Multiple sclerosis

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REVIEW

Re-evaluating the treatment of acute optic neuritis

Jeffrey L Bennett,1 Molly Nickerson,2 Fiona Costello,3 Robert C Sergott,4
Jonathan C Calkwood,5 Steven L Galetta,6 Laura J Balcer,6 Clyde E Markowitz,7
Timothy Vartanian,8 Mark Morrow,9 Mark L Moster,4 Andrew W Taylor,10
Thaddeus W W Pace,11 Teresa Frohman,12 Elliot M Frohman12,13

For numbered affiliations see ABSTRACT after the inception of visual symptoms. The emer-
end of article. Clinical case reports and prospective trials have gence of intravenous methylprednisolone for the
Correspondence to demonstrated a reproducible benefit of hypothalamic- treatment of a range of immune-mediated disorders
Dr Elliot M Frohman, pituitary-adrenal (HPA) axis modulation on the rate of prompted its application for the treatment of acute
Department of Neurology and recovery from acute inflammatory central nervous system MS exacerbations, including AON, whereby early
Neurotherapeutics, University (CNS) demyelination. As a result, corticosteroid benefits were noted regarding the course of clinical
of Texas Southwestern Medical
preparations and adrenocorticotrophic hormones are the recovery.3
Center at Dallas, 5323 Harry
Hines Blvd., Dallas, Texas current mainstays of therapy for the treatment of acute In 1992, the Optic Neuritis Treatment Trial
75235, USA; optic neuritis (AON) and acute demyelination in multiple (ONTT) provided the first comprehensive examin-
elliot.frohman@ sclerosis. ation of the benefits of steroid therapy for AON in
utsouthwestern.edu Despite facilitating the pace of recovery, HPA axis a large and representative patient cohort. In the
Received 27 March 2014 modulation and corticosteroids have failed to ONTT, patients were randomised to receive
Revised 5 August 2014 demonstrate long-term benefit on functional recovery. placebo, oral (low-dose) prednisone (1 mg/kg/day
Accepted 28 September 2014 After AON, patients frequently report visual problems, for 14 days) or high-dose intravenous methylpred-
Published Online First motion perception difficulties and abnormal depth nisolone (250 mg 4 times daily for 3 days), fol-
29 October 2014
perception despite ‘normal’ (20/20) vision. In light of lowed by oral prednisone (1 mg/kg/day for
this disparity, the efficacy of these and other therapies 11 days). At 6 months, colour vision and contrast
for acute demyelination require re-evaluation using sensitivity significantly improved in the methylpred-
nisolone arm4; however, after 1 year, there was no

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modern, high-precision paraclinical tools capable of
monitoring tissue injury. significant difference between treated and untreated
In no arena is this more amenable than AON, where patients in any functional outcomes.5 Intravenous
a new array of tools in retinal imaging and methylprednisolone was found to accelerate the
electrophysiology has advanced our ability to measure rate of visual recovery over the first 15 days.4
the anatomic and functional consequences of optic nerve Objective measures of optic nerve or retinal archi-
injury. As a result, AON provides a unique clinical model tecture were not available at the time of the
for evaluating the treatment response of the derivative ONTT; however, a subsequent study showed no
elements of acute inflammatory CNS injury: effect of corticosteroids on optic nerve atrophy.6
demyelination, axonal injury and neuronal degeneration. In a subsequent analysis, patients randomised to
In this article, we examine current thinking on the receive treatment with high-dose intravenous
mechanisms of immune injury in AON, discuss novel methylprednisolone in conjunction with 11-day
technologies for the assessment of optic nerve structure low-dose oral prednisone taper exhibited a signifi-
and function, and assess current and future treatment cantly reduced risk of developing clinically definite
modalities. The primary aim is to develop a framework MS (defined by the development of a second bona
for rigorously evaluating interventions in AON and to fide inflammatory demyelinating syndrome) over
assess their ability to preserve tissue architecture, re- the subsequent 2 years.7 Notwithstanding this
establish normal physiology and restore optimal apparently noteworthy outcome, no significant
neurological function. disease-modifying effects were confirmed beyond
the second year of ascertainment. Although the
Open Access
Scan to access more data from the ONTT have been reviewed rigor-
free content
CURRENT TREATMENT OF ACUTE OPTIC ously, some have questioned the finding that intra-
NEURITIS venous steroids may produce a short-term benefit
Corticosteroids in delaying the onset of MS and that the risk of
In 1961, Miller and colleagues demonstrated that recurrent optic neuritis increases with the use of
patients with multiple sclerosis (MS), who were oral prednisone alone.8 Concerns include the lack
treated with corticotrophin recovered more quickly of treatment blinding, post hoc analyses, small
and completely from acute relapses than did sample sizes, recoding of patient classifications and
patients treated with saline.1 A subsequent study of changes in the statistical assumptions. Despite the
acute optic neuritis (AON) by Rawson and wealth of data gathered in the ONTT, critical ques-
To cite: Bennett JL,
Nickerson M, Costello F, Liversedge2 demonstrated that a similar hastening tions regarding patient management remain
et al. J Neurol Neurosurg of visual recovery was noted after acute retrobulbar unanswered. These include the following: (1)
Psychiatry 2015;86: neuritis; however, no significant difference between whether corticosteroid treatment is beneficial in
799–808. visual outcomes could be determined 12 months patients whose symptom duration is longer than
Bennett JL, et al. J Neurol Neurosurg Psychiatry 2015;86:799–808. doi:10.1136/jnnp-2014-308185 799
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8 days; (2) whether higher doses of corticosteroids are more optic nerve head component (ONHC) of the multifocal ERG
effective than lower doses; (3) what is the optimal corticosteroid (mfERG) represent technical advancements in our ability to
regimen; (4) whether the observed increased ON recurrence characterise precisely and objectively the complex architecture
rate associated with oral prednisone also is observed in MS of the retina and optic nerve and correlate structural integrity
attacks and (5) whether high-dose methylprednisolone given with corresponding functional measures of visual system physi-
periodically will improve the prognosis for patients with MS. ology.15–22 The application of these new tools to the investiga-
tion of structure-function derangements in AON will validate
Intravenous immunoglobulin and plasma exchange using the eye as a surrogate for studying the various mechanisms
Intravenous immunoglobulin (IVIg) and plasma exchange of central nervous system (CNS) injury in MS and provide a
(PLEX) also have been studied for the treatment of AON. Roed clinical paradigm to assay the potential neuroprotective and
et al9 found no effect of IVIg on long-term visual function or neurorestorative effects of therapeutic agents. These contentions
on the latency of visual evoked potential (VEP) responses after have already been partly corroborated by a number of recent
AON. Further, IVIg did not improve visual function in patients investigations that have provided seminal insights into the
with persistent vision loss after AON.10 Alternately, PLEX has pathobiological underpinnings that drive structural and func-
demonstrated efficacy in the treatment of refractory AON11 and tional derangements in the visual system of patients with MS.
AON associated with neuromyelitis optica (NMO).12 Ruprecht
et al11 observed a significant improvement in visual recovery fol- OCT/scanning laser polarimetry
lowing the institution of PLEX in cases of refractory AON; OCT and SLP are optical imaging modalities that can measure
however, the rapid use of PLEX in this study may have masked the RNFL thickness. Already, multiple investigations have con-
any delayed benefit still to be derived from initial treatment firmed that both OCT and SLP have the capability to confirm
with intravenous methylprednisolone. In fact, the authors noted significant thinning of this inner retinal layer composed of RGC
that there is significant variability in the magnitude and tempo axons and glial tubules formed by Muller cell processes. The
of efficacy derived from corticosteroid use among patients with RNFL axons are unmyelinated and derived from the ganglion
AON. Indeed, a similar degree of variability can be observed in cells of the macular retina, which become organised at the
patients who derive clinical benefits from PLEX, either in isola- neural-retinal rim (the tissue between the papilla of the optic
tion or following corticosteroid treatment. disc and the edge of the optic cup), beyond which point they
A recent study evaluating the addition of PLEX to intravenous are consolidated as the optic nerve (composed of about 1–1.2
methylprednisolone in the acute treatment of NMO-associated million axons). As the optic nerve axons traverse the lamina cri-
AON showed significant improvements in high-contrast acuity, brosa, they acquire myelin derived from CNS oligodendrocytes,
visual fields and temporal retinal nerve fibre layer (RNFL) thick- with their corresponding electrical transmission properties trans-
ness,12 but not low-contrast letter scores or colour vision. The

