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VIEWS amp REVIEWS
Steven L Galetta MDPablo Villoslada MDNetta Levin MD PhDKenneth Shindler MD
Acute optic neuritisUnmet clinical needs and model for new therapies
ABSTRACT
Idiopathic demyelinating optic neuritis (ON) most commonly presents as acute unilateral visionloss and eye pain and is frequently associated with multiple sclerosis Although emphasis is oftenplaced on the good recovery of high-contrast visual acuity persistent deficits are frequentlyobserved in other aspects of vision including contrast sensitivity visual field testing color visionmotion perception and vision-related quality of life Persistent and profound structural and func-tional changes are often revealed by imaging and electrophysiologic techniques including opticalcoherence tomography visual-evoked potentials and nonconventional MRI These abnormalitiescan impair patientsrsquo abilities to perform daily activities (eg driving working) so they have impor-tant implications for patientsrsquo quality of life In this article we review the sequelae from ONincluding clinical structural and functional changes and their interrelationships The unmet needsin each of these areas are considered and the progress made toward meeting those needs isexamined Finally we provide an overview of past and present investigational approaches fordisease modification in ON Neurol Neuroimmunol Neuroinflamm 20152e135 doi 101212
NXI0000000000000135
GLOSSARYAD 5 axial diffusivity DTI 5 diffusion tensor imaging FA 5 fractional anisotropy GCL 5 ganglion cell layer IPL 5 innerplexiform layer mfVEP 5 multifocal VEP MS 5 multiple sclerosis MSFC 5 Multiple Sclerosis Functional Composite MT 5magnetization transfer NEI-VFQ-25 5 25-item National Eye Institute Visual Functioning Questionnaire OCT 5 opticalcoherence tomography ON 5 optic neuritis ONTT 5 Optic Neuritis Treatment Trial QOL 5 quality of life RD 5 radialdiffusivity RGC 5 retinal ganglion cell RGCL 5 retinal ganglion cell layer RNFL 5 retinal nerve fiber layer SD-OCT 5spectral-domain OCT SLCLA 5 Sloan low-contrast letter acuity TD-OCT 5 time-domain OCT VEP 5 visual-evokedpotential
Although idiopathic demyelinating optic neuritis (ON) broadly describes the vision loss associ-ated with any inflammation of the CNS white matter tract referred to as the optic nerve theterm is most commonly associated with the unilateral visual loss that occurs in multiple sclerosis(MS) Atypical ON may be associated with neuromyelitis optica infections or systemic etiol-ogies but this article will focus predominantly on the typical demyelinating ON syndrome asso-ciated with MS Typical ON is characterized by a loss of vision that develops over days and isassociated with dyschromatopsia visual field loss and pain that is often exacerbated by eyemovements1 Usually there are no retinal exudates or severe disc swelling and vision is betterthan no light perception
Significant knowledge about the clinical course of ON derives from the Optic Neuritis Treat-ment Trial (ONTT) First published in 1992 the ONTT established that high-dose IV corti-costeroid treatment slightly accelerated the rate of recovery but had no effect on long-term visual
From the Departments of Neurology (SLG LJB) Ophthalmology (SLG LJB) and Population Health (LJB) New York UniversitySchool of Medicine New York NY Center of Neuroimmunology Institut drsquoInvestigacions Biomegravediques August Pi i Sunyer (IDIBAPS) andHospital Clinic of Barcelona (PV) Barcelona Spain Department of Neurology (PV) University of California San Francisco Department ofNeurology (NL) The Agnes Ginges Center for Human Neurogenetics Hadassah Hebrew-University Medical Center Jerusalem Israel ScheieEye Institute and FM Kirby Center for Molecular Ophthalmology (KS) University of Pennsylvania Philadelphia UPMC Eye Center (HI) Eyeand Ear Institute Ophthalmology and Visual Science Research Center Department of Ophthalmology University of Pittsburgh School ofMedicine PA Department of Bioengineering (HI) Swanson School of Engineering University of Pittsburgh PA Excel Scientific Solutions(EP) Southport CT and Biogen (DC) Cambridge MA
Funding information and disclosures are provided at the end of the article Go to Neurologyorgnn for full disclosure forms The Article ProcessingCharge was paid by Envision Pharma Inc
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40(CC BY-NC-ND) which permits downloading and sharing the work provided it is properly cited The work cannot be changed in any way or usedcommercially
Neurologyorgnn copy 2015 American Academy of Neurology 1
outcomes2 Visual fields and contrast sensitiv-ity were the primary measures of efficacy andshowed a slight advantage of high-dose IVcorticosteroids over placebo at 6 months Nev-ertheless vision for most patients in all treat-ment groups at 6 months was characterized asldquonormalrdquo based on high-contrast visual acuitya secondary outcome measured using Snellencharts which was 2050 or better for 90of patients regardless of treatment assignmentThis created the impression that most patientsmake an excellent recovery following acuteON However a follow-up study 5ndash8 yearslater found abnormalities in affected eyes vsfellow eyes for the primary endpoints of con-trast sensitivity (58 vs 17) and visual field(33 vs 12) as well as the secondary end-points of high-contrast visual acuity (39 vs16) and color vision (37 vs 18)3
Furthermore as described in the sections thatfollow advances in imaging and electrophysi-ologic techniques over the past 2 decades haverevealed that persistent structural and func-tional damage is detectable following episodesof acute ON and that the associated visualdeficits may have considerable impact on qual-ity of life (QOL) measures Given the devel-opment of therapies with the potential toprevent neuroaxonal loss and facilitate remye-lination following acute ON it is time to re-assess the extent of spontaneous recovery inON and the approaches to determining out-comes so that unmet needs may be identifiedand addressed
In this article we review the evidence forpersistent functional and structural abnormali-ties in ON and their impact on visual functionand vision-related QOL We also provide anoverview of investigational approaches to treatthe underlying pathology in ON
CLINICAL COURSE AND ASSESSMENT OFVISUAL FUNCTION Typical ON develops over a7- to 10-day period and begins to resolve within2ndash3 weeks45 Initial rapid improvement in visualfunction within the first month begins to slow inan asymptotic fashion over succeeding months4 andimprovements have been observed up to 2 yearslater6 Numerous studies have found evidence ofpersistent retinal thinning optic nerve atrophy andreduced amplitude and increased latency of visual-evoked potentials (VEPs) consistent with chronic
demyelination and neuroaxonal loss as sequelae ofacute ON (see next sections) The extent of latencyrecovery appears to be more complete in youngerpatients vs older patients females vs males andpatients with less severe attacks vs more severeattacks7 Moreover recovery of different aspects ofvisual function may proceed at different rates withdifferent sensitivities among tests and to a differentextent (figure 1) Recovery of different aspects ofvisual function may also involve distinct mechanismsas patients who achieve partial recovery of static visualfunctions (eg high- and low-contrast visual acuity)after 1 month may recover those functionscompletely whereas dynamic visual function (motionperception) appears to recover at a slower constant rateirrespective of the severity of the initial deficit8
