Accepted Manuscript

Critical Review: Typical and Atypical Optic Neuritis

Anne Abel, MD, Collin McClelland, MD, Michael S. Lee

PII: S0039-6257(19)30041-4
DOI: https://doi.org/10.1016/j.survophthal.2019.06.001
Reference: SOP 6881

To appear in: Survey of Ophthalmology

Received Date: 5 February 2019

Revised Date: 22 May 2019
Accepted Date: 7 June 2019

Please cite this article as: Abel A, McClelland C, Lee MS, Critical Review: Typical and Atypical Optic
Neuritis, Survey of Ophthalmology (2019), doi: https://doi.org/10.1016/j.survophthal.2019.06.001.

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 ACCEPTED MANUSCRIPT

Critical Review: Typical and Atypical Optic Neuritis

Anne Abel, MD1,2, Collin McClelland, MD2, Michael S Lee2,3,4

1. Department of Ophthalmology, Hennepin Healthcare, Minneapolis, MN

2. Department of Ophthalmology and Visual Neurosciences, University of Minnesota
Minneapolis, MN

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3. Department of Neurology, University of Minnesota, Minneapolis, MN
4. Department of Neurosurgery, University of Minnesota, Minneapolis, MN

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Abstract

Typical optic neuritis is an idiopathic demyelinating condition that is often associated with
multiple sclerosis. This has been well characterized and has an excellent prognosis. Atypical
optic neuritis can result from an inflammatory, infectious, or autoimmune disorder.
Differentiating the two types of optic neuritis is paramount and may be challenging early on in

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the clinical course. This review describes the recent literature describing the pathophysiology,
clinical presentation, neuroimaging, and management of these disorders.

Key Words

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Optic neuritis, multiple sclerosis, neuromyelitis optica, myelin oligodendrocyte glycoprotein
antibody, inflammatory optic neuritis, infectious optic neuritis, optic perineuritis

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Method of Literature Search
A MEDLINE search was conducted for “optic neuritis”, “neuromyelitis optica spectrum
disorder”, “myelin oligodendrocyte glycoprotein antibody”, “inflammatory optic neuritis”,

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“infectious optic neuritis”, “optic perineuritis”, “MRI”, “OCT”, and “visual evoked potential”. A
few select articles were included for historical perspective, however, the review is based mainly
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on the peer-reviewed literature published in the past ten years. Emphasis was placed on the
ophthalmology literature, but selections from the neurology literature were also included.
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I. Introduction

Optic neuritis is an inflammatory optic neuropathy affecting one or both optic nerves.
Typical, or demyelinating, optic neuritis may be associated with multiple sclerosis (MS) and
is the most common type of optic neuritis. It is usually unilateral and typically affects young
Caucasian women who present with vision loss, dyschromatopsia, and painful eye

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movements. Fundus exam is often normal. Visual acuity and visual field usually recover
within a few months. Intravenous corticosteroids hasten visual recovery, but long-term
visual outcomes are favorable even without treatment (5, 23). The presence of brain
lesions consistent with demyelination on magnetic resonance imaging (MRI) increases the

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risk of developing MS (24).

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Atypical optic neuritis is essentially optic neuritis from any other cause. Atypical features
include male gender, age less than 18 or greater than 50, absence of periocular pain, and
bilaterality. No light perception vision, vision loss that progresses past two weeks, and
vision that does not improve (either with steroids or spontaneously) are also atypical

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features. On exam, uveitis, severe disc swelling, peripapillary hemorrhages and macular
exudates suggest atypical optic neuritis (24). Atypical radiographic features include
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extensive optic nerve enhancement, sheath predominant enhancement, and enhancement
of the optic chiasm or optic tract (Table 1).
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In recent years, the discovery of new autoantibodies has transformed how we diagnose and
treat inflammatory central nervous system (CNS) disease, including optic neuritis. Our
understanding of neuromyelitis optica spectrum disorder (NMOSD) and anti-myelin
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oligodendrocyte glycoprotein (anti-MOG) associated optic neuritis is quickly evolving.

Familiarity with the clinical presentation and radiographic features of these diseases will
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hopefully prompt serum autoantibody screening early in the disease course and allow us to
tailor treatment paradigms to improve outcomes.

As our understanding of optic neuritis evolves, so too, does the standard of care. Advances
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in neuroimaging techniques and the discovery of new serum autoantibodies have

transformed how we diagnose and classify optic neuritis variants. This review will discuss
the differentiating features of typical and atypical optic neuritis with an emphasis on
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demyelinating disease. We will discuss recent advances in ancillary testing, diagnostic

imaging, and treatment paradigms relevant to ophthalmologists. Pediatric optic neuritis
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will not be covered.

