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State-of-the-Art Review
Section Editors: Grant T. Liu, MD
Randy H. Kardon, MD, PhD
Neuromyelitis Optica
Mark J. Morrow, MD, Dean Wingerchuk, MD, MSc, FRCP(C)
Abstract: Neuromyelitis optica (NMO) is a disabling inflammatory condition that targets astrocytes in the optic nerves
and spinal cord. Neuro-ophthalmologists must be particularly
aware of this disorder because about half of patients present
as isolated unilateral optic neuritis months or years before a
disease-defining and often crippling bout of myelitis. NMO is
easily confused with multiple sclerosis because it is characterized by relapses that lead to stepwise accrual of deficits.
The best predictor of conversion from optic neuritis to clinical
definite NMO is the presence of a serum antibody to
aquaporin-4 called NMO-IgG. However, this test is currently
only about 75% sensitive. Suspicion of NMO should be high
in patients who present with vision of light perception or
worse or who are left with acuity of 20/50 or worse after optic
neuritis and in those with simultaneous bilateral optic
neuritis or recurrent attacks. Acute NMO relapses are
generally treated with high-dose intravenous steroids, with
plasma exchange often used as a rescue therapy for those
who do not respond. Preventative strategies against relapses
currently use broad-spectrum or selective B-lymphocyte
immune suppression, but their use is based on small,
generally uncontrolled studies. Hopefully, the future will bring
more sensitive tools for defining risk and predicting outcome,
as well as more targeted and effective forms of therapy.
Journal of Neuro-Ophthalmology 2012;32:154–166
doi: 10.1097/WNO.0b013e31825662f1
© 2012 by North American Neuro-Ophthalmology Society
N
euromyelitis optica (NMO, Devic disease) is a multifocal central nervous system (CNS) demyelinating
illness in which severe inflammatory attacks on the optic
nerves and spinal cord predominate. Until recently, some
Department of Neurology (MJM), Harbor-UCLA Medical Center,
Torrance, California; and the Department of Neurology (DW), Mayo
Clinic Scottsdale.
Disclosures: Dr. M. J. Morrow has received research support from
Novartis and Biogen-Idec and has served as speaker/consultant
for Biogen-Idec, EMD Serono, Teva Neuroscience, the American
College of Physicians, and the National Multiple Sclerosis Society.
Dr. D. Wingerchuk has received research support from Alexion,
Genzyme, Genentech, and the Guthy-Jackson Charitable Foundation.
Address correspondence to Mark J. Morrow, MD, Department of
Neurology, Harbor-UCLA Medical Center, 1000 W Carson Street, Box
492, Torrance, CA 90509; E-mail: mmorrow@labiomed.org
154
considered NMO to be a variant of multiple sclerosis (MS).
The discovery of a highly specific serum autoantibody
(NMO-IgG) in 2004, however, helped prove that NMO
is a distinct pathophysiologic condition. NMO-IgG is now
known to target aquaporin-4 (AQP4), an astrocyte water
channel that is widely distributed within the CNS. This
insight has spurred a tremendous surge of interest in clinical
and scientific aspects of NMO. Its most common neuroophthalmic presentation is unilateral optic neuritis, which
often results in severe residual visual loss. No feature has yet
been shown to fully distinguish optic nerve involvement in
NMO from that in MS. Current clinical challenges include
deciding which optic neuritis patients to screen for the
NMO-IgG antibody and how to manage those with positive
results. At present, there is no reliable method to predict
poor outcome in patients at risk for developing NMO, nor
any high-level evidence-based preventative regimen.
ILLUSTRATIVE CASE
A 54-year-old Laotian woman presented with bilateral upper
and lower extremity weakness and numbness. Between ages
47 and 52 years, she experienced 4 attacks of unilateral optic
neuritis (3 in right eye and 1 in left eye). These were treated
with steroids, but recovery was limited, leaving her no light
perception in the right eye and 20/20 in the left eye with
bilateral optic atrophy. Brain MRI was unremarkable. Spinal
cord MRI showed a 3-segment T2-intense lesion from C2 to
C5. NMO-IgG antibody was positive.
Comment
One or more bouts of optic neuritis may precede a diseasedefining attack of myelitis by months or years in NMO.
PATHOGENESIS
Myelin-bearing oligodendrocytes are the primary inflammatory target in MS, but astrocytes are lost first in NMO (1).