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forming from slow membrane to highly rapid, saltatory
early, first-line use of PLEX in the treatment of AON, however, conduction.17
has yet to be evaluated. OCT measures the interference spectrum of infrared light
that has penetrated through the retina using a spectrometer and
Erythropoietin highspeed linescan camera. In spectral domain OCT, the ‘back-
Systemic infusion of erythropoietin with and without methyl- scattered’ spectrum is Fourier transformed to obtain the magni-
prednisolone has demonstrated beneficial effects on retinal gan- tude and echo time delay of the light, thereby producing a set
glion cell (RGC) function and survival in a rat model of of axial images for analysis.23 Alternatively, SLP is an imaging
experimental autoimmune encephalomyelitis.13 Erythropoietin technique that utilises the polarising birefringence properties of
administration increased protein levels of phospho-Akt, the RNFL to determine thickness of the retinal layers.24 The
phospho-MAPK 1 and 2 and Bcl-2, indicating that activation of principal compositional element thought to contribute to RNFL
the Akt signalling pathway may be critical for limiting RGC birefringence is the intra-axonal microtubule. Because the
apoptosis after AON. In combination with methylprednisolone, SLP-derived RNFL thickness is calculated using the phase shift
erythropoietin led to partial recovery of pattern-reversal VEPs of polarised light, compensation for corneal birefringence is
and significantly improved flash electroretinograms (ERGs).13 required and may be problematic in some individuals.24
Recently, a phase 2 clinical trial compared systemic erythropoi- Owing to their distinct technologies, OCT and SLP demon-
etin with placebo in the treatment of AON in a small cohort of strate RNFL oedema and thinning with varying efficacy.
patients.14 Treatment with erythropoietin resulted in significant Specifically, OCT shows RNFL swelling (as water influences
improvement in the average thickness of the peripapillary RNFL infrared light backscatter in OCT, whereas oedema is invisible
(as measured by optical coherence tomography (OCT)) and to SLP because water is not a birefringent medium) better than
improved VEP latencies at week 16. Mean visual acuity showed SLP.25 Both technologies, however, appear equally efficient in
a trend towards improvement after erythropoietin treatment. measuring RNFL loss after acute inflammatory injury.
Given the inherent variability of optic nerve electrophysiology, Alternately, determining the true baseline RNFL thickness
the limitations of time-domain OCT, and the small study size, measure early in AON may be more accurate when utilising SLP,
the paraclinical benefits observed with erythropoietin treatment given that thickness measures are confounded by oedema in
will need to be confirmed in a multicentre prospective OCT. Despite the potential limitations of OCT in the acute
investigation. setting of AON, the advent of high-precision retinal segmenta-
tion with spectral domain OCT (see below) has elucidated excit-
Why a renewed focus on optic neuritis? ing data that suggest that detailed retinal analysis can yield
Novel technologies and an improved understanding of neuroin- baseline thickness measures that are not influenced by RNFL
flammation have provided an ideal environment for renewed oedema and provide a ‘true’ baseline measure for the longitu-
investigations into the early treatment for AON (table 1). dinal analysis of putative neuroprotective therapeutic agents.22
Spectral domain OCT, scanning laser polarimetry (SLP), diffu- The introduction of SLP and OCT in the eye clinic has
sion tensor imaging (DTI), multifocal VEPs (mfVEP) and the greatly enhanced the appreciation for the timing and extent of
800 Bennett JL, et al. J Neurol Neurosurg Psychiatry 2015;86:799–808. doi:10.1136/jnnp-2014-308185
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Table 1 Investigations into the early treatment for AON
Intervention Participants Outcome Side effects Reference