II. Typical, Demyelinating Optic Neuritis

Presentation and Diagnosis

Typical optic neuritis is a unilateral, acute, demyelinating optic neuropathy. The diagnosis is
clinical, but MRI and lumbar puncture can help to confirm the diagnosis and stratify the risk
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of developing MS. Patients classically present with acute unilateral vision loss associated
with painful eye movements and color desaturation. Presenting visual acuity spans the
range of the Snellen chart, but patients invariably have visual field loss (97.5%),
dyschromatopsia (93.8%), decreased contrast sensitivity (98%) and an afferent pupillary
defect.(23) The majority of patients start to recover vision within the first month, even
without treatment.(7)

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The Optic Neuritis Treatment Trial (ONTT) was a prospective, multicenter, randomized
controlled trial that enrolled patients with optic neuritis from 1988-1991. The ONTT
followed patients for 15 years to assess the efficacy of corticosteroid treatment on visual

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outcomes. This large study enrolled 457 patients and remains the foundation of our
understanding of demyelinating optic neuritis. The majority of patients were young

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Caucasian women (average age 32). Most patients present with pain (92%), and an
overwhelming majority (87%) of these patients’ pain was either triggered or worsened by
eye movements, making this a critical historical element. Pain with eye movements often
preceded the onset of vision loss (40%) (23). The majority of patients presented with

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retrobulbar optic neuritis, while only 35% of patients had papillitis. If disc edema were
present, it was typically mild and without associated hemorrhages or exudates (23).
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MS Risk Profile
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Approximately half of patients with optic neuritis will go on to develop MS (6). Since the
ONTT, MRI has been used to stratify the risk of MS following an episode of optic neuritis.
MS is a demyelinating CNS autoimmune disease that typically follows a relapsing-remitting
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course, but can also be progressive. In relapsing-remitting MS, between demyelinating

“attacks” (defined as monophasic episodes of monofocal or multifocal subjective and
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objective neurologic dysfunction) there is no progression of disease. A patient’s first

“attack” is called a clinically isolated syndrome (CIS). MS diagnosis requires dissemination
of these attacks in both space and time with either objective clinical or radiographic
evidence. Demyelinating optic neuritis is a common CIS, hence ophthalmologists must be
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familiar with its implications for MS diagnosis.

During an acute optic neuritis attack, fat-suppressed orbital MRI will show gadolinium
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enhancement and/or T2-weighted abnormalities and of the optic nerve. While optic
neuritis is a clinical diagnosis, neuroimaging is critical to assess for demyelinating brain
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lesions suggestive of MS. In the ONTT, brain MRI was consistent with demyelinating disease
in nearly 50% of optic neuritis patients.(23) After 15 years, 72% of patients with at least 1
brain lesion on their initial MRI were diagnosed with MS, while only 25% of patients with no
brain lesions on initial MRI developed MS. (24)

The McDonald criteria for MS diagnosis were first published in 2001. These criteria are
applied to patients presenting with a typical CIS (i.e. optic neuritis) to diagnose MS.
Recently revised in 2017, these criteria aim to improve the sensitivity and specificity of MS
diagnosis, facilitating earlier diagnosis and treatment. (74) Inevitably, patients diagnosed
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with optic neuritis will want to know if they 1) already have MS, and 2) if they do not have
MS now, what is their risk of developing MS in the future? A basic understanding of the
McDonald criteria allows the ophthalmologist to start this conversation while their patients
await neurologic consultation.

The McDonald criteria outline the clinical, radiographic, and laboratory evidence required to

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prove that demyelinating disease is disseminated in space (DIS) and disseminated in time
(DIT). Essentially, a patient must have clinical evidence of at least two neurologic attacks
with corresponding brain lesions to diagnose MS. If there is only clinical evidence for one
attack, then a combination of clinically silent MRI lesions in at least two of the four

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following areas: periventricular, cortical/juxtacortical, infratentorial, and spinal cord, and/or
the presence of CSF oligoclonal bands can fulfill the diagnostic criteria.(74) The optic nerve

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is not considered a typical lesion location for MS. While it has been suggested that MRI
optic nerve enhancement should qualify as radiographic evidence for DIS (19, 20, 22), the
2017 McDonald criteria rejected this idea. Therefore, according to the McDonald criteria, a
patient with typical optic neuritis and a normal brain MRI does not have MS. A patient with

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typical optic neuritis and one typical MS lesion on MRI also does not meet the McDonald
criteria for MS. Additionally, with an asymptomatic optic nerve lesion and a second
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enhancing brain lesion causing a CIS, the optic nerve lesion does not support the DIS
criterion, and the patient does not have MS at that point. Referral to a neurologist or
neuro-ophthalmologist at this juncture will help stratify the risk of MS and treatment
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options.