AQP4, the predominant CNS water channel, localizes to
astrocyte foot processes at the blood–brain barrier (2). It
appears to be critical in maintaining water homeostasis in
Morrow and Wingerchuk: J Neuro-Ophthalmol 2012; 32: 154-166
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State-of-the-Art Review
settings of physiologic stress. AQP4 heterotetramers assemble
into orthogonal array particles that are probably the main
binding target of the NMO-IgG antibody. Differential
expression of these isoforms may explain greater occurrence
of NMO lesions in the optic nerve and spinal cord than
elsewhere (3). Antibodies to AQP4 may enter the CNS across
permeable portions of the blood–brain barrier, where they
would immediately encounter astrocytes and could trigger
cell-dependent cytotoxicity (4). Acute NMO lesions in
patients show loss of AQP4 (5,6), in contrast to a frequent
increase in AQP4 expression in acute MS lesions (6,7).
Demyelination may occur as a secondary event in NMO
because myelin is mainly found adjacent to AQP4-rich paranodal regions (4). NMO lesions show vasculocentric deposition of immunoglobulin and complement (5,6).
Histopathologic findings of NMO-associated optic
neuritis include infiltration with lymphocytes, macrophages,
and monocytes and venular inflammation (8,9). Long-term
sequelae include cavitation and necrosis, vascular endothelial proliferation, glial proliferation or loss, and demyelination in the optic nerve and chiasm (8–10). Loss of the
retinal nerve fiber layer (RNFL) and disappearance of retinal
ganglion cell bodies attest to retrograde degeneration after
axonal loss in the optic nerve (9). Green and Cree (11) have
reported visible retinal vascular changes in NMO eyes, including arteriolar narrowing and “frosting.” This suggests
that retinal ischemic or inflammatory damage might at
times contribute to visual loss. However, Kerrison et al
(9) did not find active retinal inflammation concurrent with
NMO-associated optic neuritis in two cases.
Putative animal models have been created by administering NMO-IgG. Passive transfer of the antibody produces
central lesions if it is injected directly into the CNS with
complement (12) or when it is infused peripherally after
first interrupting the blood–brain barrier (13–15). Although
these early models have not replicated spontaneous NMO,
they do recapitulate most of its key pathologic features and
present the opportunity to develop new therapies.
GENERAL CLINICAL CHARACTERISTICS
The case report by Devic (16) and subsequent case series by
his student Gault (17) solidified the term neuromyelitis
optica over a century ago, describing a monophasic disorder
with optic neuritis and transverse myelitis of simultaneous
onset. Many experts considered NMO to be a variant of
MS. Over the past 15 years, however, a different pattern of
NMO has emerged, along with its unequivocal distinction
as a clinical and pathophysiologic entity. Most importantly,
it was recognized that NMO follows a relapsing rather than
monophasic course in over 70% of cases (Table 1) (18,19).
NMO series from around the world have suggested
consistent demographics that largely parallel MS. Women
are much more commonly affected than men, with female
to male ratios of at least 3:1. Median age of onset is
generally in the mid 30s, with a very wide range. Earlier
reports of NMO in children focused on the classic monophasic condition, which is often preceded by a viral illness
and has a benign course (20). More recent pediatric case
series, however, chiefly describe relapsing disease with
median ages of onset of 10–14 years and strong female
predominance (21–24). In a large French cohort, 10% of
all patients with NMO were younger than 18 years (22).
The authors have personally seen cases with onset as young
as 4 years and as old as 85.
Population-based studies of NMO from the French
West Indies, Cuba, Denmark, and Japan indicate prevalence rates between 0.3 and 4.4 per 100,000 people and
annual incidence rates of 0.05–0.4 cases per 100,000
person-years (25–28). The reported proportion of definite
TABLE 1. Comparison of clinical features of MS and NMO
MS
Initial clinical course
Secondary progressive course
Brain MRI lesions
Spinal cord MRI lesions
CSF WBCs during relapses
CSF oligoclonal bands
Systemic autoimmune
disease
Severity of relapses
Recovery from relapses
Response to interferons
85% relapsing–remitting
15% primary progressive
Often
Periventricular, subcortical
(Barkhof criteria)
NMO
80%–90% relapsing–remitting
10%–20% monophasic
Rare
If seen, symmetrical hypothalamic, brainstem
1–2 segments long
,50/mm3, all mononuclear
About 85%
Occasional
Resemble MS in about 10%
.3 segments acutely (can resolve or shrink)
Often .50/mm3, polymorphonuclear component
15%–30%
Common
Usually mild to moderate
Usually fair to good
Usually helpful
Usually moderate to severe
Usually fair to poor
Can worsen disease
CSF, cerebrospinal fluid; WBCs, white blood cells.