ACTH 40 IU/day×30 days (n=25) 50 patients with acute retrobulbar Patients treated with ACTH recovered ‘more Facial or ankle oedema 69

Placebo (n=25) neuritis quickly and more completely’ (high-contrast

visual acuity)
70
ACTH 40 IU/day×30 days (n=27) 54 patients with acute optic neuritis No differences in high-contrast visual acuity, Weight gain, facial oedema,
Placebo (n=27) (4 patients with MS in ACTH group visual field, macular threshold or colour vision ankle oedema, acne, depression,
and 5 in placebo group) rash
14
EPO 33 000 IU/day×3 days 40 patients with first episode optic EPO-treated patients had less RNFL thinning, IVMP—hot flashes, facial
+IVMP 1000 mg/day×3 days neuritis smaller reduction in retrobulbar diameter of flushing, mood changes and
(n=21) optic nerve and shorter VEP latencies; hyperglycaemia attributed to
Placebo+IVMP differences in visual function did not reach IVMP
1000 mg/day×3 days (n=19) significance EPO—headache
4
IVMP 1000 mg/day×3 days+oral 457 patients with acute optic The group receiving IVMP recovered visual IVMP—transient depression,
prednisone 1 mg/kg×11 days neuritis across 15 clinical centres function faster than the group receiving oral acute pancreatitis
(n=151) prednisone only; at 6 months the IVMP group IVMP, prednisone—sleep
Oral prednisone 1 mg/ had better contrast sensitivity, colour vision, a disturbance, mild mood change,
kg×14 days (n=156) trend towards better visual field, but not stomach upset and facial flushing
Placebo (n=150) better visual acuity
6 71
IVMP 1000 mg /day×3 days 66 patients with first episode acute Optic nerve atrophy at 6 months was similar Not reported
(n=33) unilateral optic neuritis for placebo and IVMP-treated groups
Placebo (n=33) IVMP did not improve visual outcomes or
lesion length
72
Plasma exchange×5 cycles 10 patients with RRMS, 1 patient 70% of patients responded to plasma Hypofibrinogenaemia
(n=23) with NMO, 12 patients with optic exchange on measures of visual acuity; no
neuritis as a clinically isolated control group was included in the study
syndrome
73
IVIg 400 mg/kg/day×5 days+IVIg 47 patients with steroid-refractory A greater proportion of the IVIg-treated Generalised headaches, infusion
400 mg/kg/day once monthly for optic neuritis in MS patients demonstrated improvement in their reactions
5 months (n=23) visual acuity compared with untreated control
No treatment (n=24) participant
74
Case report of 23 patients 23 patients with steroid-unresponsive 70% of patients showed some improvement
treated with 5 cycles of plasma optic neuritis associated with other

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exchange conditions (NMO, MS, CIS) in some
cases
61
IVMP 250 mg every 6 h×3 days 60 patients with first attack of AON; Greater RNFL thickness (overall, nasal, inferior, None reported
+oral prednisone 1 mg/ visual symptoms <8 days and superior quadrants) in memantine-treated
kg×11 days+memantine (n=29) group; no difference in visual function
IVMP 250 mg every 6 h×3 days
+oral prednisone 1 mg/
kg×11 days+placebo (n=31)
ACTH, adrenocorticotropic hormone; AON, acute optic neuritis; EPO, erythropoietin; IVIg, intravenous immunoglobulin; IVMP, intravenous methylprednisolone; MS, multiple sclerosis;
NMO, neuromyelitis optica; RNFL, retinal nerve fibre layer; RRMS, relapsing remitting MS.