Imaging
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Characteristic MS lesions are T2 hyperintense, typically ovoid and at least 3 mm long

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located in the periventricular, infratentorial, and spinal cord white matter. The latest
imaging techniques allow for detection of cortical and juxtacortical lesions, which are more
difficult to distinguish with standard MRI. Acute lesions enhance with gadolinium, while
older lesions do not, allowing radiographic DIT. (19, 74) In optic neuritis, the nerve will
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enhance, while the sheath does not. Retrobulbar optic neuritis with optic nerve
enhancement in the anterior orbit is most common.
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Treatment
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The ONTT had three arms: intravenous methylprednisolone (250mg q6 hours x 3 days
followed by prednisone 1mg/kg/day x 11 days), 2) oral prednisone (1mg/kg/day x 14 days),
and 3) oral placebo x 14 days. Oral prednisone was not superior to placebo and was
associated with increased risk of recurrent optic neuritis. IV methylprednisolone (MP)
treatment resulted in more rapid visual recovery after 30 days, but this benefit was no
longer significant after 6 months.(5) Subsequent smaller studies have found similar results:
faster recovery after IV steroids, but no significant difference in long term visual
outcomes.(32) The most recent Cochrane Review in 2015 concluded that there is still no
conclusive evidence that IV steroids improve visual outcomes after 6 months.(21)
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Therefore, the physician and patient must decide together if the more rapid visual recovery
warrants the risk of steroid treatment if the long-term visual status does not change.
Important risk stratifying factors to consider include medical co-morbidities, occupation,
caregiving status, and the status of vision in the unaffected eye.

Many neurologists and ophthalmologists do not follow IV steroid treatment with an oral

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taper because it has not been shown to affect short or long term outcomes. (60)
Additionally, the majority of neurologists and ophthalmologists have simplified the IV
methylprednisolone treatment to 1000mg IV daily for 3 days, rather than the every 6 hour
dosing that was used in the ONTT.

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While treating optic neuritis with low-dose prednisone (1mg/kg/day) is ill-advised because it

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was not effective and increased recurrence rate, the use of high-dose oral MP and high dose
prednisone in MS has inspired investigations into the use of high-dose oral corticosteroids
for optic neuritis treatment.(5) Studies have shown that >500mg daily oral corticosteroids
are bioequivalent to IV MP and have similar clinical and radiographic effects on MS flares

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(42, 48, 55). A recent controlled trial randomized 55 optic neuritis patients to receive three
days of IV MP 1000mg daily or prednisone 1250mg daily. There was no significant
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difference in best corrected visual acuity (BCVA) or visual evoked potential (VEP) P100
latency recovery between the corticosteroid groups.(49) Long-term follow up for these
patients is not yet available, so we do not yet know if there is a significant difference in
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recurrence rate for those treated with high-dose oral prednisone compared to high-dose IV
MP.
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Oral MP is often used to treat MS relapses and has been shown in a multicenter, double-
blind, randomized controlled trial that oral MP was not inferior to IV treatment for MS
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flares. (36) Oral and IV MP have not yet been studied in a prospective, randomized trial for
optic neuritis patients. A randomized controlled trial of 60 patients given 500mg oral MP
versus placebo did not find a benefit to oral MP treatment after 3 weeks.(67) It may be that
oral MP is ineffective or that this dose is too low. A recent retrospective study of 56
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patients treated with either oral or IV MP found no clinical disadvantage to oral

treatment.(53) All patients in this study received >500mg of either oral or IV MP.
Considering the dose and duration of therapy in this retrospective study was not
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standardized, we cannot yet conclude that IV and oral methylprednisolone are equivalent.
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Oral corticosteroid treatment is cheaper and more convenient for patients since it does not
require hospitalization. While IV MP is often utilized based on the ONTT, it is reasonable to
consider high-dose oral corticosteroids for patients with optic neuritis who either cannot or
will not agree to IV therapy. At this point, we have better evidence for the effectiveness of
high-dose prednisone (1250mg) compared to high-dose oral MP specifically for the
treatment of optic neuritis; however, a direct comparison has not yet been studied. As
discussed previously, low-dose oral corticosteroids should never be used to treat optic
neuritis because they are not effective and they increase the risk of recurrence.(5)
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III. NMO Spectrum Disorder

Presentation and Diagnosis

Neuromyelitis optica (Devic disease) is a severe CNS inflammatory, demyelinating disease

that preferentially affects the optic nerves and spinal cord. Initially described as bilateral,

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sequential or simultaneous optic neuritis and transverse myelitis, NMO spectrum disorder
(NMOSD) has expanded to include unilateral optic neuritis, brainstem, cerebral, and
diencephalic syndromes. (79) Initially thought to be a variation of MS, NMO is now known
to be a distinct disease often associated with antibodies against astrocyte aquaporin-4

