Series

Optic Neuropathies 2
Optic neuritis and autoimmune optic neuropathies:
advances in diagnosis and treatment
Jeffrey L Bennett, Fiona Costello, John J Chen, Axel Petzold, Valérie Biousse, Nancy J Newman, Steven L Galetta

Optic neuritis is an inflammatory optic neuropathy that is commonly indicative of autoimmune neurological Lancet Neurol 2023; 22: 89–100
disorders including multiple sclerosis, myelin-oligodendrocyte glycoprotein antibody-associated disease, and Published Online
neuromyelitis optica spectrum disorder. Early clinical recognition of optic neuritis is important in determining the September 22, 2022
https://doi.org/10.1016/
potential aetiology, which has bearing on prognosis and treatment. Regaining high-contrast visual acuity is common
S1474-4422(22)00187-9
in people with idiopathic optic neuritis and multiple sclerosis-associated optic neuritis; however, residual deficits in
This is the second in a Series of
contrast sensitivity, binocular vision, and motion perception might impair vision-specific quality-of-life metrics. three papers on optic
In contrast, recovery of visual acuity can be poorer and optic nerve atrophy more severe in individuals who are neuropathies. All papers in the
seropositive for antibodies to myelin oligodendrocyte glycoprotein, AQP4, and CRMP5 than in individuals with Series are available at: thelancet.
com/series/optic-neuropathies
typical optic neuritis from idiopathic or multiple-sclerosis associated optic neuritis. Key clinical, imaging, and
laboratory findings differentiate these disorders, allowing clinicians to focus their diagnostic studies and optimise Department of Neurology and
Department of Ophthalmology
acute and preventive treatments. Guided by early and accurate diagnosis of optic neuritis subtypes, the timely use of (Prof J L Bennett MD PhD),
high-dose corticosteroids and, in some instances, plasmapheresis could prevent loss of high-contrast vision, improve Programs in Neuroscience and
contrast sensitivity, and preserve colour vision and visual fields. Advancements in our knowledge, diagnosis, and Immunology, University of
treatment of optic neuritis will ultimately improve our understanding of autoimmune neurological disorders, Colorado School of Medicine,
Anschutz Medical Campus,
improve clinical trial design, and spearhead therapeutic innovation. Aurora, CO, USA; Departments
of Clinical Neurosciences and
Introduction with the Optic Neuritis Treatment Trial (ONTT) Surgery, University of Calgary,
Calgary, AB, Canada
Optic neuritis is a common manifestation of CNS published in 1992,5 and extending through to the
(Prof F Costello MD);
inflammatory disorders, both infectious and non- early 2000s with the identification of autoantibodies to Department of Ophthalmology
infectious.1 Although the causes of optic neuritis are AQP4 (AQP4-IgG) in neuromyelitis optica spectrum and Department of Neurology,
protean, CNS autoimmunity is of primary concern. Optic disorder (NMOSD) and myelin oligodendrocyte Mayo Clinic, Rochester, MN,
USA (Prof J J Chen MD); National
neuritis is often the first clinical manifestation of multiple glycoprotein antibodies (MOG-IgG) in myelin-oligo­
Hospital for Neurology and
sclerosis; yet paradoxically, according to the 2017 revision of dendrocyte glycoprotein antibody-associated disease Neurosurgery, University
the McDonald criteria, the optic nerve is not recognised as (MOGAD).6,7 Epidemiological studies report that in College London Hospital,
a CNS region that contributes to radiological dissem­ination people of White ethnic origin multiple sclerosis accounts London, UK (A Petzold MD
PhD); Moorfields Eye Hospital,
in space (DIS).2 An expanding array of serological markers for roughly 50–80% of optic neuritis cases, whereas
London, UK (A Petzold);
have greatly extended the spectrum of autoimmune optic around 30% remain idiopathic. Due to the lower Neuro-ophthalmology Expert
neuropathies and can now be used to diagnose disorders incidence of multiple sclerosis, NMOSD and MOGAD Centre, Amsterdam,
that are distinct from multiple sclerosis-associated optic are more frequent causes of optic neuritis in the Asian Netherlands (A Petzold);
Department of Ophthalmology
neuritis. Advances in neuro­immunology, neuroimaging, population, with NMOSD accounting for 3·4–43·5% and
(Prof V Biousse MD,
electro­physiology, and ocular imaging have also been used MOGAD for 10·2–27·6% of optic neuritis cases.8,9 Even Prof N J Newman MD),
to inform the diagnosis, prognosis, and treatment of rarer are other autoimmune optic neuropathies, such Department of Neurology
different optic neuritis subtypes, and might provide novel as GFAP-associated meningo­ encephalo­myelitis and (Prof V Biousse,
Prof N J Newman), and
measures to monitor optic nerve injury, assess disease CRMP5-IgG-associated autoimmunity. Nevertheless, the Department of Neurological
activity, and potentially enhance diagnostic sensitivity. distinct features, implications for visual recovery, Surgery (Prof N J Newman),
The aims of this Series paper are to describe the clinical prognosis, and treatment of these autoimmune optic Emory University School of
manifestations, natural history, and pathophysiology of neuropathies make their recognition paramount. Medicine, Atlanta, GA, USA;
Department of Neurology and
optic neuritis and autoimmune optic neuropathies, delin­ Department of Opthalmology,
eate serum biomarkers and imaging features that inform Multiple sclerosis NYU Langone Medical Center,
on diagnosis and prognosis, and discuss emerging Multiple sclerosis is the most common demyelinating New York, NY, USA
manage­ment strategies. This paper is the second paper in a disease associated with optic neuritis. The ONTT was a (Prof S L Galetta MD)

three-part Series in The Lancet Neurology on optic landmark, randomised placebo-controlled trial that
neuropathies.3,4 aimed to understand the efficacy of corticosteroids in the
treatment of acute unilateral optic neuritis and the
Clinical manifestations of autoimmune optic association of optic neuritis with multiple sclerosis
neuritis (panel 1).5,10–12 Clinically definite multiple sclerosis was
­

