging, and laboratory findings. Con-
2 times a day (extended-release for- siderations for differential diagnosis
mulation), with an increase to 200 mg are driven by the patients clinical
2 times a day after 1 to 2 weeks if presentation and the presence of any
needed/tolerated. This may be further red flags regarding an NMO spectrum
increased if necessary, but 200 mg disorder diagnosis. Diagnostic criteria
2 times a day is enough to control revised in 2015 stratify patients accord-
spasms in many patients. If this fails, ing to the presence or absence of
other medications typically prescribed antiYaquaporin-4 antibodies. Treat-
for spasticity, such as baclofen or ment options for acute exacerba-
tizanidine, may be useful. tions include corticosteroids, plasma
Central neuropathic pain is also exchange, and, less commonly, IVIg.
more frequent in NMO spectrum disor- Preventive therapy is critically important
ders than MS and may be quite se- given the potential severity of relapses;
vere.102 Agents typically prescribed for unfortunately data are somewhat limited,
neuropathic pain, such as gabapentin, and currently no FDA-approved thera-
pregabalin, tricyclic antidepressants, pies exist. Retrospective comparative
and duloxetine, are successful for efficacy studies seem to favor rituximab
some patients, but many continue to over other currently available treatments.
have incapacitating pain, likely related Clinical trials investigating alternative
to mechanisms of pain that are distinct agents are currently under way.
from other conditions.11 Alternative
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Review Article

Continuum (Minneap Minn) 2016;22(3):864896.

INTRODUCTION prevention of further relapses is critical.

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FIGURE 10-1 Optic neuritis involving the optic chiasm.

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cord syndrome dominated by sensory

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FIGURE 10-4 Axial T2-weighted MRI demonstrating

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FIGURE 10-6 Coronal T2-weighted

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seen are periependymal lesions adja-

Brain MRI in Neuromyelitis

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FIGURE 10-12 Axial T2-weighted

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KEY POINTS Laboratory Testing in

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TABLE 10-2 Features Differentiating Neuromyelitis Optica Spectrum Disorder From

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has an NMO spectrum disorder. Po- Progressive course or persistent gado-

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b Clinical/Laboratory Red Flags

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Etiology Features Differential Diagnoses Paraclinical Tests

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Etiology Features Differential Diagnoses Paraclinical Tests

If the neurologic presentation is con- thritis, Sjo

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Cause Clinical Radiology Laboratory

Spinal dural Usually elderly men; Flow voids on MRI spine; T2

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Cause Clinical Radiology Laboratory

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