Although patients with ON frequently regainvisual acuity to a large extent as measured by full-contrast letter charts (eg Snellen charts) low-contrast acuitysensitivity reveals permanent deficitsand is a better predictor of impairment for dailyactivities that require vision such as reading facialrecognition and driving9 Persistent deficits inlow-contrast letter acuity characteristic of ON arebetter measured using Sloan charts (Sloan low-contrast letter acuity [SLCLA]) that include versionswith 25 and 125 contrast levels to better stratifydeficits The pattern of visual field defects may helpdistinguish ON from other neuropathies In ON acentral scotoma is common and Humphrey centralvisual field perimetry frequently shows diffuse losswhereas peripheral altitudinal or other defects mayoccasionally be evident on formal perimetry Colorvision is commonly affected in ON but there is noconsistent pattern of dyschromatopsia10 More com-plex visual functions such as motion perception arealso frequently affected by ON11 Binocular summa-tion (improved vision with binocular viewing) hasalso been shown to be reduced and in some instancespatients demonstrate binocular inhibition (worsevision with binocular viewing) perhaps reflectingconcomitant disease activity in postgeniculate path-ways in some patients12 Thus evaluation of visualfunction after ON requires multiple tests to ensurecomprehensive assessment of the potential deficits
APPROACHES TO ASSESSMENT OF ON Optical
coherence tomography Assessment of structuralchanges in the course of ON has been revolutionizedover the past 2 decades by advances in optical coher-ence tomography (OCT) a technique that uses inter-ferometry of reflected light to obtain images of theretinal layers13 (figure 2) Most OCT studies ofpatients with ON have used time-domain OCT(TD-OCT) which provides cross-sectional imagesfrom different tissue levels Since the peripapillary
2 Neurology Neuroimmunology amp Neuroinflammation
retinal nerve fiber layer (RNFL) is composed ofunmyelinated optic nerve axons RNFL thinningdetected by OCT is directly interpretable asneuroaxonal degeneration More modern systemsusing spectral-domain OCT (SD-OCT) provideconsiderably improved resolution and speed and canbe used to generate 3-dimensional images formeasurements of thickness of neuronal layers
Acute ON often results in inflammatory swellingof the RNFL of the affected eye The inflammatoryswelling generally resolves within 3 months14 and isaccompanied by a period of RNFL thinning thatcontinues for up to 7ndash12 months but is most prom-inent in the first 6 months after acute ON onset515
The initial period of swelling prevents examination ofthe timing of axonal loss in the RNFL withTD-OCT In contrast the thickness of the retinalganglion cell layer (RGCL) appears to be less affectedby edema1617 so the more detailed resolution withSD-OCT may allow for a better assessment of thetiming of thinning in reference to acute ON Recentstudies suggest that thinning of the RGCL startswithin several weeks after an episode of ON andmay precede RNFL thinning1617 Ultimately RNFLthinning in affected eyes correlates with visual acuitylow-contrast letter acuity visual field color vision andVEPs (see also below)1819 thereby supporting itsfunctional relevance and RNFL thickness 75 mmhas been shown to predict reduced visual field func-tion520 Although it is not yet clear whether prevent-ing RNFL thickness from crossing that threshold canreduce the extent of associated visual deficits it isworth noting that it is also near the lower limit ofRNFL thickness when virtually all retinal ganglioncell (RGC) axons have been lost (20ndash40 mm)21
Thinning of the RNFL following an episode ofON is thought to result from axonal loss subsequentto axonal injury during the inflammatory demyelinat-ing lesion of the affected optic nerve However it isnoteworthy that detectable RNFL thinning and asso-ciated visual deficits are also observed in unaffectedeyes of patients with MS in the absence of historyof ON15 One possibility is that some ldquomildrdquo attacksare not reported or do not result in deficits that are
Figure 1 Evolution of visual function after acute optic neuritis
Figure shows the measurement of high-contrast visual acuity (VA) using the Early TreatmentDiabetic Retinopathy Study (ETDRS) charts (A) the 25 and 125 low-contrast VA using
Sloan charts (B C) and color vision using the Hardy-Rand-Rittler (HRR) pseudoisochromatic plates (D) in a cohort of37 patients with acute optic neuritis (AON) and visual assess-ment at baseline (presentation) and months 2 4 and 6 afteronset (data fromGabilondo I et al 201516) Each colored lineis data from an individual patient the solid black line repre-sents the mean from all patients and the dashed black lineshows the normal values for healthy individuals for binoculartesting (ETDRS 5 70 25 low-contrast VA 5 43 125low-contrast VA5 34 HRR5 36) Reprinted with permissionfrom Elena H Martinez-Lapiscina
Neurology Neuroimmunology amp Neuroinflammation 3
immediately evident to patients Thus in nonacuteON eyes there is a component of RNFL thinning thatmay be attributable to other causes such as subclin-ical optic nerve inflammation neurodegenerationwithin normal-appearing white matter or transsyn-aptic degeneration associated with lesions elsewherein the visual pathway22ndash24
The increased resolution of SD-OCT and the useof segmentation algorithms have allowed a moredetailed analysis of the effects of ON and MS on ret-inal structure25 (figure 2) These studies found thatRNFL thinning associated with MS with or withoutON is not confined to the peripapillary region butalso affects the macula In addition a similar pattern
Figure 2 Optical coherence tomography of the human retina
A) Detailed retinal segmentation sample on spectral-domain optical coherence tomography (OCT) image Six intraretinallayer borders can be automatically segmented (B) Correlation of anatomy with OCT for the human retina On the left is ahematoxylin amp eosin stain of the human retina in the center is a schematic representation of the cell composition of thehuman retina and on the right is a magnification of the image obtained with spectral-domain OCT (bottom) with indicationsof the retina layers identified Figure 2B reprinted with permission from Santiago Ortiz-Perez BM5 Bruch membrane CC5
of thinning is observed for the ganglion cell layerinner plexiform layers (GCL 1 IPL) in the peripap-illary region and macula A recent study in patientswith ON found that decreases of$45 mm in GCL1
IPL thickness after 1 month predicted low-contrastvisual acuity dysfunction at 6 months whereas de-creases of $7 mm predicted visual field and colorvision deficits16 In another study in patients withMS with or without a history of ON thinning of
GCL 1 IPL was most closely associated with visualfunction and vision-specific QOL26 Results of thesestudies suggest that degeneration associated with ONand MS is widespread in the RGCL
Together these studies provide compelling evi-dence for structural damage from acute ON and theyalso provide a powerful demonstration of the poten-tial for SD-OCT as a tool to assess neurodegenerativechanges in acute ON However both TD-OCT and
Figure 3 Multifocal visual-evoked potentials in optic neuritis
Figure shows the visual-evoked potentials (VEPs) in 52 sectors of the retina (A B) A case of acute optic neuritis with diffuse impairment of the VEPs in theaffected eye (A) compared with the unaffected eye (B) with significant impairment of the latencies and amplitudes (B C) After recovery from the acute opticneuritis the VEPs show a significant decrease of amplitude and latencies in most of the sectors of the affected eye (C) compared with the unaffected eye (D)Reprinted with permission from Ana Tercero
Neurology Neuroimmunology amp Neuroinflammation 5
SD-OCT appear to be less sensitive than VEPs for as-sessing the clinical and subclinical effects of ON2728
so interpretation of OCT may require complemen-tary assessments using functional techniques Fur-thermore improvements are needed to standardizeand reduce test-retest variability in SD-OCT sys-tems29 Given the rapid evolution of the technologythe technical expertise required and differencesbetween commercially available instruments30 it isalso important that criteria be established to ensurequality control for OCT as a validated outcome mea-sure a process that is under way31
VEPs Standard VEPs elicited by visual stimuli andmeasured in the occipital cortex can be used to detectfunctional changes in the visual pathway includingthe optic nerve32 In multifocal VEPs (mfVEPs)visual stimuli are provided independently to localizedregions of a wider visual field (48deg) and responses tothe stimuli are measured individually33 allowing for amore detailed analysis of visual function covering amuch larger area of the visual pathway than standardVEPs (figure 3)