Our understanding of optic neuritis has grown diagnosed in 50% of individuals (88·1% of whom
tremendously over the past three decades, beginning were of White ethnic origin) at 15 years’ follow-up.11 A

www.thelancet.com/neurology Vol 22 January 2023 89

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Correspondence to:
Prof Jeffrey L Bennett, Department Panel 1: Summary of findings from the Optic Neuritis
of Neurology and Department of Treatment Trial
Ophthalmology, Programs in
Neuroscience and Immunology, • Design: a prospective, randomised clinical trial in the USA
University of Colorado School of of 457 patients with acute optic neuritis who were enrolled
Medicine, Anschutz Medical within 8 days of their visual loss and randomly allocated to
Campus, Aurora, CO 80045, USA
treatment with intravenous methylprednisolone (250 mg
jeffrey.bennett@cuanschutz.
edu every 6 h for 3 days) followed by oral prednisone (1 mg/kg
daily for 11 days), oral prednisone (1 mg/kg daily for
14 days), or oral placebo.5
• Demographics: 77% of patients were women, and 85% of
patients identified as White. The age range was
18–45 years with a mean age of 32 years.10
• Visual outcome at 6 months: all three treatment groups
showed good visual recovery, with most patients
achieving a high-contrast letter acuity of 6/12 (20/40) or
better.5,10
• Rate of visual recovery: patients treated with the
intravenous steroid regimen recovered vision faster than
did the other groups, but the final visual outcome was no
different at 1 year.5,10
• Risk of multiple sclerosis: 50% of patients developed
clinically definite multiple sclerosis; 72% of patients with
one or more brain white matter lesions on baseline MRI
developed multiple sclerosis, emphasising the prognostic
value of brain MRI.11
• Potential red flags: clinically definite multiple sclerosis was
not diagnosed in patients with a healthy appearing MRI
scan and either no eye pain, severe optic disc oedema,
optic disc or peripapillary haemorrhages, macular
exudates, absence of a relative afferent pupillary defect,
or no light perception vision.11 These scenarios represent
potential red flags for the diagnosis of multiple
sclerosis-associated optic neuritis.
retrospective analysis of the ONTT noted that only a small
number of individuals were seropositive for
MOG-IgG (1·7%) and none for AQP4-IgG.13 The low
percentage of NMOSD-associated and MOGAD-associated
optic neuritis in the ONTT was probably, in part, due to a
study design that excluded patients with bilateral optic
neuritis and enrolled a predominantly White ethnic
population. Nevertheless, the study provided valuable
information regarding acute optic neuritis associated with
multiple sclerosis. Patients usually presented with
unilateral, subacute, painful vision loss that deteriorated
over 1 week.14 At onset, high-contrast visual acuity (HCVA)
loss ranged from 6/6 Snellen equivalent (20/20 US
notation) to no light perception. About 66% of patients
had an HCVA of 6/60 (20/200) or better at nadir, and in
only 3% of patients was there no perception of light at all.14
In more than 90% of patients, HCVA improved to 6/12
(20/40) or better after a year.5
Eye pain, dyschromatopsia, contrast sensitivity loss, and
visual field loss are common in multiple sclerosis-
associated optic neuritis (table 1).5,10,14–27 92% of patients in
90
the ONTT had eye discomfort, 70% noted worsening of
eye movement, and 40% reported eye pain before vision
loss.5,14 Decreased contrast sensitivity was present in
almost all patients and this persisted in many despite full
recovery of HCVA. The pattern of visual field loss was
quite variable, with central defects more common than
peripheral defects.26
Clinical evaluation of a patient with unilateral optic
neuritis with the swinging flashlight test will usually
reveal a relative afferent pupillary defect in the affected
eye; this finding was required for the diagnosis of optic
neuritis in the ONTT. A relative afferent pupillary defect
can be absent or unreliable due to either bilateral optic
neuritis or a history of optic neuritis in the other eye,
conditions that both need to be considered in the clinical
history and examination. Visible optic disc oedema on
funduscopy is present in about a third of adult patients
with multiple sclerosis (figure 1); however, severe optic
disc oedema is atypical for multiple sclerosis-associated
optic neuritis (table 1).5,10,14 During acute multiple sclerosis-
associated optic neuritis, MRI of the orbits typically shows
a short segment of enhancement of the optic nerve
without involvement of the optic nerve sheath or chiasm
(figure 2).4,28,29
Idiopathic optic neuritis
Idiopathic optic neuritis often has similar characteristics
to multiple sclerosis-associated optic neuritis, but does not
have a known underlying systemic cause. The incidence
and prevalence of idiopathic optic neuritis varies based on
ethnicity, geography, diagnostic criteria, and length of
follow-up. For instance, 50% of patients in the ONTT were
deemed to have idiopathic optic neuritis after 15 years of
follow-up. The high proportion of idiopathic optic neuritis
in the ONTT probably reflects the limited diversity in
ethnic enrolment, the geographical restriction to the USA,
and the use of the 1983 Poser clinical diagnostic criteria for
multiple sclerosis. Subsequent population-based studies
in heterogeneous patient populations have reported lower
proportions of idiopathic optic neuritis than those seen in
the ONTT, ranging from 10–29%.8,9,15,27 Furthermore,
misdiagnosis of optic neuritis might contribute to the
over-representation of idiopathic optic neuritis. Stunkel
and colleagues30 reported that 60% of patients who were
referred with acute optic neuritis to a tertiary centre had an
alternative diagnosis. Robust clinical characterisation is,
therefore, crucial to avoid overdiagnosis and misdiagnosis
of idiopathic optic neuritis.1 Although visual recovery after
idiopathic optic neuritis is often good, poorer visual
recovery has been noted in some cohorts of patients with
idiopathic optic neuritis.8 Impaired recovery is probably a
product of aetiological heterogeneity and a high frequency
of recurrent optic neuritis.31,32
Neuromyelitis optica spectrum disorder
The most frequent clinical manifestations of NMOSD
are optic neuritis, longitudinally extensive transverse
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Multiple sclerosis- MOGAD-associated optic NMOSD-associated optic GFAP-IgG-associated CRMP5-IgG-associated optic

associated optic neuritis neuritis neuritis meningoencephalomyelitis neuritis
Age15–20 More prevalent in adults Equally prevalent in children More prevalent in adults Mainly occurs in adults Mainly occurs in adults
than in children and adults than in children
Sex ratio (female:male)15–20 2:1 1:1 9:1 1:1 1:1
Pain15,18–20 Frequent (90%) Frequent (90%) Common (50%) Rare* Rare (3%)
Bilateral5,21,22 Rare (5%) Common (40%) Occasional (20%) Typical Typical
Severe vision loss <6/60 33% >80% >80% Rare visual acuity loss 20%; median 6/15 (20/50)
(20/200; nadir)15,16,19,21–24
Colour vision15,16,20–22,25 Abnormal Abnormal Abnormal Normal Variable
Pattern of visual field loss23,24,26,27 Diffuse: 37%; central: 29% Diffuse: 22%; central: 73% Diffuse: 26%; central: 46%; Normal: 50%; blind spot Diffuse: 7%; central: 23%;
altitudinal: 22% enlargement: 10%; arcuate constriction: 23%; altitudinal: 23%
loss: 20%†
Fundus (clinical Infrequent mild disc Frequent disc oedema: Occasional mild disc Frequent moderate disc Pre-laminar optic neuritis; disc
examination)10,14,19,21–23 oedema: 36% 70–80%; commonly oedema: 30% oedema; and rare vitritis and oedema; vitritis and retinitis are
moderate to severe: 56% periphlebitis common; and occasional macular
exudates and iritis
MOGAD=myelin-oligodendrocyte glycoprotein antibody-associated disease. NMOSD=neuromyelitis optica spectrum disorder. *No values available for eye pain incidence in GFAP disease. †These values are from
a study of ten patients.