axonal loss after retrobulbar AON. RNFL oedema as measured algorithms for OCT have been used to sensitively and reprodu-
by OCT and SLP is far more common than noted on clinical cibly measure anatomic compartments that reflect the extent of
examination.25 Oedema is evident in approximately 82% of pathological and functional injury following AON. Specifically,
affected optic nerves and remains evident in at least one quad- the thickness of the ganglion cell and inner plexiform layers
rant in the majority of patients by 12 weeks.25 On average, as (GCL+IPL) facilitates measurement of ganglion cell loss after
measured by OCT, patients with AON lose 22 mm more RNFL AON and correlates with visual function in affected
in their affected eye than in their unaffected eye in the 3–6 individuals.18 22
months after the inception of visual symptoms.26
To provide some perspective, the RNFL achieves a thickness
of approximately 100 mm by 10 years of age, and over the sub- MRI techniques
sequent 60 years of life, healthy individuals can expect to lose In contrast to OCT, conventional MRI has demonstrated mixed
approximately 10 mm of thickness (corresponding to a rate of correlations between optic nerve atrophy and visual function
approximately 0.017% annually). After AON, RNFL loss is after AON. In some investigations, the use of short-echo
evident in the majority of individuals by 3 months,25 with fluid-attenuated inversion recovery and T1-weighted spin echo
nearly all patients showing segments of RNFL loss by 3 imaging has revealed a significant relationship among the degree
months.25 26 27 RNFL thinning as measured by OCT has been of optic nerve atrophy and visual acuity, VEP amplitudes and
observed to correlate with multiple visual metrics: high-contrast latencies.30 31 Across those studies that evaluated acute changes,
acuity, low-contrast acuity, visual field and colour vision.26 28 29 the affected optic nerve was initially oedematous, with an
For example, studies have demonstrated that a relevant loss of increased mean cross-sectional area; later, optic atrophy devel-
seven letters or more in low-contrast letter acuity predicts a cor- oped. The administration of ‘high-dose’ intravenous methyl-
responding reduction in the thickness of the RNFL in MS.28 prednisolone did not prevent or attenuate the subsequent
The development and application of novel retinal segmentation development of optic nerve atrophy.32
Bennett JL, et al. J Neurol Neurosurg Psychiatry 2015;86:799–808. doi:10.1136/jnnp-2014-308185 801
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Advanced MRI metrics, such as those derived with DTI and transformation of slow membrane conduction to fast saltatory
magnetisation transfer imaging ratios (MTR), have recently been conduction, as axons traverse the lamina cribrosa and become
adapted for orbital imaging.33 Traditionally, DTI and MTR myelinated.41 After AON, the ONHC waveforms are abolished
methods have been employed infrequently for the purpose of and later recover, representing the transient effects of conduc-
orbital imaging, principally due to multiple and formidable tion block due to reversible demyelination. Frohman et al17
technical challenges. In particular, the small size and mobile have demonstrated that eyes with previous optic neuritis in
nature of the optic nerve, combined with confounding factors patients with MS exhibit changes or loss in the ONHC wave-
such as the signal intensity heterogeneity of the surrounding form that correlate with reduction in low-contrast letter acuity,
orbital structures (fat, bone and cerebrospinal fluid) mandate RNFL thickness, visual field depression and amplitude loss and
the application of rapid acquisition protocols in conjunction latency delay on mfVEP. Therefore, abnormalities of the ONHC
with high spatial resolution.34 response may provide a novel, additional pathophysiological sig-
In a non-conventional imaging study, MTR region of interest nature of optic neuritis injury for acute treatment trials.
analysis showed a correlation with full-field VEP.35 In contrast,
subsequent imaging analyses of the entire length of the optic Biomarkers
nerve demonstrated a significant relationship with visual acuity Serum and plasma neurofilament levels, heavy (NfH) and light
but not with VEP latency changes.31 The MTR (a metric related (NfL), are elevated in patients with AON, independent of the
to brain tissue integrity) in affected optic nerves declined slowly inflammatory mechanism.19 21 42 43 Supportive of a link
with a nadir of 240 days, a period that is longer than the stand- between persistent vision loss and axonal degeneration, the
ard interval for visual recovery.36 This may indicate that the levels of NfH and NfL have been observed to correlate with the
window for treating AON may extend beyond the current clin- extent of vision loss and the loss of retinal nerve fibre thickness
ical paradigm. following AON. Therefore, in addition to the aforementioned
Recently, technical refinements in receiver coil characteristics, imaging and electrophysiological measures of optic nerve integ-
combined with high-field magnetic environments, have gener- rity and function, blood measures of NfH and NfL may provide
ated improved signal–to-noise ratios for DTI measures of axonal additional information on neuronal loss and visual prognosis.
and myelin pathology in AON. Radial diffusivity has proven to
be the most sensitive metric for differentiating the unaffected Neuroimmunology
from affected optic nerves and correlates with visual recovery, AON lesions are rarely acquired for histopathological examin-
electrophysiology (VEP latency and amplitude) and RNFL thick- ation due to the limited nature of most injuries and the high
ness (OCT).33 37 DTI, therefore, provides a novel, sensitive probability for recovery. As a result, the composition of the
modality to complement RNFL structural injury in the evalu- inflammatory infiltrate in AON and the extent of glial and neur-

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ation of acute ON injury. onal injury are inferred from that of acute CNS brain and spinal
cord MS lesions. Demyelination in AON is presumed to be
Electrophysiology mediated by activation of endogenous microglia and a mixed
Electrophysiologic measures can reveal seminal features of inflammatory infiltrate consisting of T and B cells and peripheral
axonal degeneration and inflammatory demyelination within the macrophages. As in acute MS lesions, local expression of human
anterior visual system. Prolongation of the VEP P100 latency leucocyte antigen (HLA) class II antigen, Th1 and Th17 proin-
has long been used as a measure of conduction delay through flammatory T cells and axonal transections are evident.44 Tsoi
the optic nerve and is a sensitive pathophysiological signature of et al45 noted pathological findings similar to those found in
demyelination.33 38 In contrast, a reduction in VEP amplitude chronic active MS lesions in a 10-month-old ON lesions recov-
can serve as a measure of axonal injury. As a summated response ered at autopsy. These included myelin breakdown, infiltration
of multiple neuronal elements with differently oriented elec- and activation of macrophages and microglia, and gliosis. A
trical dipoles, the full-field VEP is subject to significant limita- detailed characterisation of the cellular infiltrate, measures of
tions. First, the full-field VEP is dominated by the macular axonal transection, and local cytokine secretion were not
region and may not detect a significant fraction of ON cases performed.
with peripheral field loss. Next, full-field VEP may be hampered The response of AON to interventions such as methylpredni-
by changes in waveform architecture depending on the location solone, corticotrophin and PLEX implicate the combined action
of the optic nerve lesion or visual field loss. of cellular and humoral immune processes (table 2). The anti-
Advancements in optics have introduced multifocal technol- inflammatory and immunosuppressive actions of corticosteroid
ogy to VEP studies, and increased the ability to detect small administration and hypothalamic-pituitary-adrenal axis modula-
changes within the central visual field.39 Full-field and mfVEP tion are quite complex and act at multiple levels to reduce the
studies have demonstrated utility in predicting the magnitude of acute inflammatory response.46 At the cellular level, intravenous
optic nerve injury and visual outcome in AON.39 40 The sensi- corticosteroids reduce the number of circulating monocytes and
tivity of mfVEP may be enhanced further through the use of lymphocytes by modulating cell apoptosis. At the cell surface,
low-contrast pattern-reversal stimuli (analogous to the use of they reduce the expression of adhesion molecules and matrix
low-contrast letter acuity charts), allowing for the detection of metalloproteinase expression to lessen blood-brain barrier per-
mild residual injury or occult damage in the so-called meability. In addition, corticosteroids alter the transcription of
‘unaffected’ eye.16 proinflammatory and anti-inflammatory cytokines expressed by
The traditional ERG has had limited utility in the study of peripheral blood mononuclear cells. In a recent study, the proin-
eyes in patients with MS. Nonetheless, the ONHC is a discrete flammatory cytokines IL-17A, IL-6 and IL-23p19 were downre-
late-response waveform of the ERG that can be used to detect gulated by the administration of intravenous corticosteroids in
electrophysiological changes in the context of acute AON. The patients with MS, whereas anti-inflammatory cytokines IL-10,
ONHC is produced through a modified stimulus paradigm that TGF-β1 and IL-27p28 were upregulated.47 In other investiga-
includes global flash stimuli interleaved at specific intervals in tions, two groups noted enhanced T regulatory cell (Treg) func-
the mfERG. The ONHC is thought to represent the tion after the administration of intravenous corticosteroid
802 Bennett JL, et al. J Neurol Neurosurg Psychiatry 2015;86:799–808. doi:10.1136/jnnp-2014-308185
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Table 2 Clinical measures of optic nerve function and structure
Structure/ Investigational
function technique Measurement Change in optic neuritis affected eyes