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water channels (AQP4-IgG) or MOG.(39) While there is no pathognomonic presentation of
NMOSD, highly-suggestive presentations include severe bilateral, simultaneous optic

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neuritis, longitudinally extensive transverse myelitis (LETM), and area postrema syndrome
(intractable hiccups or nausea/vomiting). The majority of patients suffer a relapsing
course, even with immunosuppressive or immunomodulatory treatment.(27)

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AQP4-seropositive NMOSD optic neuritis is usually severe. Vision loss is typically rapid and
profound. There is a female predilection, and the average age of onset is older than in
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MS.(27) In the United States, NMO is more common in females (6.5:1) and the average age
of onset is 41 years.(59) It also tends to more commonly affect patients of Asian or African
descent. On MRI, T1-weighted gadolinium enhancement or T2 hyperintense lesions
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commonly involve greater than 50% of the optic nerve length and are more likely to extend
to the posterior optic nerve or chiasm than typical, demyelinating optic neuritis (Figure 1).
Among patients with transverse myelitis, spinal MRI shows longitudinally extensive
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intramedullary lesions spanning at least 3 vertebral segments. This is in contrast to MS

spinal cord lesions that are typically shorter and involve the peripheral spinal cord.
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Additional characteristic MRI findings are seen in the less common brainstem, cerebral, and
diencephalic NMOSD syndromes.(79)

In 2015, the International Panel for NMO Diagnosis revised the NMOSD diagnostic criteria.
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AQP4-IgG seropositive NMOSD is a rather straightforward diagnosis, while AQP4

seronegative NMOSD must fulfill more stringent criteria (Figure 2). To achieve a diagnosis
of seropositive NMOSD, a patient must test positive for serum AQP4-IgG and present with
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at least one of six core clinical characteristics: 1) optic neuritis, 2) acute myelitis, 3) area
postrema syndrome (unexplained intractable hiccups or nausea/vomiting), 4) acute
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brainstem syndrome, 5) symptomatic narcolepsy or acute diencephalic syndrome with

NMOSD-typical diencephalic MRI lesions, or 6) symptomatic cerebral syndrome with
NMOSD-typical brain lesions. The first three core characteristics are the most common.

If serum AQP4-IgG is negative or unknown and alternative diagnoses have been excluded, a
patient can be diagnosed with seronegative NMOSD if they have at least two unique core
clinical characteristics (simultaneous or sequential), with at least one of them being the
most common characteristics of optic neuritis, acute myelitis with LETM, or area postrema
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syndrome. Additional characteristic radiographic patterns are also required on MRI for
seronegative NMOSD diagnosis.(79)

There are many AQP4-IgG antibody assays available including indirect immunofluorescence,
cell-based assay, flow cytometry, radioimmunoprecipitation assay, fluorescence
immunoprecipitation assay and enzyme-linked immunosorbent assay (ELISA). A cell-based

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assay is the most sensitive (76%) and specific (99%) and should be ordered whenever
available. (76) The astute provider should call the laboratory to find out if a cell-based assay
is utilized when ordering AQP4-IgG.

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AQP4-IgG mediated NMOSD may yield false negative AQP4-IgG testing upon initial
presentation, but seroconvert later. When the clinician remains highly suspicious for the

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diagnosis but the initial testing is negative, repeat AQP4-IgG testing should be considered 3-
6 months later.(40)

Other Disease Associations

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NMOSD has been associated with autoimmune diseases. Systemic lupus erythematosus
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(SLE) and Sjogren syndrome have been reported most frequently, but NMOSD has also been
reported in patients with autoimmune thyroiditis, and myasthenia gravis.(69, 78) The
frequent co-occurrence of NMOSD with these autoimmune diseases suggests that patients
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with NMOSD may have an underlying susceptibility to humoral autoimmunity, or perhaps

NMOSD is caused by these other rheumatologic diseases. Therefore, patients with known
rheumatologic disease who present with optic neuritis, transverse myelitis, or other
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NMOSD-like symptoms should be tested early for AQP4-IgG and have an MRI of their brain
and spinal cord. Early treatment of NMOSD is so critical that it needs to be seriously
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considered in rheumatologic patients before neurologic symptoms should be attributed to

their known underlying disease.

Paraneoplastic NMOSD has been reported in various cancers including lung, breast, ovarian,
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and adrenocortical carcinoma.(2, 3, 18) A recent study of 156 NMO patients found 3.2%
suffered paraneoplastic NMOSD. These patients were predominantly male with an average
age of 63 years and often presented with intractable nausea and vomiting.(68) Therefore,
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older patients, especially males, who present with NMO-like symptoms should be evaluated
for underlying malignancy.
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Treatment

There is currently no curative treatment for NMOSD. Emerging research is improving our
understanding of how astrocyte injury and necrosis leads to oligodendrocyte damage and
demyelination. We know that, by binding to astrocyte foot processes, AQP4-IgG activates
complement, antibody-dependent cell-mediated cytotoxicity, opsonization, and
complement-induced degranulation of eosinophils leading to severe CNS inflammation and
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astrocyte injury.(8) Additionally, independent of the inflammatory cascade, AQP4-IgG itself

appears to be pathogenic when bound to the AQP4 receptor, possibly from disruption of
astrocyte transcellular water transport or receptor internalization. (8) Current treatment
modalities and research are directed at suppressing this inflammatory cascade and
providing symptomatic relief.