Table 1: Demographics and clinical findings in optic neuritis and other autoimmune optic neuropathies

A B C D

Figure 1: Funduscopic images of optic neuritides

(A) Disc oedema, haemorrhage (arrowhead) and (B) peripapillary wrinkles (arrowheads) in myelin oligodendrocyte glycoprotein antibody-associated disease optic
neuritis. (C) Mild disc swelling in idiopathic optic neuritis. (D) Disc swelling and cottonwool spots (arrowhead) in CRMP5-IgG-associated optic neuritis.

myelitis, and area postrema syndrome. Most (70–90%)
patients with NMOSD are AQP4-IgG seropositive,33
which is a specific pathogenic biomarker of the disease.6
The cell-based assays for AQP4-IgG provide the highest
sensitivity and specificity for NMOSD.33 Compared with
people with multiple sclerosis, NMOSD is much less
frequent in White individuals and is more common in
patients of Asian or African descent.16 Additionally, there
is a higher female predominance (9:1 vs 2:1) and later age
of onset (mean 40 years vs 30 years) in NMOSD than
multiple sclerosis.16
Optic neuritis in patients with AQP4-IgG seropositive
NMOSD can be severe and recovery is often poor: more
than 80% of patients with NMOSD have an HCVA of
6/60 or worse at nadir, and 30% manifest a final HCVA
of 6/60 or worse (table 1).21,34 Bilateral simultaneous optic
neuritis occurs in about 20% of patients and recurrence
is common.16,21,34 Optic disc oedema is usually present in
fewer than a third (10–44%) of patients (table 1).21,34 With
NMOSD-associated optic neuritis, MRI of the orbits
often shows longitudinally extensive lesions of the optic
nerve involving multiple nerve segments, which is rarely
seen with multiple sclerosis-associated optic neuritis
(figure 2).4,16,28,29,35 Isolated involvement of either the optic
chiasm or optic tract is more common in people with
NMOSD than in individuals with other causes of optic
neuritis (figure 2). It is important to distinguish optic
neuritis subtypes because several therapies for multiple
sclerosis can worsen the course of NMOSD disease.16
Patients with AQP4-IgG-positive NMOSD are at high
risk of relapse and, therefore, chronic immunosup­
pression is recommended. Since 2019, four randomised
clinical trials have resulted in the registration of three
monoclonal antibodies for the prevention of clinical
attacks in NMOSD: eculizumab, inebilizumab, and
satralizumab.36
Myelin oligodendrocyte glycoprotein-antibody-
associated disease
MOGAD can present with optic neuritis and other CNS
demyelinating presentations, including transverse
myelitis, acute disseminated encephalomyelitis, brainstem
syndromes, encephalitis, and seizures.37,38 MOG-IgG
measured by cell-based assays are the diagnostic biomarker
of MOGAD.39 MOGAD accounts for about 5% of optic
neuritis cases in adults and up to 50% of cases in