Function High-contrast visual High-contrast resolution Worsens acutely and improves over time4
acuity
Function Low-contrast visual Low-contrast resolution Worsens acutely and improves over time4
acuity
Function Colour vision Blue-yellow and red-green defects discrimination Abnormalities in colour discrimination that correlate with RNFL
thickness29
Function ERG Physiological integrity of cone and rod responses No difference in full field ERG.75 Loss of OHNC of multifocal
ERG17
Function VEP Demyelination of the visual pathway Latency delay that improves in a fraction of affected individuals
over time22
Structure Fundus photography Shows structure of inner surface of the eye (retina, optic disc, Optic disc pallor, atrophy
macula and fundus)
Structure MRI Optic nerve atrophy, tissue injury, blood-brain barrier breakdown
Structure DTI Imaging of white matter damage and integrity of visual white Axonal and demyelinating injury to optic nerve and
matter tracts postgeniculate white matter33 76
Structure MTR Myelination status and axonal content of the optic nerve Demyelinating injury77
Structure SLP Measure RNFL thickness Shows a decrease in retardance in eyes with axonal injury
associated with visual field loss78
Structure OCT Measure RNFL thickness RNFL thickness decreases with MS and decreases further with
MS-related ON79; shows acute thickening due to edema25
Function mfERG Measures the transformation of slow membrane conduction in
unmyelinated ganglion cell axons to fast saltatory conduction in
myelinated axons
Function ONHC of the mfERG Transient effects of conduction block due to reversible Loss of this response signifies loss of myelination at the lamina
demyelination cribosa and disrupted transition from membrane to saltatory
transmission17
Function mfVEP Sensitive measure of axonal damage Abnormal latency80
Function Pupillometry Measurement of pupil diameter as an indicator of neural inhibitory Pupillary reflex metrics impaired81

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mechanisms
DTI, diffusion tensor imaging; ERG, electroretinogram; mfERG, multifocal ERG; mfVEP, multifocal VEP; MS, multiple sclerosis; MTR, magnetisation transfer imaging ratios; OCT, optical
coherence tomography; ONHC, optic nerve head component; RNFL, retinal nerve fibre layer; MTR, magnetisation transfer imaging ratios; SLP, scanning laster polarimetry; VEP, visual
evoked potential.