The severity of an attack of ON and the extent ofinflammation are correlated with an acute reductionin the amplitude of VEPs34 Reduction in VEP ampli-tude is thought to reflect functional impairment ofaxonal conduction either transiently (eg due toacute inflammation or demyelination) or persistently(due to axonal loss) Within 3ndash4 months after theacute episode the amplitude generally shows somerecovery reflecting resolution of edema and thewaveform of the VEP is well-preserved but thelatency is significantly increased This residual latencydelay is thought to result from demyelination of sur-viving axons which interferes with saltatory conduc-tion of the action potential along the optic nervelesion Some investigators have reported subsequentimprovement in latency for up to 2 years6 whereasothers have reported no further recovery after 4months8 Prolongation of latency is most evident inthe central visual field perhaps indicating that thecentral (macular) region of the optic nerve is moresusceptible to demyelination or resistant to remyeli-nation32 The central region of the optic nerve con-tains the greatest density of parvocellular fibers thatconvey static information (eg form and color) butVEP latency in patients with ON correlates morestrongly with dynamic functions (eg motion detec-tion) than with static functions This may suggestmore specific effects on magnocellular fibers orgreater vulnerability of fibers required for accuratesignal timing8
Effects of ON on VEPs have also been shown toreflect structural changes in the RNFL In a studyof 21 patients following a first episode of unilateral
ON VEP latency prolongations and amplitude re-ductions of affected eyes at baseline and 3 monthsafter onset were associated with RNFL thinning19
suggesting a relationship between the initial structuralloss and residual functional impairment In a separatestudy of 25 patients with ON with incomplete recov-ery after 1 year similar relationships between VEPlatencyamplitude and RNFL thinning were still evi-dent18 further supporting the clinical relevance ofthis technique
mfVEPs have been used in a growing number ofsmall studies to examine the pathology of ON ingreater detail35ndash38 mfVEPs detect functional changesassociated with onset and evolution of acute ON38
and may be particularly useful to assess treatmentoutcomes in clinical trials as it appears to be morereproducible than standard VEPs39 One study of 25patients with ON between 6 and 12 months afteronset found an apparent discrepancy between struc-tural and functional measures in these patients35 AsRNFL thinning progressed in the affected eyes overthis time period the mfVEP amplitude partiallyrecovered suggesting that functional recovery maybe due in part to remyelination andor neuronalplasticity
Functional data provided by VEPs and mfVEPsmake an ideal counterpart to structural retinal assess-ments using OCT However as with OCT criterianeed to be established to ensure reproducibility andvalidity of VEP results Furthermore larger-scalestudies are needed to confirm the results of currentsmaller studies
MRI Nonconventional MRI techniques offer noveltools to examine the structure of CNS tissues indetail For example magnetization transfer (MT)imaging exploits the difference in resonance in freeprotons and protons associated with macromolecules(eg myelin) the ratio of which may provide a mea-sure of myelin content40 Diffusion tensor imaging(DTI) can be used to measure asymmetric radial dif-fusivity (RD) axial diffusivity (AD) or fractionalanisotropy (FA) of water as a gauge of tissue in majornerve tracts (eg optic nerve and optic radiations)41
A small number of studies have provided supportfor use of these techniques to assess pathologicchanges in ON For example in an MT study in11 patients with ON MT ratios of affected opticnerves closely followed the course of the disease theywere significantly higher at baseline (within 8 days ofonset) but were reduced at months 3 and 642 In aseparate study in 37 patients with ON MT ratios ofaffected optic nerves were not found to be differentfrom those of unaffected nerves until 3 months afteronset43 In that study ON-associated alterations inMT ratios at 3 months correlated with high- and
6 Neurology Neuroimmunology amp Neuroinflammation
low-contrast visual deficits and with VEP latency at 6months as well as with RNFL thinning at 12 months
In a study of DTI performed within 30 days ofonset and after 1 year in 12 patients with ON FAof affected optic nerves (which is also considered apotential measure of myelination) was the onlyparameter correlated with vision at onset but didnot correlate with the extent of recovery of visual acu-ity or contrast sensitivity at 1 or 3 months44 The AD(considered a measure of axonal integrity) was theonly parameter that was correlated with worse con-trast sensitivity at 1 and 3 months This was con-firmed in a follow-up study in 25 patients in whicha lower baseline AD was also found to be correlatedwith the extent of RNFL thinning and with VEPamplitude and latency45 These were small studiesand should be interpreted with caution as eye motionmakes imaging of the optic nerve by MT ratio andDTI challenging but they do not seem to support amodel in which the extent of neurodegeneration isdetermined solely by chronic demyelination Ratherthey suggest that the initial neuroaxonal effects of theacute inflammatory injury may be more important
Although these ldquononconventionalrdquo MRI techni-ques hold promise as a tool to investigate underlyingprocesses and assess recovery in ON there are substan-tial challenges to widespread use For example theacquisition times are frequently longer than is practical
for routine human studies and imaging is complicatedby motion artifacts caused by moving the eye orhead46 In addition there is no consensus on sequencesand protocols for their application in ON These fac-tors have limited widespread adoption of these ap-proaches and have likely contributed to theinconsistencies in findings Thus further technologicalimprovements and standardization of techniques forimaging of ON lesions will be required before theycan be considered as reliable measures of outcomesin clinical trials
QOL Visual deficits in patients with ON are likely tohave a marked impact on daily activities and QOLPatients frequently rate vision among the mostimportant physical functions affected by MS47 How-ever vision is poorly or insufficiently represented onstandard objective measures of physical functionsuch as the Expanded Disability Status Scale andfunctional assessment instruments such as the Mul-tiple Sclerosis Functional Composite (MSFC) Addi-tion of SLCLA charts to the MSFC has been reportedto better capture MS-related disability48 One patient-reported outcome instrument the 25-item NationalEye Institute Visual Functioning Questionnaire(NEI-VFQ-25) has become a commonly usedmeasurement of vision-specific health-related QOLWhen administered to patients from the ONTT 5ndash8years after the episode of acute ON scores on the NEI-VFQ-25 were lower than for an older disease-freecohort3 In patients with MS correlations with NEI-VFQ-25 scores have been demonstrated for low-contrast visual acuity49 binocular summation12
motion perception50 and loss of RGCs25 (figure 4)Moreover a 10-item supplement has been developedto better capture aspects more relevant to neuro-ophthalmology such as double vision and difficultieswith viewing motion51 A follow-up study has alsoreported its ability to distinguish patients with MSwith a history of ON52
TREATMENTS An important unmet need withrespect to ON is the availability of effective treatmentsto prevent or reverse long-term visual dysfunctionGiven the narrow window of time during whichmost recovery occurs it seems reasonable to suggestthat an effective treatment be initiated as soon aspossible after ON onset with the aim of promotingRGC survival and either extending the window forremyelination or accelerating the rate and extent towhich it occurs Data emerging from OCT studiessuggest that RGC loss may begin within weeks ofthe event thereby narrowing the time to initiateneuroprotective therapy