Adapted from Wingerchuk et al (57).
Morrow and Wingerchuk: J Neuro-Ophthalmol 2012; 32: 154-166
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State-of-the-Art Review
NMO among adults and children with inflammatory demyelinating diseases (including MS) varies widely, with
a range of 1%–22% in a group of recent studies (21,28–
32). The authors’ experiences suggest a value toward the
lower end of this range for their clinic populations in the
United States. NMO appears to account for a greater proportion of CNS demyelinating disease in non-Caucasians,
including African Americans, Hispanics, Afro-Brazilians,
black Africans, Asians, and Native Americans. A high percentage of Japanese patients thought to have MS have predominant involvement of the optic nerves and spinal cord,
often termed “opticospinal MS.” A masked assessment
showed that more than half of patients with this condition
were seropositive for the NMO-IgG antibody, suggesting
NMO as the correct diagnosis (33,34). Familial NMO is
rare, accounting for no more than 3% of established cases
(35). Its existence, however, suggests that genetic factors may
play a role in disease susceptibility. Human leukocyte antigens associated with increased NMO risk include
DPB1*0501 in Asians and DRB1*0301 in Caucasians
(36,37). Analysis of AQP4 gene single-nucleotide polymorphisms did not detect variations associated with general
NMO susceptibility (38).
NMO-related disability accrues almost exclusively from
incomplete recovery of relapses. A secondary progressive
course is common in MS but rare in NMO (39). Patients
with monophasic NMO tend to have worse initial attacks
than those with relapsing disease but better long-term prognosis. Individual attacks tend to be more severe and leave
more residual deficits than in MS. In one series, half of
patients with NMO had severe visual impairment in at least
1 eye or required ambulatory aids within 5 years of onset
(40). A small group of patients with NMO have a more
favorable course (41). Relapsing NMO tends to progress
more slowly in children than in adults, with lower annualized relapse rates (22). Higher initial rates of relapse with
more severe residua predict early death (42).
Key features help to differentiate relapsing NMO and
MS and are similar in adults and children. Roughly half of
patients present with isolated optic neuritis; approximately
20% of these attacks are bilateral (18,22–24,43–45). The
remaining half usually present as isolated myelitis with
numbness, tingling, or weakness of the arms, legs, or trunk
that develops over hours to days. Myelitis is often associated
with bowel or bladder dysfunction. In about 10% of
patients with NMO, concurrent optic nerve and spinal cord
involvement characterizes the initial attack. During acute
attacks of MS, cerebrospinal fluid (CSF) typically contains
fewer than 50 white blood cells per cubic millimeter, mostly
lymphocytes. In contrast, NMO attacks often produce dramatic CSF pleocytosis with significant numbers of neutrophils or eosinophils. Oligoclonal bands are found in the
CSF of about 85% of MS patients but 30% or fewer of
those with NMO (46). Although many patients with NMO
have brain MRI abnormalities, these are usually mild and
nonspecific (47). Up to 10% of antibody-positive, clinically
definite patients with NMO have MRI abnormalities consistent with MS (Fig. 1A). Others have lesions in unique
locations like the hypothalamus and caudal medulla (see
below). Spinal cord MRI features of MS and NMO often
differ significantly. Acute MS-associated cord lesions are
usually one vertebral segment long, but NMO lesions are
FIG. 1. MRI in an NMO-IgG–positive 32-year-old woman. NMO presented as simultaneous bilateral visual loss and myelopathy at age 4, with recurrence at age 7 that left the patient totally blind bilaterally with severe myelopathy. A. Axial FLAIR
MRI of the brain reveals periventricular lesions resembling MS. B. Sagittal short T1-inversion recovery (STIR) MRI shows
longitudinally extensive signal change along the length of the cervical cord (between the arrows). MS, multiple sclerosis;
NMO, neuromyelitis optica.
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Morrow and Wingerchuk: J Neuro-Ophthalmol 2012; 32: 154-166
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State-of-the-Art Review
typically 3 or more segments long (Fig. 1B). Acute NMO
lesions tend to be centrally located within the cord, cause
cord expansion, and enhance with gadolinium. Nonacute
spinal cord MRI can be misleading because elongated
NMO lesions can shrink into smaller spots that are typical
of MS (Fig. 2).