treatment for acute MS relapse.48 49 These results suggest that melanocortin peptides. Melanocortin peptides bind to
corticosteroid therapy may restore impaired Treg function and G-protein coupled cell surface melanocortin receptors, of which
reset the ratio of proinflammatory and anti-inflammatory cyto- five have been identified as melanocortin receptors 1–5
kines after acute inflammatory demyelination. Although the (MC1R–MC5R).52 The binding of ACTH to MC2R in the
potent anti-inflammatory effects of glucocorticoids have proven adrenal glands results in steroidogenesis. The other MCRs,
to be useful for increasing the rate of resolution of AON, it is however, are located throughout the body and are responsible
possible that they have a negative impact on remyelination. In for a variety of functions including direct, steroid-independent
the cuprizone and experimental autoimmune encephalomyelitis reduction of inflammation in the periphery and in the CNS
animal models, high-dose glucocorticoids were found to inhibit (reviewed in52). Melanocortin peptides also have a unique role
remyelination,50 51 suggesting that there may be a need for in maintaining immunological homoeostasis in the eye; they
AON therapies that can promote a more conducive environment have been reported to induce a functionally important popula-
for remyelination and neuronal recovery. tion of CD4+ regulatory T cells in the experimental auto-
PLEX is presumed to mediate a therapeutic effect, at least in immune uveitis animal model.53 Additionally, there are reports
part, through the removal of pathogenic humoral and plasma that melanocortin peptides can have neurotrophic effects.54
factors. Indeed, PLEX has been shown to benefit both patients Clinical studies with advanced physiological measures will need
with idiopathic AON and those with NMO AON.11 12 The to be performed to elucidate whether these properties are rele-
utility of PLEX for the treatment of AON suggests that anti- vant in optic neuritis.
bodies and/or proinflammatory serum components may facilitate
optic nerve injury in AON. Optic neuritis: alternative inflammatory injuries
A fraction of patients with AON experience this syndrome in
Novel anti-inflammatory actions of adrenocorticotropin the context of NMO, a demyelinating disorder directed against
hormone the aquaporin-4 (AQP4) water channel, with predilection
Recent studies have shown that α-melanocyte stimulating for the optic nerves and spinal cord. Compared with that of
hormone and adrenocorticotropic hormone (ACTH) have anti- MS-associated ON, vision loss secondary to ON in the context
inflammatory effects in a number of models of acute CNS and of NMO is typically severe (acuity loss, visual field loss),55 with
ocular inflammation. ACTH is a member of the a lower predilection towards significant recovery and a greater
pro-opiomelanocortin-derived family of peptides called amount of axonal degeneration as measured by OCT.56 The
Bennett JL, et al. J Neurol Neurosurg Psychiatry 2015;86:799–808. doi:10.1136/jnnp-2014-308185 803
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greater magnitude in severity of the clinical syndrome, coupled promptly to treatment with systemic corticosteroids. These indi-
with a worse prognosis for functional recovery in viduals relapsed rapidly on steroid withdrawal, and the condi-
NMO-associated optic neuritis, may be a result of the targeted tion was labelled chronic relapsing inflammatory optic
destruction of CNS and retinal astrocytes. neuropathy (CRION) to distinguish it from typical optic neur-
Among the broad diversity of CNS ‘housekeeping’ functions, itis. Arndt et al63 described an additional cohort of patients
astrocytes support neurotransmission and myelination, facilitate with recurrent isolated optic neuritis (RION) who experienced
the clearance of extracellular potassium and water and facilitate repeated attacks of AON that resolved without treatment but
nerve conduction. Further, astrocytes produce cytokines, such as resulted in progressive vision loss over time. No patients with
platelet-derived growth factor, that stimulates the proliferation CRION or RION presented with or developed MRI lesions
and differentiation of oligodendrocyte precursors into premyeli- consistent with MS, and testing for antibodies against AQP-4
nating oligodendrocytes.57 Consequently, the loss of astrocytes revealed that only a small fraction of these individuals suffered
in NMO-associated optic neuritis may impair remyelination, an from NMO.64 Patients with CRION or RION likely represent a
adaptive response to injury with trophic, protective, ion channel small fraction of AON with a unique immunopathology. This
and energetic ramifications. could be due to targeting of a unique optic nerve-specific
The depletion of astrocytes within the proximity of active antigen or a deficient T regulatory response, or perhaps it is a
CNS injury in NMO may also result in a protracted state of consequence of a novel inflammatory response. The prospective
demyelination resulting in an inefficient method of axonal trans- evaluation of patients with acute CRION and RION with
mission by membrane rather than saltatory (nodal/paranodal) immunological measures, OCT and electrophysiology will be
conduction. In the healthy CNS, astrocytic processes drape critical for identifying novel diagnostic and therapeutic
themselves around the axons at myelin internodes and serve approaches.
almost as a ‘place-setting’ for the orderly positioning of myelin
wraps. When astrocyte loss is coupled with chronic demyelin- New therapies for the treatment of acute demyelinating
ation, the intrinsic organisation of myelination and the cluster- injury
ing sodium channels at the nodes of Ranvier and paranodal The array of MS therapies has increased rapidly over the past
regions is altered, and axonal conduction becomes inefficient. decade. Therapies approved in the 1990s, β-interferon and gla-
Interestingly, mice lacking glial fibrillary acidic protein (GFAP), tiramer acetate, have been joined by new treatments with novel
an astrocyte-specific intermediate filament, demonstrate mechanisms of action: inhibition of leucocyte adhesion (natali-
impaired optic nerve myelination, implicating the importance of zumab); interference with S1P-mediated lymph node egress (fin-
astrocyte integrity in myelination.58 golimod); interference with lymphocyte replication
The much broader distribution of sodium channels necessary (teriflunomide) and activation of the oxidative stress response