Despite the lack of long-term benefits of high-dosecorticosteroids patients with acute ON are frequently
Figure 4 Relationship of thickness of retinal layers to quality of life and low-contrast visual acuity
Scatter plot and fitted linear regression line showing relationships of ganglion cell layer plusinner plexiform layer (GCL 1 IPL) thickness to 25-item National Eye Institute Visual Func-tioning Questionnaire (NEI-VFQ-25) composite scores and low-contrast visual acuity at25 level The regression lines represent fitted values for mean GCL 1 IPL thickness foreach value of NEI-VFQ-25 or low-contrast visual acuity the gray shaded areas show the95 confidence intervals from the SEs of the predictions for the fitted lines Linear corre-lations were significant QOL5 quality of life Reprinted from Ophthalmology 119(6) WalterSD et al Ganglion cell loss in relation to visual disability in multiple sclerosis 1250ndash12572012 with permission from Elsevier26
Neurology Neuroimmunology amp Neuroinflammation 7
provided these drugs as symptomatic treatment tospeed resolution of acute inflammation Patients areoften assessed by MRI to determine their risk forMS but it is not clear that disease-modifying thera-pies for relapsing forms of MS are effective to preventneurodegeneration when ON occurs while receivingthese treatments For example interferon b was not
found to prevent RFNL thinning in patients withON53 Natalizumab has been shown to reduce lossof vision54 and improve VEPs55 in patients withrelapsing-remitting MS but there are no data toindicate treatment benefits specifically in patientswith ON A phase II study of fingolimod in acutedemyelinating ON is complete although it is not
Table Phase II and III studies in typical optic neuritis
Startend datesa Treatment
Time from eventto studyinitiation Primary endpoint Statusa
Primary efficacyresults Study numbera
July 1988b (end datenot provided)
Oral prednisone 1 mgkg for 14 d vsmethylprednisolone 1000 mg IV for3 d then oral prednisone 1 mgkgfor 11 d vs placebo
8 d Visual field and contrastsensitivity over 6 mo
Completedc No significanteffect2
NCT00000146
August 1995ndashDecember1997
Immunoglobulin 04 gkg IV QD for3 d then 3 infusionsmo for 3 mo vsplacebo
$6 mo High-contrast visualacuity (100 ETDRScharts)
Completed No significanteffect56
NCT00000117
August 2006ndashJuly 2011 Erythropoietin 33000 units IV for3 d vs placebo
10 d RNFL thickness at 4 8and 16 wks
Completed Significantly lessRNFL thinning at 16wk57
NCT00355095
September 2006ndashMay2011
Simvastatin 80 mg QD PO vsplacebo
4 wk Contrast sensitivity at3 mo
Completedc No significanteffect58
NCT00261326
March 2008ndashJanuary2011
Atacicept 150 mg SC weekly vsplacebo
Not specified RNFL thickness up to48 wks
Terminated None available NCT00624468
February 2009ndashFebruary2011
Glatiramer acetate 20 mg SC QD vsplacebo
Not specified RNFL thickness at 6 mo Completed None available NCT00856635
February 2010ndashJanuary2013
Minocycline 100 mg BID vs notreatment
30 d RNFL thickness every3 mo for 9 mo
Terminated None available NCT01073813
May 2010ndashMarch 2013 Visual reconstitution therapy vssaccadic eye movement training
60ndash80 d or 12mo
Visual field at 6 mo Completed None available NCT01274702
May 2011ndashDecember2013
Dalfampridine 10mg BID vs placebo $12 mo Contrast sensitivity(5 ETDRS charts)
Completed None available NCT01337986
July 2011ndashDecember2012
Vitamin D 50000 unitswk vsvitamin withheld
Not applicable(preventionstudy)
RNFL thickness at10ndash32 d after opticneuritis
Unknown None available NCT01465893
November 2011ndashAugust2014
Phenytoin 15 mgkgd for 3 d then4 mgkgd for 13 wks vs placebo
14 d RNFL thickness at6 mo
Completedd Significantly lessRNFL thinning at6 mod
NCT01451593
March 2012ndashSeptember2014
Oral prednisone 1250 mg vsmethylprednisolone 1000 mg IV for3 d each
14 d VEP latency Unknown None available NCT01524250
December 2012ndashOctober2014
BIIB033 (anti-LINGO-1) 100 mgkgIV every 4 wks vs placebo
28 d VEP latency Completed None available NCT01721161
February 2013ndashFebruary2015
Amiloride 10 mg QD vs placebo for5 mo
28 d RNFL thickness at 6 mo12 mo
Recruiting None available NCT01802489
July 2013ndashJune 2016 Fingolimod 05 mg QD vs interferonb-1b
30 d VEP latency Recruiting None available NCT01647880
August 2013ndashMay 2014 Fingolimod 05 mg QD vs placebo Not specified RNFL thickness at18 wks
Completed None available NCT01757691
October 2013ndashJanuary2016
MD1003 100 mg TID vs placebo Not specified High-contrast visualacuity (100 ETDRScharts)
Recruiting None available NCT02220244
March 2014ndashApril 2016 Amiloride hydrochlorothiazide100 mgd vs placebo
10 d RNFL thickness at24 wks
Recruiting None available NCT01879527
November 2014ndashDecember 2018
Erythropoietin 33000 units IV for3 d vs placebo
10 d RNFL thickness at 6 mo Recruiting None available NCT01962571
Abbreviations ETDRS5 Early Treatment Diabetic Retinopathy Study RNFL5 retinal nerve fiber layer SC5 subcutaneous VEP5 visual-evoked potentiala From ClinicalTrialsgov except where indicated otherwiseb The Optic Neuritis Treatment Trial included a 15-year follow-up periodc Based on published resultd Reported at American Academy of Neurology 2015 Annual Meeting April 18ndash25 Washington DC
8 Neurology Neuroimmunology amp Neuroinflammation
clear that enrollment goals were met Another phaseIIIII study is under way but study results are not yetavailable (table)
Based on promising results from animal studiesand small clinical studies IV immunoglobulin wasinvestigated in patients with one or more episodesof typical ON and irreversible loss of visual acuitybut was terminated early due to negative results56
(table) Since that time various investigational ther-apies have shown promise in early preclinical andclinical studies and a number of phase II and IIIstudies have been completed or are under way Forexample in a placebo-controlled study of IV eryth-ropoietin for 3 days as an add-on to methylpredni-sone in patients with a first episode of ON withinthe previous 10 days those treated with erythropoi-etin demonstrated reduced RNFL thinning lessdecrease in optic nerve diameter and shorter VEPlatency57 Although the mechanism by which eryth-ropoietin may exert these effects is poorly under-stood it may involve the neuroprotective effectsof this hormone during acute inflammation Inanother placebo-controlled study in patients withsymptom duration of 4 weeks and reduced con-trast sensitivity simvastatin (a hypercholesterolemiamedication) narrowly missed significance on theprimary efficacy outcome (contrast sensitivity)but improvements were noted for VEP latencyand amplitude58 However imbalances in random-ization and technical issues may have contributed tothe observed effects59 A study in ON testing possibleneuroprotective effects of phenytoin an anticonvul-sant has recently completed and another study testingeffects of amiloride hydrochlorothiazide a diuretic iscurrently underway Nevertheless it is an open ques-tion whether a neuroprotective agent can domore thandelay degeneration of axons if they remain chronicallydemyelinated Finally BIIB033 a fully-human anti-body to LINGO-1 an inhibitor of myelination andneuroaxonal growth has shown promise in preclinicaland early clinical testing60 and a phase II study in ONwas recently completed
CONCLUSIONS It is now clear that recovery fromON is frequently incomplete which adversely affectsthe QOL of patients In addition there remain con-siderable gaps with respect to understanding assess-ing and treating this disease to prevent long-termdeficits Nevertheless ongoing work holds promisefor all of these areas The application of newertechnologies continues to provide new insight intothe underlying disease processes and increasedappreciation of the injury that occurs followingON The development of these new tools mayincrease the ability to detect meaningful changes invision with therapeutic intervention and study