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A B C D
Figure 2: MRI of optic neuritides
(A) Longitudinal post-contrast optic nerve lesion (arrowhead) in NMOSD. (B) Chiasmal lesion (arrowhead) in NMOSD. (C) Intracanalicular and intracranial lesion (arrowheads) in multiple sclerosis-
associated optic neuritis. (D) Longitudinal intraorbital optic nerve lesions (arrowheads) and (E) perineuritic and orbital fat enhancement (arrowheads) in myelin-oligodendrocyte glycoprotein
antibody-associated disease. (F) Post-contrast linear perivascular enhancement (arrowheads) in GFAP-associated meningoencephalomyelitis. NMOSD=neuromyelitis optica spectrum disorder.
children.9,40,41 Unlike multiple sclerosis and NMOSD,
MOGAD has no clear sex or ethnic association (table 1).17,37
There are several salient features of MOGAD-
associated optic neuritis (table 1). Optic disc oedema,
which frequently is severe, is a common occurrence
(70–80%) and might be associated with peripapillary
haemorrhages and peripapillary wrinkles (figure 1).21,22
Compared with papilloedema—ie, bilateral disc oedema
caused by raised intracranial pressure—most MOGAD-
associated optic neuritis presents with substantial vision
loss and optic nerve and sheath enhancement on orbital
MRI imaging (figure 2). The enhancement of the optic
nerve on MRI is often robust, and more than half the
length of the nerve is affected in 80% of patients, with
MRI enhancement extending to the orbital fat in 50% of
MOGAD-associated optic neuritis attacks (figure 2).4,22,28
The optic chiasm might be involved, usually from a
longitudinal lesion affecting almost the full length of the
optic nerve.42 Pain is a prominent feature, and bilateral
simultaneous optic nerve involvement occurs in up to
50% of patients.21,22,41,43 Vision loss is often severe at nadir
(similar to NMOSD-associated optic neuritis), but
typically recovers well. Only 5–14% of individuals with
MOGAD-associated optic neuritis have a final HCVA
of 6/60 or worse.21,22,43,44 A substantial proportion of
patients with MOGAD will have relapsing disease, with
recurrent optic neuritis being the most common
manifestation.22,43,45 Pain and vision loss are generally
responsive to corticosteroids, and might be steroid-
dependent.21,46,47 Steroid-dependent optic neuritis requires
further investigation for systemic disease, which includes
sarcoidosis. Simultaneous or sequential optic neuritis
and transverse myelitis affect some patients with
MOGAD; in some cohorts, up to 42% of patients with
AQP4-IgG seronegative NMOSD are positive for
MOG-IgG.8,48 Notably, in addition to isolated optic
neuritis, MOGAD has been reported to be associated
with multiple ophthalmic features (eg, uveitis, acute
macular neuroretinopathy, neuroretinitis, papilloedema
from intracranial hypertension, and venous stasis
retinopathy), which might be challenging for neurologists
to identify.49 For this reason, seeking neuro-ophthalmic
consultation for patients with MOGAD will best identify
mechanisms of vision loss, and optimise care. The
spectrum of ocular and CNS manifestations of MOGAD
92
E F
is growing, but it is important to keep in mind that the
current MOG-IgG assay can have false-positive results,
particularly at low titres, and therefore atypical
presentations of MOGAD must be evaluated with
scrutiny and might require re-testing.50
Autoimmune GFAP-associated
meningoencephalomyelitis
GFAP-associated meningoencephalomyelitis is a rela­
tively rare steroid-responsive, and sometimes steroid-
dependent, disease accompanied by GFAP auto­anti­bodies
(GFAP-IgG).18,51 Some patients with autoimmune
GFAP-associated meningo­encephalo­myelitis present with
painless bilateral optic disc oedema. Vision loss is typically
mild, and central visual acuity is often initially preserved;
however, patients can develop worsening visual function
over time. Other associated ocular findings can include
mild vitritis and selective venular leakage on fluorescein
angiogram (table 1).23 The bilateral nature of the optic disc
oedema with relatively preserved vision can mimic
papilloedema from intracranial hypertension, although
most patients have normal opening pressures on lumbar
puncture.23 The diagnosis is made by examining for
GFAP-IgG in the CSF. Autoimmune GFAP-associated
meningoencephalo­myelitis is often mono­phasic; however,
some patients have a relapsing course, requiring chronic
immunotherapy.18 Typically, there is no enhancement of the
optic nerve on MRI,18 but in rare cases enhancement might
be observed.52 Many patients will have pathognomonic
perivascular radial white matter enhancement on brain
MRI (figure 2).51
CRMP5-IgG-associated optic neuritis
Autoantibodies against CRMP5 (CRMP5-IgG) are present
in paraneoplastic syndromes with diverse neurological
manifestations, including polyradiculoneuropathy, cranial
neuropathies, myelopathy, cerebellar ataxia, optic neuritis,
and basal ganglionitis.53 The majority of patients (70%)
have an underlying cancer, most commonly small-cell
lung carcinoma.53 Up to 20% of patients with CRMP5-IgG
autoimmunity will have optic neuritis, which typically
presents with rapid, painless, bilateral, subacute
progressive vision loss (table 1).19,25 Vitritis, retinitis, or
both are present in most patients, but isolated optic
neuritis can be present.19 Median HCVA at presentation is
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6/15 (20/50), but can range from 6/6 (20/20) to count
fingers vision. Although the diagnosis of CRMP5-IgG-
associated optic neuritis is rare, the combination of optic
neuritis with optic disc oedema, vitritis, and retinitis,
particularly in the presence of other neurological deficits
and suspected malignancy, should prompt testing for
CRMP5-IgG (figure 1). Similar to GFAP-IgG-associated
optic neuropathy, optic disc oedema is typically present.19
Because pathology is pre-laminar, acute CRMP5-IgG-
associated optic neuritis rarely causes enhancement of the
optic nerve on MRI, which might help to distinguish it
from other causes of autoimmune optic neuritis.19,25
Pathophysiology of optic neuritis and
autoimmune optic neuropathies
Astrocytic, oligodendroglial, and neuronal antigens, such
as AQP4, GFAP, MOG, and CRMP5, have been identified
as antigenic targets in autoimmune optic neuritis
subtypes, and the distribution and structure of these
target antigens are likely to affect the nature of the
immune response and the extent of optic nerve injury.
Autoantibodies against extracellular plasma membrane
proteins, such as AQP4 and MOG, are capable of
mediating tissue injury through multiple effector
functions—ie, complement-dependent cytotoxicity, anti­
body-dependent cell-mediated cytotoxicity, and antibody-
dependent cell-mediated phagocytosis. By contrast,
auto­antibodies against intracellular proteins, such as
GFAP and CRMP5, are unlikely to contribute directly to
tissue injury, in which autoreactive effector T cells and
phagocytic macrophages are the primary effectors of
CNS injury.
AQP4-IgG pathophysiology in NMOSD-associated optic
neuritis
AQP4-IgG in NMOSD can trigger multiple pathological
responses. AQP4 is assembled into large orthogonal
arrays of particles on CNS astrocytes, forming an ideal
scaffold for optimal binding of AQP4-IgG and the
fabrication of autoantibody platforms that efficiently
activate the classical complement cascade.54,55 Although
AQP4-IgG binding to AQP4 orthogonal arrays of
particles is determined by monovalent interactions
between a single antigen binding fragment (Fab) armand
its epitope,54 divalent AQP4-IgG is necessary to initiate
targeted astrocyte destruction.55 Complement-dependent
cytotoxicity causes bystander injury to adjacent
oligodendroglia and produces anaphylatoxins that attract
and activate microglia and polymorphonuclear and
mononuclear cells. These cells mediate further injury
through antibody-dependent cell-mediated cytotoxicity,
complement-mediated degranulation, and cytokine and
antibody-dependent cell-mediated phagocytosis.56,57
AQP4 is expressed on optic nerve astrocytes, retinal
astrocytes, and Müller cells, allowing for multiple
mechanisms of potential visual impairment. Retinas
from NMOSD autopsies show inner retinal microglial
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cells and a mild reduction in Müller cell glutamine
synthetase staining but no evidence of immune cell
infiltration or complement deposition.58 A study using
full-field electroretinography noted potential Müller cell
dysfunction in patients with NMOSD, but a separate
study using multifocal electroretinography found no
abnormalities.59,60 Studies on outer retinal changes in
NMOSD by optical coherence tomography (OCT) have
also been variable. Some studies show no outer retinal
changes whereas other studies show optic neuritis-
independent foveal changes, outer layer retinal thinning,
or both.59–62 There is no clear symptomatic vision loss in
patients with subtle OCT or electroretinography changes,
and therefore the potential effect of direct retinal injury
on visual function in NMOSD remains to be elucidated.
MOG-IgG pathophysiology in MOGAD-associated optic
neuritis
Similar to NMOSD, MOGAD histopathology shows
evidence of both antibody-dependent and antibody-
independent immunopathology—ie, complement depo­
sition, inflammatory CD4-predominant T-cell infiltrates,
granulocytosis, astrogliosis, microglial activation,
moderate axonal loss, and preservation of oligodendrocyte
precursors.63 By contrast to NMOSD, MOG-IgG comple­
ment activation is unlikely to be the initiating mech­
anism. The assembly of MOG in the myelin outer leaflet
and the epitope specificity of human MOG-IgG are
suboptimal for activation of the classical complement
cascade, because direct administration of human
MOG-IgG and complement into rodent brain or onto
rodent brain slices causes minimal myelin pathology.64,65
Intrathecal administration of epitope-enriched human
serum MOG-IgG in concert with adoptive transfer of
either cognate or non-cognate autoreactive T cells
indicates roles for MOG in antigen presentation and
antibody-dependent cell-mediated phagocytosis.66
Autoantibody pathophysiology in multiple sclerosis-
associated optic neuritis
Although a definitive target antigen has yet to be
identified in multiple sclerosis, autoantibodies cloned
from multiple sclerosis patients against a myelin antigen
are sufficient to induce complement-mediated demyeli­
nation in brain slices.67 Active multiple sclerosis lesions
show evidence of humoral immunopathology, including
prominent complement deposition and B-cell infiltration.
Although the composition of the T-cell infiltration differs
in multiple sclerosis and MOGAD,63 similar lesion
histopathology suggests that common mechanisms are
driving tissue injury.
Pathophysiology of GFAP-IgG-associated and
CRMP5-IgG-associated autoimmunity
GFAP and CRMP5 are intracellular astrocytic and
neuronal proteins. Therefore, autoantibodies against
GFAP and CRMP5 are unlikely to play a direct role in
93
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Multiple sclerosis-associated or MOGAD-associated optic neuritis NMOSD-associated optic neuritis