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to reconstitute axonal conduction in the setting of chronic pathway (dimethyl fumarate). The ability of these therapies to
demyelination is commensurately associated with a greater ener- minimise injury or promote recovery after acute demyelination,
getic demand on intra-axonal mitochondria.59 The greater however, has rarely been evaluated. Based on their rapid onset
demand for ATP is at least partly related to the need to establish and CNS penetration, some of these newer MS therapies may
and maintain an altered equilibrium, secondary to multiple offer promise in limiting vision loss and facilitating recovery
derangements in ion currents and altered channel characteristics. after AON. A single dose of natalizumab, administered soon
For example, newly synthesised sodium channels undergo pore after the onset of an MS relapse, did not hasten clinical recovery
closure, and thereby cessation of membrane depolarisation, in but decreased Gd-enhancing lesion volume.65 The lack of a
response to elevated temperature resulting in the clinical mani- demonstrable change in the rate of clinical recovery may have
festation of Uhthoff ’s phenomenon. In addition, the accumula- been due to the variety of clinical presentations, the insensitivity
tion of intra-axonal sodium and calcium can result in of the clinical measure (Expanded Disability Status Scale) and
mitochondrial damage and bioenergetic failure through the pro- the lack of sensitive paraclinical tools to assess the impact on
duction of reactive oxygen species. Potential players include anatomic and physiological changes. Indeed, fingolimod recently
inactivating sodium channels (eg, Nav1.6), sodium/calcium has shown efficacy in ameliorating AON in the experimental
exchangers (eg, NCX), glutamate receptors (eg, GluR), acid- autoimmune optic neuritis animal model when administered
sensing channels (eg, ASIC1), cation channels (eg, TRPM4) and during the effector phase of the disease.66 A similar effect has
voltage-dependent calcium channels (eg, VDCC).12 60 The been noted using dimethyl fumarate after the onset of CNS
resulting intra-axonal energetic supply-demand mismatch can inflammation in the experimental autoimmune encephalomyelitis
eventually provoke the liberation of excitatory amino acids, such model.67 The potential neuroprotective action of fingolimod and
as glutamate, culminating in irreversible axonal injury and neur- dimethyl fumarate in these animal models suggests that these
onal demise, the presumed underpinning of chronic disability in agents may be ideally suited for the acute treatment of AON.
AON. In support of this mechanism, a small trial using the There are now therapeutic approaches with the capability of
N-methyl-D -aspartate receptor antagonist, memantine, demon- inducing remyelination in experimental animal models. In a
strated less thinning of the RNFL in treated versus placebo par- toxin-induced rodent model of demyelination, an antibody
ticipants.61 Currently, the sodium channel-blocking agent, against LINGO1, a CNS protein that acts as a negative regulator
phenytoin, and the acid-sensing channel blocker, amiloride, are of oligodendrocyte precursor differentiation, promoted CNS
being used in clinical trials in AON. These clinical trials use remyelination by creating a microenvironment conducive to
RNFL thickness, as measured by OCT and SLP, as surrogate oligodendrocyte differentiation.68 Anti-LINGO1 monoclonal
measures of neuroprotection. antibody has been humanised and is being tested in early clinical
Recent work has identified a small group of patients who trials of patients with MS. Reparative agents such as
present with AON but whose clinical course demonstrates atyp- anti-LINGO1 may offer a unique avenue for facilitating the res-
ical recurrent activity or dependency on immunosuppression. In toration of visual function in AON.
2003, Kidd et al62 described a cohort of patients who presented Advancements in the understanding of the mechanisms
with painful, subacute optic neuropathy and responded underlying acute CNS demyelination, novel developments in the
804 Bennett JL, et al. J Neurol Neurosurg Psychiatry 2015;86:799–808. doi:10.1136/jnnp-2014-308185
 Multiple sclerosis

J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2014-308185 on 29 October 2014. Downloaded from http://jnnp.bmj.com/ on September 19, 2021 by guest. Protected by
ability to measure axonal and myelin injury, treatments with Henderson et al27 have estimated sample sizes for clinical trials
novel anti-inflammatory and immunomodulatory mechanisms, of therapeutic agents in AON, when using OCT as the outcome
and an unmet therapeutic need warrant a renewed investigation measure, and demonstrated that as few as 75 patients per treat-
of the treatment of AON. Clinical research on AON with both ment arm are needed to provide 90% power for a modest 40%
established and new agents can provide information on multiple effect size. The increased sensitivity of GCL+IPL measurement
complementary outcomes: clinical recovery, tissue preservation may reduce enrolment requirements further.22 A positive result
and remyelination. The resulting data on visual acuity (high and from a smaller OCT trial may provide the needed impetus
low contrast), visual fields, colour vision, peripapillary RNFL to investigate the impact on clinical outcomes in a larger phase
thickness, GCL+IPL thickness, ONHC responses in mfERG, 3 trial.
mfVEP and DTI will provide an elaborate framework in which
to decipher a specific agent’s effect on inflammation, axonal
integrity, neuronal survival, oligodendrocyte injury and Future directions
remyelination. Advances in our understanding of demyelinating injury and the
development of novel structural and physiological metrics of
optic nerve integrity provide a promising environment for
Clinical trials for AON therapy future translational and clinical research in AON (figure 1). In
Given the significant visual improvement (median recovery 20/ addition, the close relationship between idiopathic AON and
16) observed in the ONTT placebo group,5 future clinical trials other CNS demyelinating lesions allows the results of AON
to evaluate new AON treatments will likely require significant studies to immediately impact our understanding of MS patho-
patient numbers to ensure adequate powering. As a result, the physiology and treatment. Using sensitive metrics such as OCT,
need for substantial patient enrolment may dissuade the assess- ONHC, mfVEPs and DTI, future investigations may simultan-
ment of certain compounds with potentially moderate clinical eously address questions regarding the mechanism and timing of
effects. Therefore, the analysis of retinal architecture by OCT oligodendrocyte and RGC injury, the beneficial effects of immu-
and related methods may prove to be a valuable surrogate for nomodulatory and neuroprotective therapies, and the efficacy of
neuroprotection after acute inflammatory injury. Indeed, restorative interventions.

copyright.

Figure 1 Schematic of the retina, optic nerve and postchiasmal afferent visual system. Potential therapeutic targets (blue text) and measures of
visual function (green text) are illustrated above and below the diagram, respectively (RNFL, retinal nerve fibre layer; ERG, electroretinogram; OCT,
optical coherence tomography; ONHC, optic nerve head component; SLP, scanning laster polarimetry; VEP, visual evoked potential; DTI, diffusion
tensor imaging; MTR, magnetisation transfer imaging ratios).
Bennett JL, et al. J Neurol Neurosurg Psychiatry 2015;86:799–808. doi:10.1136/jnnp-2014-308185 805
 Multiple sclerosis