results suggest that timing is critical Developmentof guidelines to ensure consistency in theirapplication should also improve interpretation offindings and thereby improve the quality ofassessments Finally several therapies have shownpromise in preclinical and early clinical testingTherefore there is reason to be optimistic thatstrategies may soon be identified to improve theprognosis for patients with ON Given therelationship between ON and MS it seems likelythat any such developments for ON may havesubstantial implications for understanding assessingand treating MS as well
AUTHOR CONTRIBUTIONSAll authors participated in the conception of the article interpretation of
the data and revision of the manuscript and they approved the final ver-
sion Biogen provided funding for writing and editorial support in the
development of this paper and they reviewed and provided feedback
on the paper to the authors The authors had full editorial control of
the paper and provided their final approval of all content
ACKNOWLEDGMENTThe authors thank Dr Elena H Martinez-Lapiscina Dr Santiago Ortiz-
Perez and Dr Ana Tercero from the Center of Neuroimmunology Insti-
tute of Biomedical Research August Pi SunyerHospital Clinic Barcelona
University of Barcelona for creating figures 1 2B and 3 respectively
Lauren Nagy of Excel Scientific Solutions copyedited and styled the man-
uscript per journal requirements and this editorial support was funded by
Biogen
STUDY FUNDINGWriting and editorial support was funded by Biogen
DISCLOSURESL Galetta has received consulting honoraria and travel fundingspeaker
honoraria from Genzyme and Biogen and is on the editorial board for
Neurology and Journal of Neuro-Ophthalmology P Villoslada serves on
advisory boards for Novartis Roche Neurotec Pharma and Bionure
Pharma has consulted for Novartis Roche TFS Heidelberg Engineer-
ing MedImmune Diagna Biotec and Neurotec Pharma is an academic
editor for PLoSONE is on the editorial board for Neurology amp Therapy
and Current Treatment Options in Neurology has received research sup-
port from European Commission Genzyme Biogen Instituto Salud
Carlos III Marato TV3 Novartis and Roche and holds patents and
owns stocksstock options with Bionure Pharma N Levin receives
research support from National Multiple Sclerosis Foundation
K Shindler received research support from the FM Kirby Foundation
Harbor Therapeutics National Eye Institute National Multiple Sclerosis
Foundation Research to Prevent Blindness Sirtris Pharmaceuticals
ITMAT and Stemnion Inc has received speaker honoraria from Med-
ical College of Wisconsin and Temple University is an associate editor
for Frontiers in Neurology Neuro-Ophthalmology receives publishing roy-
alties from UpToDate and Oakstone Publishing and has consulted for
medical-legal cases H Ishikawa received research support from the NIH
E Parr is a full-time employee of Excel Scientific Solutions who were
funded by Biogen to provide editorial and writing support for this paper
D Cadavid is a full-time employee of Biogen owns stock options in
Biogen and has patent applications pending related to the use of drugs
that block LINGO-1 to treat demyelination in multiple sclerosis LJ
Balcer received consulting fees from Acorda Biogen Genzyme Novartis
Questcor and Vaccinexe serves on a clinical trial advisory board for
Biogen and serves on a scientific advisory board for Genzyme Go to
Neurologyorgnn for full disclosure forms
Received February 12 2015 Accepted in final form May 13 2015
Neurology Neuroimmunology amp Neuroinflammation 9
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Neurol 20141383ndash99
2 Beck RW Cleary PA Anderson MM Jr et al Optic Neu-
ritis Study Group A randomized controlled trial of cor-
ticosteroids in the treatment of acute optic neuritis N
Engl J Med 1992326581ndash588
3 Cole SR Beck RW Moke PS Gal RL Long DT Optic
Neuritis Study Group The National Eye Institute Visual
Function Questionnaire experience of the ONTT Invest
Ophthalmol Vis Sci 2000411017ndash1021
4 Beck RW Cleary PA Backlund JC The course of visual
recovery after optic neuritis Experience of the Optic
Neuritis Treatment Trial Ophthalmology 1994101
1771ndash1778
5 Costello F Hodge W Pan YI Eggenberger E Coupland S
Kardon RH Tracking retinal nerve fiber layer loss after
optic neuritis a prospective study using optical coherence
tomography Mult Scler 200814893ndash905
6 Brusa A Jones SJ Plant GT Long-term remyelination
after optic neuritis a 2-year visual evoked potential and
psychophysical serial study Brain 2001124468ndash479
7 Malik MT Healy BC Benson LA et al Factors associated
with recovery from acute optic neuritis in patients with
multiple sclerosis Neurology 2014822173ndash2179
8 Raz N Dotan S Chokron S Ben-Hur T Levin N Demy-
elination affects temporal aspects of perception an optic
neuritis study Ann Neurol 201271531ndash538
9 Leat SJ Legge GE Bullimore MA What is low vision A re-
evaluation of definitions Optom Vis Sci 199976198ndash211
10 Martiacutenez-Lapiscina EH Ortiz-Peacuterez S Fraga-Pumar E et al
Colour vision impairment is associated with disease severity
in multiple sclerosis Mult Scler 2014201207ndash1216
11 Raz N Dotan S Benoliel T Chokron S Ben-Hur T
Levin N Sustained motion perception deficit following
optic neuritis behavioral and cortical evidence Neurology
2011762103ndash2111
12 Pineles SL Birch EE Talman LS et al One eye or two a
comparison of binocular and monocular low-contrast acu-
ity testing in multiple sclerosis Am J Ophthalmol 2011
152133ndash140
13 Gabriele ML Wollstein G Ishikawa H et al Optical
coherence tomography history current status and lab-
oratory work Invest Ophthalmol Vis Sci 201152
2425ndash2436
14 Henderson AP Altmann DR Trip AS et al A serial study
of retinal changes following optic neuritis with sample size
estimates for acute neuroprotection trials Brain 2010133
2592ndash2602
15 Petzold A de Boer JF Schippling S et al Optical coher-
ence tomography in multiple sclerosis a systematic review
and meta-analysis Lancet Neurol 20109921ndash932
16 Gabilondo I Martiacutenez-Lapiscina EH Fraga-Pumar E
et al Dynamics of retinal injury after acute optic neuritis
Ann Neurol 201577517ndash528
17 Huang-Link Y-M Al-Hawasi A Lindehammar H Acute
optic neuritis retinal ganglion cell loss precedes retinal
nerve fiber thinning Neurol Sci 201536617ndash620
18 Trip SA Schlottmann PG Jones SJ et al Retinal nerve
fiber layer axonal loss and visual dysfunction in optic neu-
ritis Ann Neurol 200558383ndash391
19 Henderson AP Altmann DR Trip SA et al Early factors
associated with axonal loss after optic neuritis Ann Neurol
201170955ndash963
20 Costello F Coupland S Hodge W et al Quantifying
axonal loss after optic neuritis with optical coherence
tomography Ann Neurol 200659963ndash969
21 Hood DC Anderson SC Wall M Kardon RH Structure
versus function in glaucoma an application of a linear
model Invest Ophthalmol Vis Sci 2007483662ndash3668
22 Balk LJ Steenwijk MD Tewarie P et al Bidirectional
trans-synaptic axonal degeneration in the visual pathway
in multiple sclerosis J Neurol Neurosurg Psychiatry 2014
86419ndash424
23 Gabilondo I Martiacutenez-Lapiscina EH Martiacutenez-Heras E
et al Trans-synaptic axonal degeneration in the visual path-
way in multiple sclerosis Ann Neurol 20147598ndash107
24 Alshowaeir D Yiannikas C Garrick R et al Latency of
multifocal visual evoked potentials in nonoptic neuritis eyes
of multiple sclerosis patients associated with optic radiation
lesions Invest Ophthalmol Vis Sci 2014553758ndash3764
25 Sakai RE Feller DJ Galetta KM Galetta SL Balcer LJ
Vision in multiple sclerosis the story structure-function cor-
relations and models for neuroprotection J Neuroophthalmol
201131362ndash373
26 Walter SD Ishikawa H Galetta KM et al Ganglion cell
loss in relation to visual disability in multiple sclerosis
Ophthalmology 20121191250ndash1257
27 Di Maggio G Santangelo R Guerrieri S et al Optical
coherence tomography and visual evoked potentials which
is more sensitive in multiple sclerosis Mult Scler 201420
1342ndash1347
28 Naismith RT Tutlam NT Xu J et al Optical coherence
tomography is less sensitive than visual evoked potentials
in optic neuritis Neurology 20097346ndash52