idiopathic optic neuritis
MRI: acute findings anterior visual pathways4,16,18–20,22,25,27–29,35,40,42,52,70
Optic nerve lesion Focal Often longitudinally extensive Longitudinally extensive
length
Optic nerve lesion Orbital and canalicular more common Longitudinal lesions typically involve Longitudinal lesions typically involve
location than intracranial orbital, canalicular, and intracranial; orbital orbital, canalicular, and intracranial;
involvement most common intracranial involvement most common
Chiasm involvement Rare Often associated with longitudinally Commonly involved; more often as isolated
extensive optic nerve lesion lesion
Optic tract Rare Rare Might be present
involvement
Optic nerve signal T2 signal with oedema and T1-gadolinium T2 signal with oedema and T1-gadolinium T2 signal with oedema and T1-gadolinium
enhancement enhancement enhancement
Perineuritic or orbital Rare Common Rare
fat enhancement
Visual evoked potentials: acute findings43,71–73
P100 latency delay Common Common Common
P100 amplitude loss Infrequent Common Infrequent
Extinguished VEP Infrequent Infrequent Common
Optical coherence tomography: chronic findings4,20,44,74
pRNFL thinning Present Severe Severe
mGCIPL thinning Present Severe Severe
INL thickening Present Present Present
OPL thinning Present Present Severe
MMO frequency Present Frequent Frequent
MOGAD=myelin-oligodendrocyte glycoprotein antibody-associated disease. NMOSD=neuromyelitis optica spectrum disorder. pRNFL=peripapillary retinal nerve fibre layer.
mGCIPL=macular ganglion cell-inner plexiform layer. INL=inner nuclear layer. OPL=outer plexiform layer. MMO=microcystic macular oedema. VEP=visual evoked potential.

Table 2: MRI, VEPs, and optical coherence tomography in different forms of optic neuritis

driving an inflammatory response. Histopathological
findings from autoimmune GFAP-associated meningo­
encephalomyelitis shows mixed inflammatory infiltrates,
with antibody-secreting cells present in the interstitial and
perivascular Virchow-Robin spaces.68,69 By contrast,
histopathology from CRMP5-IgG-associated optic neuritis
shows primarily CD8 T-cell infiltrates with patchy loss of
axons and myelin.25 Glial and axonal injury are absent in
most autoimmune GFAP-associated meningoencephalo­
myelitis pathology samples, and there is no loss of
astrocytic GFAP expression. These findings suggest that
the production of GFAP-IgG might be a damage-related
secondary effect.69 Perivascular inflammation in auto­
immune GFAP-associated meningo­encephalo­myelitis
might account for both the prominent isolated optic nerve
head oedema and the linear perivascular radial gadolinium
enhancement observed on MRI.51
Diagnosis of optic neuritis and autoimmune
optic neuropathies
MRI, visual field testing, visual evoked potentials (VEPs),
and OCT can aid in the diagnosis of optic neuritis. On
MRI, acute optic neuritis typically manifests with
T2-weighted signal change, oedema, and T1-gadolinium
enhancement of the affected optic nerve (figure 2).
Although not definitive, the length of the lesion, the optic
nerve segment affected, and the presence of perineuritic
and orbital fat enhancement might help to guide
serological testing and therapy for different optic neuritis
subtypes (table 2).70 Furthermore, the presence and
distribution of brain and spinal cord lesions could further
assist with diagnosis.2,35,38,51,75 The pattern of visual field
loss shows variability among and within disorders
(table 1).23,24,26,27 Prolonged VEP P100 latencies and
decreased amplitudes do not typically differentiate the
different optic neuritis disorders acutely (table 2).43,71–73 At
presentation, OCT measures of peripapillary retinal
nerve fibre layer (pRNFL) thickness might be normal or
increased, depending on the extent of optic disc oedema.
Chronic optic atrophy ensues with progressive pRNFL
and macular ganglion cell-inner plexiform layer
(mGCIPL) thinning and inner nuclear layer thickening;
in severe instances, microcystic macular oedema forms
in the inner nuclear layer (table 2).4,20,44,74 In patients with
recurrent visual symptoms, longitudinal changes in
visual fields, VEPs, and OCT might be helpful in
cementing an optic neuritis diagnosis.
Treatment of acute optic neuritis
Corticosteroids
The mainstay of optic neuritis treatment is high-dose
corticosteroids, usually in the form of intravenous
methylprednisolone for 3 days.5 However, in the real
world of clinical practice, clinicians might extend