J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2014-308185 on 29 October 2014. Downloaded from http://jnnp.bmj.com/ on September 19, 2021 by guest. Protected by
With these objectives in mind, a future AON treatment trial Acknowledgements The authors thank MedVal Scientific Information Services,
need only utilise a few sites to enrol a sufficient number of parti- LLC, for editorial assistance.
cipants to evaluate multiple effects of a therapeutic agent. For Contributors JLB, EMF – conceived, designed and drafted the review. MN, FC,
example, a recent two-institution clinical trial (clinicaltrials.gov; RCS, JCC, SLG, LJB, CEM, TV, MM, MLM, AWT, TWP, TF – performed critical
revisions of the manuscript for important intellectual content.
NCT01838174) has been designed to compare the anti-
inflammatory, neuroprotective and restorative effects of ACTH Funding Editorial assistance was funded by Questcor Pharmaceuticals, Inc.
and methylprednisolone using OCT and electrophysiology. Competing interests All authors attended a scientific advisory board hosted by
Using OCT of the peripapillary RNFL and macula, the trial will Questcor Pharmaceuticals, Inc. JLB receives grants from the Guthy Jackson Research
Foundation and the NIH (EY022936); serves as a consultant for Novartis
compare RNFL loss and GCL+IPL thinning to compare the Pharmaceuticals, Alnaylam Pharmaceuticals, MedImmune, Chugai Pharmaceuticals,
neuroprotective effects of these compounds on axonal and RGC EMD Serono, Abbott Pharmaceuticals, Genentech, Genzyme and Questcor
survival. In addition, OCT will be used to examine whether the Pharmaceuticals; receives licence royalties for a patent re Compositions and Methods
differential anti-inflammatory effects of ACTH and methylpred- for the Treatment of Neuromyelitis Optica; and serves on the editorial boards of the
nisolone affect the rate of resolution of optic nerve head Multiple Sclerosis Journal and Journal of Neuro-ophthalmology. MN employee of
Questcor Pharmaceuticals, Inc. FC receives grants from the Multiple Sclerosis Society
oedema and the timing of RNFL thinning and RGC loss. of Canada, speaker fees from EMD Serono and serves as a consultant for Novartis
Sensitive electrophysiological metrics such as mfVEPs and the Pharmaceuticals. RCS serves as a consultant for Biogen-Idec, EMD Serono, Teva
ONHC of the mfERG will be used in concert with OCT to Neuroscience, Lundbeck, Pfizer, Thrombogenics, Sanofi-Aventis, Novartis
evaluate the extent of and recovery from demyelinating injury. Pharmaceuticals, BioClinica, Covance, Glaxo-Smith-Kline, Questcor, Heidelberg
Engineering, Merck, United States Department of Defense, and the Food And Drug
While novel in integrating many new approaches for the Administration; receives speaker honoraria from Biogen-Idec, EMD Serono, Teva
evaluation of optic nerve integrity and function, this study high- Neuroscience, Lundbeck, Pfizer, Novartis Pharmaceuticals, Sanofi-Aventis and
lights many of the unresolved questions facing the optimal Questcor. JCC receives research support from Novartis Pharmaceuticals, Biogen-Idec
design of clinical trials in AON. What is the optimal window for and Roche; receives speaking fees from Acorda Therapeutics, Novartis
the enrolment and institution of therapy in AON? Small trials Pharmaceuticals, Biogen-Idec, EMD Serono, Genzyme, Bayer Healthcare, Acorda
Therapeutics, Questcor and Teva Neuroscience; and receives consultant fees from
with encouraging results on neuroprotection suggest the Novartis Therapeutics, Biogen-Idec, Genzyme, Acorda Therapeutics and Questcor.
window may be small (8–10 days). Ultimately, however, the SLG serves as a consultant for Vaccinex and Biogen-Idec. LJB receives consulting
therapeutic window may vary based on the mechanism of action fees from Biogen-Idec, Questcor and Vaccinex. CEM serves as a consultant for
of the agent (ie, anti-inflammatory or neuroprotective), method Biogen-Idec, Teva Neuroscience, Bayer Healthcare, EMD-Serono, Questcor, Novartis,
Genzyme, Roche and Genentech. TV receives speaker honoraria and consulting fees
of administration (oral, intravenous, retrobulbar) and pharmaco- from Biogen, Teva Neuroscience, Novartis, Genzyme, EMD Serono and Questcor.
dynamics (time to therapeutic level/effect in target tissue). What MM receives research support from Novartis Pharmaceuticals. MLM receives speaker
is the optimal outcome measure? Is it anatomic (RNFL thick- honoraria from Biogen-Idec and Novartis Pharmaceuticals and research support from
ness), electrophysiological (mfVEP, ONHC) or functional (VF, Acorda Therapeutics. AWT receives consulting fees from Palatin Technologies. TF
receives speaker honoraria and consulting fees from Biogen-Idec, Teva Neuroscience,

copyright.
LCVA)? As noted previously, each metric has merits and limita-
Novartis Pharmaceuticals, Genzyme and Acorda Therapeutics. EMF receives speaker
tions. In the short term, a pragmatic approach may be best. honoraria and consulting fees from Biogen-Idec, Teva Neuroscience, Novartis
Sensitive measures of axonal, glial or neuronal injury such as Pharmaceuticals, Genzyme and Acorda Therapeutics.
OCT and mfVEP may be ideal to identify treatment effects in Provenance and peer review Not commissioned; externally peer reviewed.
small cohorts. Afterwards, compounds with significant results
Open Access This is an Open Access article distributed in accordance with the
can be moved forward into larger trials designed to document Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
clinical improvement in AON and other demyelinating injuries. permits others to distribute, remix, adapt, build upon this work non-commercially,
The data acquired from this and other ongoing AON trials will and license their derivative works on different terms, provided the original work is
likely provide the foundation for using AON as a paradigm dis- properly cited and the use is non-commercial. See: http://creativecommons.org/
licenses/by-nc/4.0/
order for clinical and translational studies of demyelinating
disease.

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808 Bennett JL, et al. J Neurol Neurosurg Psychiatry 2015;86:799–808. doi:10.1136/jnnp-2014-308185