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Acute Treatment

For acute attacks of NMO, the most recent guidelines published by the Neuromyelitis
Optica Study group (NEMOS) in 2014 recommend early treatment with 1 gram intravenous

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(IV) methylprednisolone daily for five days. (75) If symptoms worsen or do not improve,
NEMOS recommends therapeutic plasma exchange (PLEX). Retrospective analysis suggests

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that early, simultaneous treatment with IV methylprednisolone and PLEX may improve
disability outcomes.(1, 71) The best clinical outcomes have been reported in patients who
are treated with IV methylprednisolone and PLEX within 48 hours of symptom onset, with
similar outcomes in patients treated within the first five days.(12) Residual disability

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appears to increase with additional treatment delay, and unfortunately, the majority of
patients who benefit from early (<5 days) combined IV methylprednisolone-PLEX treatment
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still do not recover to their pre-treatment baseline.(12)

Chronic Treatment
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With the potential to accumulate additional severe neurologic disability with each relapse,
long-term immunosuppression is recommended once the NMOSD diagnosis is
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confirmed.(75) While most ophthalmologists will not manage chronic immunosuppressive

therapy, it is important for all to understand that current clinical paradigms are evolving.
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Due to our rapidly expanding understanding of NMOSD and our relatively recent ability to
confidently diagnose this disease, well-designed long-term studies of treatment efficacy do
not yet exist. For long-term immunosuppression, azathioprine and rituximab are the most
widely prescribed and are considered first-line agents by NEMOS. A recent prospective,
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multicenter trial found that rituximab decreased relapse rate and improved disability scores
after two years.(13) Mycophenolate mofetil, methotrexate, and mitoxantrone are
considered second-line therapy.(75) While there is currently no FDA-approved NMOSD
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treatment, clinical trials are actively underway for tocilizumab (anti-IL6 monoclonal
antibody) and inebilizumab (anti-CD19 monoclonal antibody), and eculizumab (anti-C5
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protein monoclonal antibody). Aquaporumab, a non-pathologic anti-AQP4 antibody that

selectively blocks the AQP4 IgG that causes NMO, is the most specific NMOSD therapeutic in
development and has shown promise in animal studies, but there are currently no
published studies in humans. Importantly, MS drugs including interferon-beta, natalizumab,
and fingolimod exacerbate NMOSD, underlining the importance of accurate and early
NMOSD diagnosis.(4, 26, 34, 37, 47, 56, 57, 70)

Imaging
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While MRI is not required to diagnose seropositive NMOSD, brain and spinal cord MRI with
gadolinium are critical to early NMOSD diagnosis, especially because it can take weeks for
AQP4-IgG results to return from the lab. Given the improved disability outcomes with early
treatment, clinicians should maintain a low threshold to obtain neuroimaging when NMOSD
is suspected as this could help justify immunosuppressive treatment prior to lab result
availability. Early neuroimaging can also help rule out MS and therefore avoid the NMOSD

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exacerbation caused by the various aforementioned MS treatments.

Acute demyelinating lesions in NMOSD are similar to MS lesions in that they are
hyperintense on T2-weighted imaging and enhance with gadolinium on T1-weighted

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images. The pattern and shape of the lesions are different, however, and can help
differentiate the two diseases radiographically. The classic radiographic findings in NMOSD

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are 1) extensive optic nerve lesions (>50% of the nerve length), often more posterior than
seen in MS (Bilateral optic nerve and/or chiasmal involvement are also highly suspicious for
NMOSD), 2) LETM, which, by definition involve >3 consecutive vertebral segments and
predominantly affect the central spinal cord. Acute lesions will enhance for weeks to

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months following the onset of an attack. Chronically, NMOSD lesions are characterized by
central spinal cord atrophy. In contrast to the central cord in involvement in NMOSD, MS
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spinal cord lesions are typically shorter and involve the peripheral cord.(33, 79)