29 Araie M Test-retest variability in structural parameters
measured with glaucoma imaging devices Jpn J Ophthal-
mol 2013571ndash24
30 Watson GM Keltner JL Chin EK Harvey D Nguyen A
Park SS Comparison of retinal nerve fiber layer and cen-
tral macular thickness measurements among five different
optical coherence tomography instruments in patients with
multiple sclerosis and optic neuritis J Neuroophthalmol
201131110ndash116
31 Schippling S Balk L Costello F et al Quality control for
retinal OCT in multiple sclerosis validation of the
OSCAR-IB criteria Mult Scler 201521163ndash170
32 Rinalduzzi S Brusa A Jones SJ Variation of visual evoked
potential delay to stimulation of central nasal and tem-
poral regions of the macula in optic neuritis J Neurol
httpnnneurologyorgcgicollectionmultiple_sclerosisMultiple sclerosisfollowing collection(s) This article along with others on similar topics appears in the
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httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2015 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
outcomes2 Visual fields and contrast sensitiv-ity were the primary measures of efficacy andshowed a slight advantage of high-dose IVcorticosteroids over placebo at 6 months Nev-ertheless vision for most patients in all treat-ment groups at 6 months was characterized asldquonormalrdquo based on high-contrast visual acuitya secondary outcome measured using Snellencharts which was 2050 or better for 90of patients regardless of treatment assignmentThis created the impression that most patientsmake an excellent recovery following acuteON However a follow-up study 5ndash8 yearslater found abnormalities in affected eyes vsfellow eyes for the primary endpoints of con-trast sensitivity (58 vs 17) and visual field(33 vs 12) as well as the secondary end-points of high-contrast visual acuity (39 vs16) and color vision (37 vs 18)3
Furthermore as described in the sections thatfollow advances in imaging and electrophysi-ologic techniques over the past 2 decades haverevealed that persistent structural and func-tional damage is detectable following episodesof acute ON and that the associated visualdeficits may have considerable impact on qual-ity of life (QOL) measures Given the devel-opment of therapies with the potential toprevent neuroaxonal loss and facilitate remye-lination following acute ON it is time to re-assess the extent of spontaneous recovery inON and the approaches to determining out-comes so that unmet needs may be identifiedand addressed
In this article we review the evidence forpersistent functional and structural abnormali-ties in ON and their impact on visual functionand vision-related QOL We also provide anoverview of investigational approaches to treatthe underlying pathology in ON
CLINICAL COURSE AND ASSESSMENT OFVISUAL FUNCTION Typical ON develops over a7- to 10-day period and begins to resolve within2ndash3 weeks45 Initial rapid improvement in visualfunction within the first month begins to slow inan asymptotic fashion over succeeding months4 andimprovements have been observed up to 2 yearslater6 Numerous studies have found evidence ofpersistent retinal thinning optic nerve atrophy andreduced amplitude and increased latency of visual-evoked potentials (VEPs) consistent with chronic
demyelination and neuroaxonal loss as sequelae ofacute ON (see next sections) The extent of latencyrecovery appears to be more complete in youngerpatients vs older patients females vs males andpatients with less severe attacks vs more severeattacks7 Moreover recovery of different aspects ofvisual function may proceed at different rates withdifferent sensitivities among tests and to a differentextent (figure 1) Recovery of different aspects ofvisual function may also involve distinct mechanismsas patients who achieve partial recovery of static visualfunctions (eg high- and low-contrast visual acuity)after 1 month may recover those functionscompletely whereas dynamic visual function (motionperception) appears to recover at a slower constant rateirrespective of the severity of the initial deficit8
Although patients with ON frequently regainvisual acuity to a large extent as measured by full-contrast letter charts (eg Snellen charts) low-contrast acuitysensitivity reveals permanent deficitsand is a better predictor of impairment for dailyactivities that require vision such as reading facialrecognition and driving9 Persistent deficits inlow-contrast letter acuity characteristic of ON arebetter measured using Sloan charts (Sloan low-contrast letter acuity [SLCLA]) that include versionswith 25 and 125 contrast levels to better stratifydeficits The pattern of visual field defects may helpdistinguish ON from other neuropathies In ON acentral scotoma is common and Humphrey centralvisual field perimetry frequently shows diffuse losswhereas peripheral altitudinal or other defects mayoccasionally be evident on formal perimetry Colorvision is commonly affected in ON but there is noconsistent pattern of dyschromatopsia10 More com-plex visual functions such as motion perception arealso frequently affected by ON11 Binocular summa-tion (improved vision with binocular viewing) hasalso been shown to be reduced and in some instancespatients demonstrate binocular inhibition (worsevision with binocular viewing) perhaps reflectingconcomitant disease activity in postgeniculate path-ways in some patients12 Thus evaluation of visualfunction after ON requires multiple tests to ensurecomprehensive assessment of the potential deficits
APPROACHES TO ASSESSMENT OF ON Optical
coherence tomography Assessment of structuralchanges in the course of ON has been revolutionizedover the past 2 decades by advances in optical coher-ence tomography (OCT) a technique that uses inter-ferometry of reflected light to obtain images of theretinal layers13 (figure 2) Most OCT studies ofpatients with ON have used time-domain OCT(TD-OCT) which provides cross-sectional imagesfrom different tissue levels Since the peripapillary
2 Neurology Neuroimmunology amp Neuroinflammation
retinal nerve fiber layer (RNFL) is composed ofunmyelinated optic nerve axons RNFL thinningdetected by OCT is directly interpretable asneuroaxonal degeneration More modern systemsusing spectral-domain OCT (SD-OCT) provideconsiderably improved resolution and speed and canbe used to generate 3-dimensional images formeasurements of thickness of neuronal layers
Acute ON often results in inflammatory swellingof the RNFL of the affected eye The inflammatoryswelling generally resolves within 3 months14 and isaccompanied by a period of RNFL thinning thatcontinues for up to 7ndash12 months but is most prom-inent in the first 6 months after acute ON onset515
The initial period of swelling prevents examination ofthe timing of axonal loss in the RNFL withTD-OCT In contrast the thickness of the retinalganglion cell layer (RGCL) appears to be less affectedby edema1617 so the more detailed resolution withSD-OCT may allow for a better assessment of thetiming of thinning in reference to acute ON Recentstudies suggest that thinning of the RGCL startswithin several weeks after an episode of ON andmay precede RNFL thinning1617 Ultimately RNFLthinning in affected eyes correlates with visual acuitylow-contrast letter acuity visual field color vision andVEPs (see also below)1819 thereby supporting itsfunctional relevance and RNFL thickness 75 mmhas been shown to predict reduced visual field func-tion520 Although it is not yet clear whether prevent-ing RNFL thickness from crossing that threshold canreduce the extent of associated visual deficits it isworth noting that it is also near the lower limit ofRNFL thickness when virtually all retinal ganglioncell (RGC) axons have been lost (20ndash40 mm)21
Thinning of the RNFL following an episode ofON is thought to result from axonal loss subsequentto axonal injury during the inflammatory demyelinat-ing lesion of the affected optic nerve However it isnoteworthy that detectable RNFL thinning and asso-ciated visual deficits are also observed in unaffectedeyes of patients with MS in the absence of historyof ON15 One possibility is that some ldquomildrdquo attacksare not reported or do not result in deficits that are