94 www.thelancet.com/neurology Vol 22 January 2023


intravenous dosing for 5–7 days to gauge treatment
response, particularly in the context of suspected
MOGAD or NMOSD.16,75,76 Findings of the ONTT showed
that high-dose (1 g per day) intravenous methylpred­
nisolone for 3 days followed by 2 weeks of oral prednisone
led to faster recovery in patients with optic neuritis than
in patients receiving placebo.5 Subsequent investigations
have shown that the dose of corticosteroids might be
more important than the route; a 2018 randomised
clinical trial showed that 3 days of high-dose oral
prednisone (1250 mg) was equivalent to 1000 mg
intravenous methylprednisolone for optic neuritis.77 Data
to support high-dose corticosteroid treatment for greater
than 3 days in multiple sclerosis-associated optic neuritis
is absent; however, based on clinical judgment, extended
treatment might be useful in patients with recrudescent
or recalcitrant eye pain or vision loss. Nonetheless, it is
important to note that, in the ONTT, administration of
corticosteroids had no final effect on visual function
1 year after multiple sclerosis or idiopathic optic neuritis.
Since optic neuritis in the ONTT was almost exclusively
idiopathic or associated with multiple sclerosis,13 data on
responsiveness to high-dose corticosteroids might not be
applicable to the full spectrum of autoimmune optic
neuropathy subtypes. MOGAD-associated optic neuritis is
generally very responsive to corticosteroid treatment;
however, the long-term effects of corticosteroids on
recovery remain uncertain.22,75,78,79 Visual outcomes
following high-dose intravenous methylprednisolone in
NMOSD-associated optic neuritis are less favourable than
other subtypes of optic neuritis;76 however, early steroid
treatment (<48 h after diagnosis) might speed up
recovery.79,80 An oral prednisone taper after high-dose
corticosteroid therapy is generally unnecessary for
multiple sclerosis-associated optic neuritis; however, some
patients with MOGAD might require a longer taper or
show steroid dependency requiring months of oral
prednisone therapy.37,81 A survey done in 2020 of MOGAD
experts showed that slightly more than half of providers
recommended treatment with corticosteroids for 3 months
or more after an acute MOGAD attack; however, this was
less commonly recommended for treatment in children.82
Plasmapheresis
Plasmapheresis has been used for the treatment of severe
demyelinating attacks,83 steroid refractory optic neuritis,84
and NMOSD relapses.85,86 Despite plasma­pheresis being
commonly used in severe or steroid-refractory demyelin­
ating disease, scant randomised clinical trial data are
available to support its efficacy, and there have been no
large clinical trials in people with optic neuritis.8 Retro­
spective studies suggest that plasmapheresis within
7 days of onset of NMOSD-associated optic neuritis might
lead to better outcomes than delayed treatment.85,86
Because of the poor outcomes of NMOSD-associated
optic neuritis, early plasma­pheresis within 5–7 days of
vision loss is often recom­ mended and might be
www.thelancet.com/neurology Vol 22 January 2023
Series
considered at the onset of the visual impairment in cases
with a confirmed diagnosis of AQP4-IgG seropositive
NMOSD. Alternatively, a trial of high-dose intravenous
cortico­
steroids for 5 days could be followed by
plasmapheresis.
Intravenous immunoglobulins
Data supporting the efficacy of intravenous immuno­
globulins for acute optic neuritis are scant. Although
findings of an open-label, non-randomised prospective
trial suggested that intravenous immunoglobulin
treatment improved outcomes in steroid-refractory
multiple sclerosis-associated optic neuritis,87 randomised
clinical trials have shown no benefit with intravenous
immunoglobulins for acute or chronic optic neuritis.88,89
A retrospective study evaluating the outcomes of optic
neuritis attacks in NMOSD suggested that a combination
of intravenous immunoglobulins and corticosteroid
treatment might lead to better outcomes for severe
events.90 Intravenous immunoglobulins might be an
alternative for patients with recurrent optic neuritis who
have shown no benefits with—or shown intolerance to—
immunosuppressant agents, and for those who cannot
receive plasmapheresis.
Prognosis for visual recovery
The short-term and long-term prognoses for visual
recovery vary with optic neuritis subtype, and they are
probably affected by age, race, sex, genetic background,
and environmental factors.8 In the ONTT, most patients
with optic neuritis showed visual improvement within
30 days of symptom onset, regardless of treatment.5
Among the 278 patients in the ONTT with a baseline
HCVA of 6/15 or worse, all 278 patients improved by at
least one line of visual acuity, and all except six patients
improved by at least three lines, after 6 months.10 Based
on the data from the ONTT, no improvement in HCVA
by at least one line at 3 or more weeks after symptom
onset is a red flag in patients with presumed idiopathic
or multiple sclerosis-associated optic neuritis, and this
absence of improvement should prompt consideration
of alternative diagnoses.5,10 The ONTT also showed that
baseline HCVA was the best predictor of 6-month
visual acuity outcome.5,10,12 Yet, even among patients
with optic neuritis who present with severe visual loss
(≤6/60 [20/200] HCVA), recovery of HCVA to 6/12 or
better occurred in 82% of patients.10
Patients with MOGAD-associated optic neuritis also
tend to have better functional outcomes.8 In a case series
of 87 patients with optic neuritis who were seropositive
for MOG-IgG, only five (6%) individuals had a final
HCVA of 6/60 or worse.22 Recurrent optic neuritis attacks
probably contribute to poor outcomes.22 Most patients
with MOGAD-associated optic neuritis have robust
visual recovery, with a mean HCVA of 6/9 (20/30) in
affected eyes,22 only slightly worse than for patients with
idiopathic or multiple sclerosis-associated optic neuritis.5
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In the setting of NMOSD-associated optic neuritis,
visual prognosis can be poorer than it is for other
subtypes of optic neuritis.21,34 Approximately 30% of