The first report of the NMO-IgG antibody, using an
indirect immunofluoresence assay, found it to be 73%
sensitive and 91% specific for distinguishing clinically
defined NMO from MS (33). These data have been confirmed in widespread patient populations, although antibody positivity has ranged as low as 50% depending on
the specific test used. An enzyme-linked immunosorbent
assay is now commercially available. The highest sensitivities, about 75%, are attained with assays that detect IgG
binding to cells expressing recombinant AQP4 (48). CSF
AQP4 antibodies have been detected in some seronegative
patients (49). Widely accepted clinical and laboratory criteria were developed for NMO in 1999 (18) and then
updated in 2006 with incorporation of antibody status
(Table 2) (50).
The discovery of the pathogenic antibody has allowed for
recognition of a wider array of clinical and radiologic
characteristics associated with NMO. Certain brain MRI
lesions that would be atypical for MS have proven to be
common in NMO. These aggregate in regions with a high
density of AQP4 and include caudal medullary lesions
that present with hiccups and nausea and diencephalic
lesions that cause somnolence and endocrine disturbances
(Figs. 2, 3) (51–53). Large cerebral white matter lesions
suggesting tumefactive MS (54) or posterior reversible
encephalopathy syndrome (55) (PRES) may also occur in
NMO (Fig. 4). Patients with features of NMO often have
serologic or clinical evidence of systemic lupus erythematosus, Sjogren syndrome, or other autoimmune conditions
(56). Because these patients are commonly seropositive for
NMO-IgG, it is likely that their systemic autoimmune condition is coincidental rather than causative.
Patients with isolated optic neuritis or myelitis and
a positive NMO-IgG antibody are currently described as
having “NMO spectrum disorder” (57). This at-risk state
might be considered comparable to clinically isolated syndrome in patients who have had a single episode consistent
with demyelination and brain MRI abnormalities suggestive of
MS. In one study of patients presenting with transverse myelitis, 55% of those who were seropositive developed recurrent
myelitis or NMO-defining optic neuritis within a year (58).
No seronegative patient had such an event. Given the high
risk for future attacks with serious residua, detection of NMOIgG may allow for early initiation of preventative therapy.
NEURO-OPHTHALMIC CONSEQUENCES
OF NMO
Optic neuritis is a required element for clinically definite
NMO according to widely accepted criteria (Table 2) (50).
It is the initial clinical manifestation in about half of
patients (18,43–45). Reported lags between initial optic
neuritis and a disease-defining attack of myelitis averaged
about 2 years in 5 large series of patients, with ranges from
a few months to decades (18,19,45,59,60). Recurrent
attacks of optic neuritis may occur before or after myelitis
and lead to a stepwise loss in visual function. Table 3 summarizes visual outcomes in several large NMO series. The
Optic Neuritis Treatment Trial (ONTT) provides comparative data in a cohort in whom over half were eventually
diagnosed with MS (61). Current NMO criteria were not in
place during the ONTT, and it is not known how many
patients actually converted to NMO rather than MS; only 1
patient was known to have NMO with certainty (62,63).
TABLE 2. Diagnostic criteria for NMO
FIG. 2. T2 sagittal MRI demonstrates NMO-typical caudal
medullary lesion (upper arrow) along rostral continuation of
central spinal canal. Such lesions may cause nausea,
vomiting, hiccups, lower cranial nerve palsies, and nystagmus. Lower arrows show residua of cord lesions at C4–C5
and T5, now less than 3 segments in length. NMO, neuromyelitis optica.
Morrow and Wingerchuk: J Neuro-Ophthalmol 2012; 32: 154-166
Required (at least 1 attack of each of the following)
Optic neuritis
Transverse myelitis
Supportive (at least 2 of the following 3)
Brain MRI: normal or lesions not meeting criteria for MS
Spinal cord MRI: lesion extending continuously over 3 or
more vertebral segments
NMO-IgG seropositivity
NMO, neuromyelitis optica.
Adapted from Wingerchuk et al (50).
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State-of-the-Art Review
FIG. 3. Axial brain MRI shows symmetric hypothalamic lesion typical of NMO surrounding the inferior aspect of third ventricle
(arrows). A. FLAIR image. B. Gadolinium-enhanced T1 image. Lesions in this location can cause somnolence, polyphagia,
and endocrinopathy. NMO, neuromyelitis optica.
Entry demographics for the ONTT were similar to most
current NMO and MS series, with a 3:1 female predominance and mean age of 32 years.
Differences between NMO and the ONTT populations
can be appreciated in the prevalence of severe visual loss.