Prior to the most recent NMOSD diagnostic guidelines, a normal brain MRI (with the
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exception of non-specific white matter changes) was required for diagnosis.(77) We now
know that the majority of patients with NMOSD actually have brain MRI abnormalities.(9,
14, 33, 43, 62) The characteristic MS brain lesions, including perpendicularly oriented
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periventricular lesions (Dawson fingers), periventricular lesions in the inferior temporal

lobe, cortical lesions, and juxtacortical lesions, are rarely seen in NMOSD. Characteristic
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brain MRI findings in NMOSD include 1) dorsal medullary lesions adjacent to the 4th
ventricle involving area postrema, 2) hypothalamic, thalamic, and periependymal lesions
surrounding the 3rd ventricle 3) long corpus callosum lesions (>1/2 length of corpus
callosum), and 4) large, hemispheric, often tumefactive subcortical deep white matter
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lesions.(79) Corpus collosum (CC) lesions are common in both MS and NMO, but their
configuration is different. In MS, CC lesions are ovoid and perpendicular to the lateral
ventricles, while CC lesions in NMOSD are typically longer, acutely edematous, and can
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extend extensively into the adjacent white matter.(33) While non-specific, multiple
punctate T2/FLAIR hyperintensities in the subcortical and deep white matter are the most
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common brain MRI lesions seen in NMOSD.(33)

IV. Myelin oligodendrocyte glycoprotein antibody (MOG-IgG) associated optic neuritis

Overview
Optic neuritis associated with anti-myelin oligodendrocyte glycoprotein antibody (MOG-
IgG) has recently emerged as a distinct form of optic neuritis and NMOSD. The discovery of
the MOG-IgG autoantibody and the recent availability of a commercial cell-based assay has
increased our ability to diagnose this disease. Our understanding and characterization of
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MOG-IgG optic neuritis is rapidly evolving, especially now that established optic neuritis
research populations with long term follow up can be retrospectively tested for MOG-IgG.
Patients with MOG-IgG optic neuritis often present with a NMOSD-like phenotype or
chronic relapsing inflammatory optic neuritis (CRION).(15, 66) The majority of patients
present with isolated optic neuritis; however, simultaneous transverse myelitis and
encephalitis also occur. (15, 28, 66)

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MOG-IgG optic neuritis is more prevalent in females. Two retrospective studies found an
average presenting age of 31 years, while one study found and average onset age 40 years.
MOG-IgG optic neuritis occurs more frequently among Caucasian individuals. (15, 28, 66)

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Bilaterality is common (approximately 40%).(15, 28, 65-66) The majority of patients have
optic disc edema, which tends to be more pronounced than when present in typical MS-

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related optic neuritis. (15, 16, 28, 65-66) Re-examination of the ONTT data found that three
of the patients with optic disc edema actually had MOG-IgG disease.(16) The overwhelming
majority of patients suffer from recurrent optic neuritis attacks (80-93%). Similar to
NMOSD disease, visual loss at presentation can be profound, but visual recovery in MOG-

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IgG tends to be better (20/20-20/30 range), although it is frequently steroid dependent.(15,
28, 30) One recent retrospective review found 40% of AQP4 IgG seronegative NMOSD
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patients were MOG-IgG positive.(65) Among patients who present with NMOSD
phenotype, checking for MOG-IgG in addition to AQP4-IgG is important, as these two
autoantibodies do not co-exist, and MOG-IgG has a much better prognosis following
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treatment.(28-30)

In MOG-IgG positive patients, the coexistence of rheumatologic disease appears to be less

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common. In a multicenter, retrospective study of 50 MOG-IgG patients, only 8.5% had

concurrent rheumatologic disease (rheumatoid arthritis and autoimmune thyroiditis).
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Interestingly, coexistent autoantibodies were present in 42% of these patients.(28) Case

reports of MOG-IgG optic neuritis have also suggested associations with seizures, herpes
simplex infection, and vaccinations, but data are lacking.(25, 31, 52)
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Imaging

Orbital MRI in MOG-IgG optic neuritis shows T2 hyperintensity and T1 post gadolinium
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enhancement of the optic nerve. Extensive (>1/2) optic nerve lesions are common and may
extend into the chiasm, although this appears less common than in AQP4-IgG optic
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neuritis.(11, 15, 28, 82) Unlike AQP4-IgG disease, the majority of brain MRIs in MOG-IgG
disease are normal.(11, 28, 82) Two recent studies, each of 50 MOG-IgG optic neuritis
patients found perineural enhancement on the MRI in 50% and 39% of patients,
respectively.(15, 28) Perineural enhancement is not seen in AQP4-IgG or typical
demyelinating optic neuritis, and its presence should raise suspicion for MOG-IgG disease or
optic perineuritis (see below).