Figure 1 Evolution of visual function after acute optic neuritis
Figure shows the measurement of high-contrast visual acuity (VA) using the Early TreatmentDiabetic Retinopathy Study (ETDRS) charts (A) the 25 and 125 low-contrast VA using
Sloan charts (B C) and color vision using the Hardy-Rand-Rittler (HRR) pseudoisochromatic plates (D) in a cohort of37 patients with acute optic neuritis (AON) and visual assess-ment at baseline (presentation) and months 2 4 and 6 afteronset (data fromGabilondo I et al 201516) Each colored lineis data from an individual patient the solid black line repre-sents the mean from all patients and the dashed black lineshows the normal values for healthy individuals for binoculartesting (ETDRS 5 70 25 low-contrast VA 5 43 125low-contrast VA5 34 HRR5 36) Reprinted with permissionfrom Elena H Martinez-Lapiscina
Neurology Neuroimmunology amp Neuroinflammation 3
immediately evident to patients Thus in nonacuteON eyes there is a component of RNFL thinning thatmay be attributable to other causes such as subclin-ical optic nerve inflammation neurodegenerationwithin normal-appearing white matter or transsyn-aptic degeneration associated with lesions elsewherein the visual pathway22ndash24
The increased resolution of SD-OCT and the useof segmentation algorithms have allowed a moredetailed analysis of the effects of ON and MS on ret-inal structure25 (figure 2) These studies found thatRNFL thinning associated with MS with or withoutON is not confined to the peripapillary region butalso affects the macula In addition a similar pattern
Figure 2 Optical coherence tomography of the human retina
A) Detailed retinal segmentation sample on spectral-domain optical coherence tomography (OCT) image Six intraretinallayer borders can be automatically segmented (B) Correlation of anatomy with OCT for the human retina On the left is ahematoxylin amp eosin stain of the human retina in the center is a schematic representation of the cell composition of thehuman retina and on the right is a magnification of the image obtained with spectral-domain OCT (bottom) with indicationsof the retina layers identified Figure 2B reprinted with permission from Santiago Ortiz-Perez BM5 Bruch membrane CC5
of thinning is observed for the ganglion cell layerinner plexiform layers (GCL 1 IPL) in the peripap-illary region and macula A recent study in patientswith ON found that decreases of$45 mm in GCL1
IPL thickness after 1 month predicted low-contrastvisual acuity dysfunction at 6 months whereas de-creases of $7 mm predicted visual field and colorvision deficits16 In another study in patients withMS with or without a history of ON thinning of
GCL 1 IPL was most closely associated with visualfunction and vision-specific QOL26 Results of thesestudies suggest that degeneration associated with ONand MS is widespread in the RGCL
Together these studies provide compelling evi-dence for structural damage from acute ON and theyalso provide a powerful demonstration of the poten-tial for SD-OCT as a tool to assess neurodegenerativechanges in acute ON However both TD-OCT and
Figure 3 Multifocal visual-evoked potentials in optic neuritis
Figure shows the visual-evoked potentials (VEPs) in 52 sectors of the retina (A B) A case of acute optic neuritis with diffuse impairment of the VEPs in theaffected eye (A) compared with the unaffected eye (B) with significant impairment of the latencies and amplitudes (B C) After recovery from the acute opticneuritis the VEPs show a significant decrease of amplitude and latencies in most of the sectors of the affected eye (C) compared with the unaffected eye (D)Reprinted with permission from Ana Tercero
Neurology Neuroimmunology amp Neuroinflammation 5
SD-OCT appear to be less sensitive than VEPs for as-sessing the clinical and subclinical effects of ON2728
so interpretation of OCT may require complemen-tary assessments using functional techniques Fur-thermore improvements are needed to standardizeand reduce test-retest variability in SD-OCT sys-tems29 Given the rapid evolution of the technologythe technical expertise required and differencesbetween commercially available instruments30 it isalso important that criteria be established to ensurequality control for OCT as a validated outcome mea-sure a process that is under way31
VEPs Standard VEPs elicited by visual stimuli andmeasured in the occipital cortex can be used to detectfunctional changes in the visual pathway includingthe optic nerve32 In multifocal VEPs (mfVEPs)visual stimuli are provided independently to localizedregions of a wider visual field (48deg) and responses tothe stimuli are measured individually33 allowing for amore detailed analysis of visual function covering amuch larger area of the visual pathway than standardVEPs (figure 3)
The severity of an attack of ON and the extent ofinflammation are correlated with an acute reductionin the amplitude of VEPs34 Reduction in VEP ampli-tude is thought to reflect functional impairment ofaxonal conduction either transiently (eg due toacute inflammation or demyelination) or persistently(due to axonal loss) Within 3ndash4 months after theacute episode the amplitude generally shows somerecovery reflecting resolution of edema and thewaveform of the VEP is well-preserved but thelatency is significantly increased This residual latencydelay is thought to result from demyelination of sur-viving axons which interferes with saltatory conduc-tion of the action potential along the optic nervelesion Some investigators have reported subsequentimprovement in latency for up to 2 years6 whereasothers have reported no further recovery after 4months8 Prolongation of latency is most evident inthe central visual field perhaps indicating that thecentral (macular) region of the optic nerve is moresusceptible to demyelination or resistant to remyeli-nation32 The central region of the optic nerve con-tains the greatest density of parvocellular fibers thatconvey static information (eg form and color) butVEP latency in patients with ON correlates morestrongly with dynamic functions (eg motion detec-tion) than with static functions This may suggestmore specific effects on magnocellular fibers orgreater vulnerability of fibers required for accuratesignal timing8
Effects of ON on VEPs have also been shown toreflect structural changes in the RNFL In a studyof 21 patients following a first episode of unilateral
ON VEP latency prolongations and amplitude re-ductions of affected eyes at baseline and 3 monthsafter onset were associated with RNFL thinning19
suggesting a relationship between the initial structuralloss and residual functional impairment In a separatestudy of 25 patients with ON with incomplete recov-ery after 1 year similar relationships between VEPlatencyamplitude and RNFL thinning were still evi-dent18 further supporting the clinical relevance ofthis technique
mfVEPs have been used in a growing number ofsmall studies to examine the pathology of ON ingreater detail35ndash38 mfVEPs detect functional changesassociated with onset and evolution of acute ON38
and may be particularly useful to assess treatmentoutcomes in clinical trials as it appears to be morereproducible than standard VEPs39 One study of 25patients with ON between 6 and 12 months afteronset found an apparent discrepancy between struc-tural and functional measures in these patients35 AsRNFL thinning progressed in the affected eyes overthis time period the mfVEP amplitude partiallyrecovered suggesting that functional recovery maybe due in part to remyelination andor neuronalplasticity
Functional data provided by VEPs and mfVEPsmake an ideal counterpart to structural retinal assess-ments using OCT However as with OCT criterianeed to be established to ensure reproducibility andvalidity of VEP results Furthermore larger-scalestudies are needed to confirm the results of currentsmaller studies