In the ONTT, 36% of eyes showed nadir visual acuity of
20/200 or worse and 7% of eyes were light perception or no
light perception (61,64). In contrast, NMO eyes are initially
20/200 or worse in up to 80% of optic neuritis cases and no
light perception in over 30% (18,44,60,65). Long-term outcome discrepancies are even more striking. In patients with
NMO for at least 5 years, about half have vision of 20/200
FIG. 4. Coronal FLAIR image reveals a chronic cavitary left
temporal lesion in a patient with NMO spectrum disorder
(arrow). Such lesions often appear tumefactive acutely, with
ring enhancement, edema, and mass effect similar to MS.
MS, multiple sclerosis; NMO, neuromyelitis optica.
158
or worse in at least 1 eye and about 20% have this level of
impairment in both eyes (18,44,45,59). About 30% of
patients are left with visual acuity of #20/200 after their first
bout of optic neuritis (44,45). In contrast to NMO, 15-year
follow-up in the ONTT yielded only about 4% of patients
with acuity of 20/200 or less in one eye and fewer than 2%
with this level of loss in both eyes (66). Median acuity was
20/20 after 15 years in the ONTT (66), compared to means
of 20/32 to 20/50 at about 10 years in NMO (45,59).
Other than visual acuity, most series have not included
information on initial characteristics that might help to
distinguish optic neuritis in NMO from MS. In the
ONTT, eye pain and optic disk edema were reported in
92% and 35% of patients, respectively (61). Two retrospective series of NMO-associated optic neuritis reported initial
eye pain in 27% (44) and 67% (67). Another series noted
optic disk edema (papillitis) in 5% of cases of optic neuritis
associated with NMO but only 10% of cases associated
with MS, a much lower value than the ONTT (59). In
patients with NMO, asymptomatic disk edema can occur
when the fellow eye shows symptomatic papillitis (68).
Visual field analysis reveals localized peripheral defects more
frequently in optic neuritis associated with NMO than with
MS, but there is considerable overlap (69). Both conditions
cause predominantly central impairment (69,70).
Simultaneous bilateral optic neuritis was thought to be
sufficiently atypical that it was an exclusion criterion for the
ONTT. In a series of 472 MS patients reviewed by Burman
et al (71), only 0.4% presented with bilateral optic neuritis
as their first neurologic attack compared to 20% presenting
with unilateral optic neuritis. Simultaneous bilateral optic
neuritis occurred at some point in the course of only 2% of
their MS cohort and comprised 4% of all optic neuritis
attacks. In contrast, acute, isolated, bilateral optic neuritis
Morrow and Wingerchuk: J Neuro-Ophthalmol 2012; 32: 154-166
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Morrow and Wingerchuk: J Neuro-Ophthalmol 2012; 32: 154-166
TABLE 3. Synopsis of 8 large series of visual outcome in NMO compared with Optic Neuritis Treatment Trial final data
Simultaneous Isolated ON as
Presenting
Bilateral ON as
Problem
Initial Visual
Event, % (Uni- or Bilateral)
Year
Subjects
(n)
O’Riordan (19)
1996
12
5
35
92
83
83
42
N/A
Wingerchuk (18)
1999
71
10.6
36
72
68
11
52
37% NLP
de Seze (65)
2002
13
8.6
37
77
100
85
15
58% #20/200
Ghezzi (43)
Merle (59)
2004
2007
46
30
8.8
9.6
40
30
80
93
100
100
20
13
57
77
N/A
N/A
Rivera (60)
2008
24
5.8
36
71
68
3
23
80% #20/200
Papais-Alvarenga (44)
2008
60
8
N/A
90
100
18
53
78% #20/200
Collongues (45)
2010
125
10
35
75
73
N/A
37
N/A
Optic Neuritis Study
Group (66)
2008
294
.15
32
77
50
N/A
100
36% #20/200
Mean/Median Female,
Age Onset, y
%
Relapsing
Course, %
VA at Peak in
Affected Eye
VA at Follow-up
83% #CF
at least 1 eye
48% #20/200
at least 1 eye
54% #20/200
at least 1 eye
N/A
70% #20/200
at least 1 eye
91% #20/200
at least 1 eye
63% #20/200;
23% NLP,
at least 1 eye
45% #20/200
at least 1 eye
3% #20/200
at least 1 eye
Four NMO trials were selective for relapsing disease only, whereas others included patients with monophasic illness.
CF, count fingers; N/A, not applicable; NLP, no light perception; NMO, neuromyelitis optica; ON, optic neuritis; VA, visual acuity.