IV. Inflammatory Optic Neuritis

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Chronic Relapsing Inflammatory Optic Neuropathy (CRION)

CRION is a steroid-dependent, recurrent optic neuritis. Diagnostic criteria were proposed in

2014 that required optic nerve enhancement on MRI and AQP4 seronegativity.(61) These
patients tend to have excellent visual outcomes, but require long-term corticosteroid
therapy. CRION shares many features with the recently characterized MOG-IgG optic

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neuritis, and it appears that a significant subset with this previously described idiopathic
disease actually have MOG-IgG optic neuritis. A recent study of 64 CRION patients found
that the overwhelming majority (92%) were positive for MOG-IgG.(38)

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Optic neuritis can be a manifestation of systemic inflammatory diseases including SLE, anti-
phospholipid antibody syndrome, Sjogren syndrome, sarcoidosis, granulomatosis with

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polyangiitis, and primary CNS vasculitis.(10, 17, 41, 46, 50, 72-73) These entities should be
ruled out before making a diagnosis of CRION. In patients without known systemic
rheumatologic disease, diagnosis is challenging. Clinical suspicion should be raised in
patients with an atypical clinical course, atypical imaging features, or atypical associated

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symptoms. Laboratory evaluation should include both AQP4-G4-IgG and MOG-IgG with
additional autoantibody testing directed by the patients review of systems.
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V. Infectious Optic Neuritis
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Syphilis, tuberculosis, Lyme disease, Bartonella, herpetic disease, West Nile virus, and
human immunodeficiency virus (HIV) can all cause optic neuritis. Review of systems and
atypical features including fever, immunosuppression, and recent travel should raise clinical
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suspicion. A complete review of systems is critical, and an ophthalmologist should not

hesitate to involve infectious disease or refer to neurology when this is suspected. These
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patients often need an extensive laboratory workup including lumbar puncture with
thorough cerebrospinal fluid testing.

VI. Perineuritis
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Optic perineuritis is a rare disorder of the optic nerve sheath. While the majority of cases
are idiopathic, underlying inflammatory and infectious causes must be considered. Patients
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present similar to optic neuritis; however, perineuritis is not associated with MS. Typical
presentation includes vision loss and pain with eye movements. The patients are often
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older than in typical demyelinating optic neuritis (average age 41 years) and the vision loss
characteristically progresses over weeks rather than days. MRI will show optic nerve sheath
enhancement, while the optic nerve itself is typically normal.(63) Optic perineuritis is
exquisitely sensitive to steroids. Both the pain and visual symptoms respond quickly to
corticosteroid therapy, often within 24 hours. Optic perineuritis has been associated with
syphilis, sarcoidosis, granulomatosis with polyangiitis, and Crohn disease.(44, 45, 54, 58, 64,
81) In addition to a complete review of systems, fluorescent Treponema antibody (FTA-
abs), anti-neutrophil cytoplasmic antibodies (ANCA), serum angiotensin converting enzyme
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(ACE), and chest X-ray should be considered in these patients. MOG-IgG testing should also
be considered, especially in patients who have enhancement of the nerve and sheath.

VII. Optical Coherence Tomography and Electrophysiologic Testing

While optic neuritis represents a clinical diagnosis, ancillary testing can provide helpful

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information in addition to MRI. Optical coherence tomography (OCT) and visual evoked
potentials (VEP) are commonly used to support an optic neuritis diagnosis, monitor disease
course, and predict visual recovery. While OCT is widely available in ophthalmic practice,
VEP is predominantly limited to academic medical centers. Ophthalmologists and

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neurologists should be familiar with both tests.

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Optical Coherence Tomography (OCT)

OCT is a quick, non-invasive, reproducible, and widely available imaging modality for the

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retina and peripapillary retinal nerve fiber layer (pRNFL). The utility of OCT in clinical
practice is evolving rapidly. Until recently, pRNFL OCT was used primarily to detect axonal
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loss secondary to a previous optic neuritis episode as well as a marker for MS disease
progression. The relatively recent availability of ganglion cell layer (GCL) and inner plexiform
layer (IPL) segmentation with spectral domain OCT is revolutionizing our understanding of
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optic nerve and retinal disease, including optic neuritis.

As an example, a recent prospective study of 33 eyes with acute optic neuritis found that
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acute pRNFL thickening is common (46%) within fifteen days of symptom onset (35)
Meanwhile, pRNFL loss was not detected until 3 months after symptom onset, whereas
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GCL+IPL thinning was seen at one month. The authors concluded that GCL+IPL thickness
may be a better biomarker than pRNFL thickness early in the disease course.