patients with NMOSD will remain functionally blind
(HCVA of 6/60 or worse) in their affected eye after an
optic neuritis event, and 70% of those with a relapsing
disease course will manifest an HCVA of 6/60 or worse.20
A 2019 large multicentre study of 441 patients with
NMOSD showed that younger age of onset was associated
with an increased risk of recurrent optic neuritis and
blindness; the risk of blindness was also higher in
patients of African descent than in White patients.91
In a prospective study of paediatric patients with optic
neuritis, the underlying autoimmune disorder, the
presence of brain MRI white matter lesions, non-White
race, and non-Hispanic ethnicity affected vision at
presentation.92 However, it remains unclear how these
variables might affect long-term prognosis. Despite
nearly identical levels of neuroaxonal and retinal atrophy,
better visual outcomes have been observed in paediatric
patients with MOGAD-associated optic neuritis than in
their adult counterparts.93 Neuroplasticity in visual
association cortex has been reported as a damage-
independent determinant of visual recovery after optic
neuritis.94 Age-dependent differences in binocular
summation might also drive differences in visual
outcome.93,95
Quantifying visual recovery after optic neuritis
Visual recovery after optic neuritis has traditionally been
quantified by using static percepts of form, including
HCVA, colour vision, and perimetry techniques.
Panel 2: Extending dissemination in space criteria to the optic nerve
Case study
• A 41-year-old man presented with isolated vertigo that spontaneously resolved
• Brain MRI showed three periventricular T2 lesions that did not account for the vertigo
• 2 months later, the patient experienced acute vision loss in the right eye with
retrobulbar pain that worsened with eye movements; examination showed central
acuity loss, a right afferent pupillary deficit, and dyschromatopsia; he developed right
optic disc pallor in concert with peripapillary retinal nerve fibre layer loss and macular
ganglion cell-inner plexiform layer thinning on OCT
• Clinical concern of multiple sclerosis-associated optic neuritis was raised; MRI of the
orbits substantiated the presence of right optic neuritis; however, the brain and spinal
cord MRI did not show any new lesions; CSF analysis showed intrathecally produced IgG
• Formally, a diagnosis of multiple sclerosis cannot be made with the 2017 McDonald
criteria because neither the periventricular brain MRI lesions nor the optic nerve injury
or lesion meet dissemination in space criteria;2 within the next 2 years, the patient
became depressed, his gait deteriorated, and a clinical diagnosis of multiple sclerosis
was made
• Incorporating the optic nerve as a fifth anatomical location for dissemination in space in
the McDonald criteria for multiple sclerosis would have accelerated a diagnosis, helped
to initiate guideline-compliant targeted treatment, and potentially prevented
neurological injury; clinical, MRI, and optical coherence tomography criteria are now
available to reach high diagnostic sensitivity and specificity for optic nerve lesions1,4,112,113
96
However, HCVA is a relatively crude psychophysical
measure of optic nerve dysfunction and does not capture
the day-to-day challenges faced by patients with optic
neuritis. Even when HCVA improves to 6/12 or better,
patients with multiple sclerosis-associated optic neuritis
often show persistent deficits in low-contrast letter acuity
(LCLA) testing, and report corresponding reductions in
quality-of-life scores.96 Clinically meaningful changes in
LCLA have been defined as a ten-letter (or two-line)
reduction in the number of letters an individual can
distinguish; a 2017 study showed reductions of just seven
LCLA letters or five HCVA letters (one line) might also
be functionally relevant.96 Of note, although static visual
testing is the mainstay of most ophthalmic evaluations,
these testing techniques do not evaluate motion
perception, which is commonly impaired after optic
neuritis.97 In a prospective study of 21 patients, Raz and
colleagues showed that HCVA, contrast sensitivity,
colour vision, and standard automated perimetry
measures improved within 1–4 months in eyes with optic
neuritis, yet motion perception remained impaired over
a 1-year period.97,98 Motion perception deficits, such as the
Pulfrich effect (ie, the illusion that lateral motion of an
object has a depth component), might persist despite
good recovery of HCVA. The association of motion
perception deficits with VEP data,98 suggests that
demyelination in the afferent visual pathway causes
dysfunctional transmission of high temporal frequency
information needed for accurate perception of movement
in depth. Numerous OCT studies have shown that
permanent neuroaxonal injury, measured as thinning of
the pRNFL and mGCIPL layers of the inner retina, is
observed almost universally after optic neuritis.4,99–101 After
an acute optic neuritis event, most patients will lose
10–20 μm of their pRNFL thickness within 3–6 months.96,99
Furthermore, the extent of pRNFL and mGCIPL thinning
predicts long-term visual impairment after optic neur­
itis.101 A thickness of the pRNFL measuring less than
75 μm correlates with an irreversible linear decline in
visual field mean sensitivity in eyes with optic neuritis.99
The improved sensitivity of newer outcome measures—
including LCLA, VEP, OCT, and motion perception
techniques—challenges conven­ tional concepts regar­
ding recovery after optic neuritis, and probably
­
accounts for why 87% of patients presenting with
HCVA 6/12, or greater, report persistent visual
problems.102
The McDonald criteria and optic neuritis
The 2017 revision of the McDonald criteria did not
incorporate the optic nerve as a CNS region that could be
used to determine radiological DIS.2 Therefore, the
diagnosis of multiple sclerosis in patients presenting
with optic neuritis is challenged by impediments not
faced by patients with other clinically isolated syndromes.
For instance, a patient with an internuclear ophthal­
moplegia and an enhancing brainstem lesion in the
www.thelancet.com/neurology Vol 22 January 2023