159
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State-of-the-Art Review
First Author
Mean Disease
Duration, Last
Examination, y
State-of-the-Art Review
was the initial presentation of NMO in 11%–20% of
patients in several larger series (18,27,44,59). Concurrent
bilateral attacks account for about 20% of all NMO-related
optic neuritis in relapsing cases and are even more common
in monophasic disease. Recurrent optic neuritis may be
another harbinger of NMO. Pirko et al (72) reported 72
patients with recurrent optic neuritis occurring before any
other neurologic manifestations. Of these, 8 (11%) converted
to NMO, 20 (28%) converted to MS, and 44 (61%) did not
develop signs of either condition over a mean follow-up of
approximately 9 years. Patients who developed NMO
showed a higher female to male ratio and more frequent
and severe attacks of optic neuritis than those who converted
to MS or to neither condition. Recurrent optic neuritis that is
destined to become definite NMO seems distinct from the
condition described as chronic relapsing inflammatory optic
neuropathy (CRION) by Kidd et al (73). Similarities between NMO and CRION include severe recurrent visual
loss and predominance in young women. In CRION, both
eyes are usually involved within 1 month of onset and demonstrate optic disk edema. In contrast to NMO, patients
with CRION appear exquisitely sensitive to steroids, improving rapidly with treatment and relapsing within weeks after
steroids are tapered. One report showed positive NMO-IgG
antibodies in only 1/19 CRION patients (74).
NMO may involve the optic chiasm and tracts, giving
rise to bitemporal or homonymous hemianopic visual field
defects (75–77). Chiasmal and tract involvement may be
seen on MRI (18,78) and has been identified pathologically
(8,10,52,67). Atypical cerebral white matter lesions, such as
those of PRES, may cause retrogeniculate visual loss (55).
Eye movements may also be affected in NMO, usually in
association with brainstem lesions. Reported abnormalities
include upbeating, downbeating, or mixed horizontaltorsional nystagmus (78); wall-eyed bilateral internuclear
ophthalmoplegia (79); and opsoclonus (78). Diplopia is
one of the most common brainstem symptoms of NMO
(80). Oscillopsia has been described without identifiably
abnormal eye movements (81).
ANCILLARY TESTING
In patients presenting with a single attack of optic neuritis
and no neurologic history, the prevalence of NMO-IgG
positivity has been reported to be 3%–5% (74,82), rising
into the 10%–20% range in patients with recurrent attacks
(82,83). Two reports examined antibody status in patients
presenting with optic neuritis, most recurrent, with followup averaging over 2 years (82,83). A subsequent attack of
myelitis consistent with NMO occurred in 10 of 20 (50%)
of those with positive antibodies but only in 1 of 82 seronegative patients (1%). Even after a decade, however, not all
seropositive patients with recurrent optic neuritis will have
suffered myelitis (84).
160
Which optic neuritis patients should be tested for NMOIgG? (85,86). In support of widespread screening is the
observation that attacks of NMO are particularly disabling.
Relapse rates are about twice those of MS, and disability
thresholds are reached much faster (45,87). Against widespread screening is the relative infrequency of NMO in
patients presenting with uncomplicated optic neuritis, the
cost of the test, and uncertainty regarding the best course of
therapy in at-risk individuals. Most would recommend
antibody testing in those with bilateral visual symptoms,
recurrent optic neuritis, poor visual outcomes, or concurrent autoimmune disease, assuming that they lack typical
changes of MS on MRI (Table 4). Because at least 25% of
patients with clinically defined NMO are seronegative, one
should maintain a high index of suspicion and consider
long-term immunosuppression in patients with recurrent
severe bouts of unexplained optic neuropathy (88). Retesting seronegative NMO suspects is worthwhile, especially
during a recurrent attack when antibody levels typically rise.
Immunosuppression or recent plasma exchange may reduce
NMO-IgG levels, yielding a false-negative result. A recent
report suggests that elevation of serum glial fibrillary acidic
protein, an astrocyte component, may distinguish isolated
optic neuritis in NMO from MS (89).