Visual Evoked Potential (VEP)

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VEP is an electrophysiologic test that measures electrical signals over the occipital cortex in
response to a visual stimulus. The most common stimulus is an alternating checkerboard
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(pattern VEP), but a bright light stimulus can be used for low vision patients (flash VEP).
Damage anywhere along the afferent visual pathway can diminish the speed and/or
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amplitude of the VEP waveform. Demyelination increases the P100 latency (the first
positive waveform peak), but does not affect waveform amplitude. Ischemic, compressive,
and toxic optic neuropathies primarily reduce waveform amplitude and do not affect the
P100 latency. Therefore, increased P100 latency is suggestive of optic neuritis. Clinical
utility is limited because the pattern VEP can be affected by uncorrected refractive error,
media opacities like cataract, and patient inattention. It also requires electrode placement
on the scalp. Multifocal VEP (mfVEP) is a newer technology that may localize
electrophysiologic abnormalities more specifically than traditional VEP. The setup is
involved and the testing is long, making it less practical for clinical use.
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In the past, comparison of OCT to VEP has been somewhat controversial. A previous study
comparing VEP to time domain OCT found that prolonged P100 VEP latency was more
sensitive than RNFL thinning for detecting optic neuritis (81% versus 60%, respectively).(51)
However, a recent retrospective study of 51 patients found GCL-IPL thinning was 96%
sensitive than in unilateral optic neuritis.(80) The ubiquity of spectral domain OCT including

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macular segmentation and its relative ease of use will make it difficult for VEP to remain
relevant outside academia.

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VIII. Conclusion

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Optic neuritis describes a diverse group of inflammatory and infectious optic neuropathies.
Typical, demyelinating optic neuritis was well characterized by the ONTT. Atypical
presenting features, radiographic findings, or clinical course should raise clinical suspicion
for an atypical optic neuritis variant. The discovery of novel autoantibodies including AQP4-

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IgG and MOG-IgG has improved our ability to distinguish these disease variants, which will
ultimately direct therapy and improve patient outcomes. Unlike typical demyelinating optic
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neuritis, many of the atypical optic neuritis variants require early immunosuppressive
therapy to minimize long term disability. Therefore, ophthalmologists must remain up-to-
date as our understanding of optic neuritis evolves so they can facilitate prompt laboratory
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and imaging evaluations as well as referrals to neurology or neuro-ophthalmology when

needed.
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Method of Literature Search

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A MEDLINE search was conducted for “optic neuritis”, “neuromyelitis optica spectrum
disorder”, “myelin oligodendrocyte glycoprotein antibody”, “inflammatory optic neuritis”,
“infectious optic neuritis”, “optic perineuritis”, “MRI”, “OCT”, and “visual evoked potential”. A
few select articles were included for historical perspective, however, the review is based mainly
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on the peer-reviewed literature published in the past ten years. Emphasis was placed on the
ophthalmology literature, but selections from the neurology literature were also included.
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Figure Legends

Figure 1.
Neuroimaging features of typical versus atypical optic neuritis. In typical optic neuritis, there is
often T2 hyperintensity of the optic nerve (not shown) and T1 gadolinium enhancement of the
anterior orbital optic nerve (A). Bilateral optic neuritis and extensive optic nerve enhancement

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(>50% of the optic nerve length) are atypical features (B). Chiasmal involvement is also
suggestive of atypical disease (not shown).

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Figure 2.
Neuromyelitis optica spectrum disorder (NMOSD) diagnostic criteria. NMOSD diagnostic

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criteria vary based on aquaporin-4 (AQP4) immunoglobulin G (IgG) status (A). Cell-based assay
is strongly recommended. In AQP4-IgG positive patients, the diagnosis is rather
straightforward. In addition to the positive AQP4-IgG the patient needs to have at least one
core clinical characteristic (B). In patients with negative or unknown AQP4-IgG status, the

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diagnostic criteria are more stringent. These patients must have at least two unique core
clinical characteristics (disseminated in space), and at least one of the core clinical
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characteristics must be optic neuritis, transverse myelitis, or area postrema syndrome (B).
Additionally, patients with negative or unknown AQP4-IgG status must fulfil additional MRI
requirements to make the NMOSD diagnosis (C). Alternative diagnoses must also be excluded
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for all patients diagnosed with NMOSD. Adapted from Wingerchuk DM, Banwell B, Bennett JL,
Cabre P, Carroll W, Chitnis T, et al. International consensus diagnostic criteria for neuromyelitis
optica spectrum disorders. Neurology. 2015;85(2):177-89.
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Wingerchuk DM, Banwell B, Bennett JL, Cabre P, Carroll W, Chitnis T, et al. International
consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology.
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2015;85(2):177-89.
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Typical Atypical
Clinical Features Unilateral Bilateral
Female Male
Painful Painless
Onset 32 years (average) Onset <18 or > 50 years
Normal optic disc (2/3), mild Pronounced disc edema,

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disc edema (1/3) vitritis
Improvement within 1 month Progressive vision loss > 2
weeks

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Dyschromatopsia > acuity loss 20/200 or worse
Radiographic Features Anterior optic nerve Extensive (>1/2) posterior
enhancement optic nerve, chiasmal, or

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optic nerve sheath
enhancement

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Table 1. Typical versus atypical features of optic neuritis.
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