medial longitudinal fasciculus would require only one
other non-enhancing T2 lesion in the periventricular,
juxtacortical, cortical, or spinal cord areas to qualify for
the diagnosis of multiple sclerosis; a symptomatic patient
with optic neuritis, however, would require two such
lesions, in addition to MRI or CSF evidence of
dissemination in time (DIT). Indeed, evaluating a
prospective cohort of 160 patients with a clinically
isolated syndrome, about 15% more patients would have
met DIS criteria for multiple sclerosis if the optic nerve
was included as a lesion site.103
A patient with optic neuritis and an atypical baseline
brain MRI might be burdened with an undue delay in
their multiple sclerosis diagnosis. Patients with optic
neuritis and with a high risk for developing multiple
sclerosis (two or more brain white matter lesions) are at
substantial risk for a new clinical attack or new MRI
lesion,11,104 and multiple studies indicate that there are
substantial consequences to delaying diagnosis and
treatment of such patients—ie, they will have an increased
number and volume of T2 lesions, a larger volume of
gadolinium-enhancing lesions, and greater brain atro­
phy.104–106 Data from a long-term analyses have shown that
patients with clinically isolated syndrome who are treated
early have a decreased risk of disability.107,108 The develop­
ment of new T2 lesions, or worsening T2 lesion volume in
the first 2 years of disease, has been correlated with
disability progression and whole brain atrophy 10–13 years
later.109,110 These MRI findings are in line with histo­
pathological observations of profound axonal loss in the
first year after disease onset.111 Thus, patients with optic
neuritis and an atypical baseline brain MRI (panel 2) are
no different from patients with clinically isolated
syndrome manifesting with other symptomatic lesions,
and they would benefit from early therapy.11,108
In addition to accelerating the diagnosis of multiple
sclerosis in patients with optic neuritis, the incorporation
of the optic nerve into DIS—but not DIT—criteria might
enhance multiple sclerosis diagnostic sensitivity and
accuracy.114 OCT, VEP, and orbital MRI might augment
current DIS criteria for patients with clinically isolated
syndrome.4 A 2019 multicentre study of 1530 patients
with multiple sclerosis and 368 controls found that an
absolute inter-eye difference of 5 μm (relative difference
of 5%) in the mean pRNFL, or 4 μm (4%) in mean
mGCIPL thickness, were indicative of previous optic
nerve injury.112 These cutoff values are supported by
population-based OCT data from 72 120 individuals with
detailed ophthalmological data.113 Similarly, prolongation
of VEP P100 is a sensitive marker of previous optic nerve
injury in visually asymptomatic patients and is effective
at detecting subclinical optic neuritis.114,115 Orbital MRI is
highly sensitive for optic neuritis lesion detection within
30 days of symptom onset.4 Furthermore, double
inversion recovery MRI has been reported to sensitively
identify both asymptomatic, symptomatic, and bilateral
optic neuritis lesions.116
www.thelancet.com/neurology Vol 22 January 2023
Series
Search strategy and selection criteria
References for this Series paper were identified by searches of
PubMed between Jan 1, 1969 and April 12, 2022. References
from relevant articles published over the past 5 years were
prioritised. We also searched the Cochrane library, MEDLINE,
and Embase. The search terms were “optic neuritis”,
“autoimmune optic neuritis”, “AQP4”, “neuromyelitis optica”,
“NMO”, “neuromyelitis optica spectrum disease”, “NMOSD”,
“myelin oligodendrocyte glycoprotein”, “MOGAD”, “multiple
sclerosis”, “ONTT”, “optical coherence tomography”, and
“visual evoked potential”. There were no language restrictions.
Review of reference lists of each selected article was used to
identify other relevant publications. The final reference list
was generated on the basis of the relevance to topics covered
in this paper and the quality of the publication.
Conclusions and future directions
Optic neuritis is frequently associated with multiple
sclerosis or other autoimmune conditions. Specific
antibodies have been identified, including those against
AQP4 and MOG, that produce characteristic clinical and
imaging findings. These newly defined optic neuritis
subtypes often require therapies aimed at diminishing
their specific pathological attack on the optic nerve.
Further research into the factors associated with vision
loss and the predilection for optic nerve involvement in
MOGAD and NMOSD is warranted. Blood–brain barrier
integrity, antigen organisation, metabolic activity,
neuronal and glial ion channel expression, and local
production of complement inhibitors might have
important roles and be amenable to therapeutic
modulations.
Although prognosis for visual recovery after
optic neuritis can be good, particularly for idiopathic optic
neuritis and multiple sclerosis-associated optic neuritis,
many patients have impaired visual quality of life and
complaints of persistent visual dysfunction. Unfortu­
nately, there are no medications that improve the final visual
outcome for these patients, leaving a large treatment void
and an unmet therapeutic need. Orbital MRI, VEP, and
OCT provide sensitive methods for detecting optic nerve
injury and might be used to substantiate a diagnosis of
optic neuritis in some clinical circumstances.117 Patients
with optic neuritis and MRI findings supporting
demyelinating disease would benefit from early diagnosis
and treatment. Our understanding of the diverse
mechanisms that produce optic nerve inflammation will
expand with new biomarkers and pave the way for better
classification schemes that target therapies for optic
neuritis subtypes. Future reparative therapies will
probably emerge to complement current acute treatments
and improve visual outcomes.
Contributors
JLB, VB, NJN, and SLG devised the idea for this review. JLB, FC, JJC,
AP, and SLG contributed to the literature search. JLB, FC, JJC, AP, VB,
97
 Series
NJN, and SLG designed and drafted the figures and tables. JLB, FC, JJC,
AP, and SLG prepared the initial manuscript draft. All authors
contributed to, reviewed, and approved the final draft of the paper.
Declaration of interests
JLB reports payment for consultation from MedImmune/Viela Bio/
Horizon Therapeutics, Alexion, Chugai, Clene Nanomedicine, Genentech,
Genzyme, Mitsubishi Tanabe Pharma, Reistone Biopharma, Beigene, and
Roche; personal fees from AbbVie; grants from Novartis, Mallinckrodt,
and Alexion; data safety monitoring board work for Roche–Genentech and
Clene Nanomedicine; and has a patent for aquaporumab issued.
FC reports payment for consultation from Roche, Alexion, and Frequency
Therapeutics, and speakers’ fees from Accure Therapeutics, Alexion,
Neurodiem, and the Sumaira Foundation. JJC reports payment for
consultation from UCB, Horizon, and Roche. AP received grant support
for remyelination trials in multiple sclerosis for the Amsterdam University
Medicam Centre, Department of Neurology, Multiple Sclerosis Centre
(RESTORE trial), University College London (RECOVER trial), and Fight
for Sight (nimodipine in optic neuritis trial); received royalties or licences
from Up-to-Date (Wolters Kluver) on a book chapter; received speaker fees
for the Heidelberg Academy; participates on advisory board for SC Zeiss
OCTA Angi-Network, Novartis OCTiMS study; holds leadership roles for
governing board IMSVISUAL; is chairman of ERN-EYE Neuro-
ophthalmology (until October, 2020), board member of National Dutch
Neuro-ophthalmology Association; received equipment from OCT
angiography from Zeiss (Plex Elite); and received medical writing support
from Novartis for a manuscript. SLG reports payment for consultation
from Biogen and Genentech. VB is a consultant for GenSight Biologics
and Neurophoenix, and receives research support from GenSight
Biologics and Santhera/Chiesi. NJN is a consultant for GenSight Biologics,
Santhera/Chiesi, Stealth Biotherapeutics, and Neurophoenix; receives
research support from GenSight Biologics and Santhera/Chiesi; is a
participant in educational webinars sponsored by WebMD-Global
Medscape and First Class; and is a medical-legal consultant in matters
not related to this work.
Acknowledgments
JLB is supported by National Institutes of Health (NIH) grants
R01-EY022936, R21-032399, and R01-NS115488. VB and NJN are
supported in part by department grants (Department of Ophthalmology,
Emory University School of Medicine, Atlanta, GA USA) from the
NIH/National Eye Institute core grant P30-EY06360, and from Research
to Prevent Blindness (New York, NY USA). The National Institute for
Health and Care Research Biomedical Research Centre at Moorfields
Eye Hospital supported AP.
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