Anatomic and physiologic testing shows both symptomatic and subclinical deficits in eyes of patients with
NMO. Compared to MS, eyes with NMO-associated optic
neuritis show more severe RNFL loss on optical coherence
tomography. Average thickness reductions are 30–40 mm in
NMO versus 10–20 mm in MS (Fig. 5, Table 5) (11,90–
93). Ratchford et al (91) estimated that a first attack of
TABLE 4. Suggested criteria for testing NMO-IgG in
isolated optic neuritis
Clinical
Visual acuity at nadir of LP or NLP
Visual acuity after recovery of 20/50 or worse
Symptomatic bilateral visual loss
Recurrent optic neuritis
Mild symptoms or findings of myelopathy
Systemic autoimmune disease
Ancillary
Brain MRI not consistent with MS
Mean OCT-RNFL thickness of ,70 mm
Severe, bilateral, or recurrent visual loss are more common in
NMO than in MS. Subtle evidence of spinal cord dysfunction may be
present in patients without clear history of myelitis. Many patients
with NMO have concurrent systemic autoimmune disease. These
clinical findings should raise suspicion, especially when they are
not accompanied by brain MRI changes typical of MS. OCT measures of mean RNFL thickness could also be used to discriminate
between MS and NMO; a final value of ,70 microns measured 3
or more months after onset is uncommon in idiopathic or MSassociated optic neuritis.
LP, light perception; MS, multiple sclerosis; NLP, no light perception; NMO, neuromyelitis optica; OCT, optical coherence
tomography; RNFL, retinal nerve fiber layer.
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FIG. 5. Peripapillary RNFL thickness plots from spectral-domain OCT in a 63-year-old woman with 17-year history of NMO and
at least 4 episodes of optic neuritis. Visual acuity was 20/70, right eye, and NLP, left eye. A and C. Graphs of patient’s data
(dark black trace) over 360° circumference. B and D. Mean data in each sector. A and B. Right eye. C and D. Left eye. Both
eyes show severe diffuse loss, with mean values of 53 mm, right eye, and 37 mm, left eye. All quadrants are thinned at
P , 0.01 (red sectors) or P , 0.05 (yellow) level compared with normal. In contrast, MS eyes usually show mean RNFL
thickness of 70 mm or more, and thinning often involves only the temporal quadrant. G, global (overall) mean; I, inferior; MS,
multiple sclerosis; N, nasal; NLP, no light perception; NMO, neuromyelitis optica; N:T, nasal to temporal ratio; OCT, optical
coherence tomography; PMB, papillomacular bundle; S, superior; T, temporal.
NMO-associated optic neuritis reduces mean RNFL thickness by 31 mm, with each subsequent attack subtracting
another 10 mm. RNFL thinning is more evenly distributed
around the peripapillary circumference in NMO than in
MS, where it often selectively involves the temporal quadrant (11,90,92–94). Syc et al (95) identified thinning of the
inner plexiform-ganglion cell layer complex in the maculas
of NMO eyes compared with controls, even in those without a history of optic neuritis. Subclinical RNFL loss has
been observed in NMO eyes by some authors (90), but not
others (91,95). Bouyon et al (96) reported progressive
RNFL thinning in patients with NMO without an interval
history of optic neuritis, suggesting a noninflammatory
component of axonal loss as seen in MS (97). RNFL thickness has been correlated with high- and low-contrast visual
acuity, contrast sensitivity, visual fields, and overall disability (Expanded Disability Status Scale [EDSS] score) in
NMO, as it has in MS (11,90,91,94). Some have found
that RNFL thickness is lower in NMO than in MS, even
after adjusting for poorer visual acuity in the former
(11,92). However, the “break point” of mean RNFL thickness below which visual loss occurs is similar in NMO (93)
and MS (98) at about 70 mm.
Visual evoked potentials (VEP) are typically absent or
delayed in NMO eyes that have suffered optic neuritis,
although they occasionally may show reduced amplitude
alone (19,59,99). Subclinical abnormalities may also be
seen. In a group of patients with myelitis and positive
NMO-IgG antibodies but no history of optic neuritis,
4 of 8 had abnormal VEP (100). Conventional MRI shows
typical changes of acute optic neuritis with NMO, including optic nerve enlargement, increased T2 signal, and
enhancement (Fig. 6) (101). These changes are often more
extensive than in MS, frequently bilateral and involving the
TABLE 5. Summary of OCT comparison studies
First Author
Year
Mean RNFL
Controls, mm
Mean RNFL
MS-ON eyes, mm
Mean RNFL
NMO-ON eyes, mm
Differences in Quadrant
Values, NMO vs MS
Merle (90)
Ratchford (91)
Naismith (92)
Green (11)
Nakamura (93)
2008
2009
2009
2009
2010
106
102
N/A
N/A
N/A
84
88
77
82
84
65
64
55
59
64
Ytemporal and inferior
N/A
Ysuperior, inferior, and nasal
N/A; Yall quadrants vs normal
Ysuperior and inferior
Mean RNFL thickness in normal controls vs eyes with history of optic neuritis in MS and NMO. Right column summarizes comparisons
between mean data in 4 testing quadrants in NMO and MS eyes. Values are about 20 mm lower in NMO eyes than in MS, consistently less
than 70 mm. Values in individual quadrants, especially inferior, are often lower in NMO than in MS. MS affects the temporal quadrant
predominantly.
N/A, not applicable; NMO, neuromyelitis optica; OCT, optical coherence tomography; RNFL, retinal nerve fiber layer.
Morrow and Wingerchuk: J Neuro-Ophthalmol 2012; 32: 154-166
161
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State-of-the-Art Review
FIG. 6. Contrast-enhanced T1 coronal MRI in NMO patient
with acute bilateral optic neuritis shows enhancement of the
intracranial optic nerves (arrows). NMO, neuromyelitis optica.
optic chiasm and tracts (102). Spinal MRI occasionally
shows small cord lesions in NMO-IgG–positive patients
with isolated optic nerve disease (100).
Of these, azathioprine (109,110), mycophenolate (111),
and rituximab (112,113) are probably the most commonly
used for long-term prophylaxis. Azathioprine and mycophenolate are oral drugs that are generally well tolerated but not
fully effective for 4–6 months. With these, adding a "bridge
therapy" that has more rapid onset is advisable; oral prednisone is usually used and can be tapered when full effect of
the long-term drug is expected. Rituximab is a monoclonal
antibody that targets CD20, destroying B lymphocytes but
not plasma cells. Its advantages include rapid onset of action
(full activity within 2 weeks) and infrequent dosing (2 infusions approximately every 6 months). In the absence of
comparative controlled trials, it remains unclear which treatment is superior. It is likely that no single drug is the best
for every patient with NMO.
Improved understanding of NMO pathophysiology is
facilitating development of new therapies. Eculizumab,
a monoclonal antibody that targets the terminal component
of complement, is being evaluated for relapse prevention
(114). Strategies aimed at blocking the binding of NMOIgG to AQP4 are also being exploited. Aquaporumab is
a highly selective, nonpathogenic, AQP4-binding antibody
that prevents cytotoxicity in animal models and cell cultures
(115). A variety of small molecules have also been identified
as potential binding inhibitors (116). For example, sivelestat
inhibits neutrophil elastase and reduces lesions in an animal
model resembling NMO (117).
FUTURE DIRECTIONS
Treatment
Acute and disease-modifying treatment for NMO is limited
by an absence of randomized controlled trials (103). Corticosteroids, typically intravenous methylprednisolone 1 g daily
for 5 consecutive days, represent first-line therapy for NMO
attacks. Nakamura et al (93) suggested a neuroprotective
effect of high-dose steroids when they are given within the
first 2–3 days after onset of NMO-associated optic neuritis,
but not later. Many severe NMO attacks respond inadequately to corticosteroid treatment. Plasma exchange
improves clinical outcomes for steroid-unresponsive relapses,
including optic neuritis (104,105). Intravenous immune
globulin is sometimes tried for acute NMO attacks, but
efficacy data are limited.
Relapse prevention is the key to preserving neurologic
function in NMO. Some patients with NMO have been
diagnosed with MS initially and treated with immunomodulatory drugs such as beta interferon. However, interferons
and other MS therapies like natalizumab and fingolimod
may actually aggravate NMO (106–108). The most appropriate treatment approach in NMO is immunosuppression
that is effective against antibody-mediated diseases. Current
options include azathioprine, mycophenolate mofetil,
rituximab, mitoxantrone, cyclophosphamide, methotrexate,
intravenous immunoglobulin, and prednisone (103).
162
An essential first step in reducing the consequences of NMO
is early recognition of at-risk patients. This requires careful
assessment of those with optic neuritis or myelitis and
judicious testing for the NMO-IgG antibody. Many patients
who go on to have definite NMO are persistently seronegative; new methods will have to be found to detect the
disorder and, better yet, to predict its outcome. Along with
such biomarkers must come information about the best
course of preventative therapy. Current strategies of broadspectrum or selective B cell immunosuppression carry
significant long-term risk. There is no high-level evidencebased guidance on how aggressively to start treatment, how
long to continue after the last clinical relapse, or which drugs
provide the best combination of efficacy and long-term
safety. A better understanding of the mechanisms by which
NMO causes CNS injury will hasten development of novel
targeted therapies.
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