MRI Nonconventional MRI techniques offer noveltools to examine the structure of CNS tissues indetail For example magnetization transfer (MT)imaging exploits the difference in resonance in freeprotons and protons associated with macromolecules(eg myelin) the ratio of which may provide a mea-sure of myelin content40 Diffusion tensor imaging(DTI) can be used to measure asymmetric radial dif-fusivity (RD) axial diffusivity (AD) or fractionalanisotropy (FA) of water as a gauge of tissue in majornerve tracts (eg optic nerve and optic radiations)41
A small number of studies have provided supportfor use of these techniques to assess pathologicchanges in ON For example in an MT study in11 patients with ON MT ratios of affected opticnerves closely followed the course of the disease theywere significantly higher at baseline (within 8 days ofonset) but were reduced at months 3 and 642 In aseparate study in 37 patients with ON MT ratios ofaffected optic nerves were not found to be differentfrom those of unaffected nerves until 3 months afteronset43 In that study ON-associated alterations inMT ratios at 3 months correlated with high- and
6 Neurology Neuroimmunology amp Neuroinflammation
low-contrast visual deficits and with VEP latency at 6months as well as with RNFL thinning at 12 months
In a study of DTI performed within 30 days ofonset and after 1 year in 12 patients with ON FAof affected optic nerves (which is also considered apotential measure of myelination) was the onlyparameter correlated with vision at onset but didnot correlate with the extent of recovery of visual acu-ity or contrast sensitivity at 1 or 3 months44 The AD(considered a measure of axonal integrity) was theonly parameter that was correlated with worse con-trast sensitivity at 1 and 3 months This was con-firmed in a follow-up study in 25 patients in whicha lower baseline AD was also found to be correlatedwith the extent of RNFL thinning and with VEPamplitude and latency45 These were small studiesand should be interpreted with caution as eye motionmakes imaging of the optic nerve by MT ratio andDTI challenging but they do not seem to support amodel in which the extent of neurodegeneration isdetermined solely by chronic demyelination Ratherthey suggest that the initial neuroaxonal effects of theacute inflammatory injury may be more important
Although these ldquononconventionalrdquo MRI techni-ques hold promise as a tool to investigate underlyingprocesses and assess recovery in ON there are substan-tial challenges to widespread use For example theacquisition times are frequently longer than is practical
for routine human studies and imaging is complicatedby motion artifacts caused by moving the eye orhead46 In addition there is no consensus on sequencesand protocols for their application in ON These fac-tors have limited widespread adoption of these ap-proaches and have likely contributed to theinconsistencies in findings Thus further technologicalimprovements and standardization of techniques forimaging of ON lesions will be required before theycan be considered as reliable measures of outcomesin clinical trials
QOL Visual deficits in patients with ON are likely tohave a marked impact on daily activities and QOLPatients frequently rate vision among the mostimportant physical functions affected by MS47 How-ever vision is poorly or insufficiently represented onstandard objective measures of physical functionsuch as the Expanded Disability Status Scale andfunctional assessment instruments such as the Mul-tiple Sclerosis Functional Composite (MSFC) Addi-tion of SLCLA charts to the MSFC has been reportedto better capture MS-related disability48 One patient-reported outcome instrument the 25-item NationalEye Institute Visual Functioning Questionnaire(NEI-VFQ-25) has become a commonly usedmeasurement of vision-specific health-related QOLWhen administered to patients from the ONTT 5ndash8years after the episode of acute ON scores on the NEI-VFQ-25 were lower than for an older disease-freecohort3 In patients with MS correlations with NEI-VFQ-25 scores have been demonstrated for low-contrast visual acuity49 binocular summation12
motion perception50 and loss of RGCs25 (figure 4)Moreover a 10-item supplement has been developedto better capture aspects more relevant to neuro-ophthalmology such as double vision and difficultieswith viewing motion51 A follow-up study has alsoreported its ability to distinguish patients with MSwith a history of ON52
TREATMENTS An important unmet need withrespect to ON is the availability of effective treatmentsto prevent or reverse long-term visual dysfunctionGiven the narrow window of time during whichmost recovery occurs it seems reasonable to suggestthat an effective treatment be initiated as soon aspossible after ON onset with the aim of promotingRGC survival and either extending the window forremyelination or accelerating the rate and extent towhich it occurs Data emerging from OCT studiessuggest that RGC loss may begin within weeks ofthe event thereby narrowing the time to initiateneuroprotective therapy
Despite the lack of long-term benefits of high-dosecorticosteroids patients with acute ON are frequently
Figure 4 Relationship of thickness of retinal layers to quality of life and low-contrast visual acuity
Scatter plot and fitted linear regression line showing relationships of ganglion cell layer plusinner plexiform layer (GCL 1 IPL) thickness to 25-item National Eye Institute Visual Func-tioning Questionnaire (NEI-VFQ-25) composite scores and low-contrast visual acuity at25 level The regression lines represent fitted values for mean GCL 1 IPL thickness foreach value of NEI-VFQ-25 or low-contrast visual acuity the gray shaded areas show the95 confidence intervals from the SEs of the predictions for the fitted lines Linear corre-lations were significant QOL5 quality of life Reprinted from Ophthalmology 119(6) WalterSD et al Ganglion cell loss in relation to visual disability in multiple sclerosis 1250ndash12572012 with permission from Elsevier26
Neurology Neuroimmunology amp Neuroinflammation 7
provided these drugs as symptomatic treatment tospeed resolution of acute inflammation Patients areoften assessed by MRI to determine their risk forMS but it is not clear that disease-modifying thera-pies for relapsing forms of MS are effective to preventneurodegeneration when ON occurs while receivingthese treatments For example interferon b was not
found to prevent RFNL thinning in patients withON53 Natalizumab has been shown to reduce lossof vision54 and improve VEPs55 in patients withrelapsing-remitting MS but there are no data toindicate treatment benefits specifically in patientswith ON A phase II study of fingolimod in acutedemyelinating ON is complete although it is not
Table Phase II and III studies in typical optic neuritis
Startend datesa Treatment
Time from eventto studyinitiation Primary endpoint Statusa
Primary efficacyresults Study numbera
July 1988b (end datenot provided)
Oral prednisone 1 mgkg for 14 d vsmethylprednisolone 1000 mg IV for3 d then oral prednisone 1 mgkgfor 11 d vs placebo
8 d Visual field and contrastsensitivity over 6 mo
Completedc No significanteffect2
NCT00000146
August 1995ndashDecember1997
Immunoglobulin 04 gkg IV QD for3 d then 3 infusionsmo for 3 mo vsplacebo
$6 mo High-contrast visualacuity (100 ETDRScharts)
Completed No significanteffect56
NCT00000117
August 2006ndashJuly 2011 Erythropoietin 33000 units IV for3 d vs placebo
10 d RNFL thickness at 4 8and 16 wks
Completed Significantly lessRNFL thinning at 16wk57
NCT00355095
September 2006ndashMay2011
Simvastatin 80 mg QD PO vsplacebo
4 wk Contrast sensitivity at3 mo
Completedc No significanteffect58
NCT00261326
March 2008ndashJanuary2011
Atacicept 150 mg SC weekly vsplacebo
Not specified RNFL thickness up to48 wks
Terminated None available NCT00624468
February 2009ndashFebruary2011
Glatiramer acetate 20 mg SC QD vsplacebo
Not specified RNFL thickness at 6 mo Completed None available NCT00856635
February 2010ndashJanuary2013
Minocycline 100 mg BID vs notreatment
30 d RNFL thickness every3 mo for 9 mo
Terminated None available NCT01073813
May 2010ndashMarch 2013 Visual reconstitution therapy vssaccadic eye movement training
60ndash80 d or 12mo
Visual field at 6 mo Completed None available NCT01274702
May 2011ndashDecember2013
Dalfampridine 10mg BID vs placebo $12 mo Contrast sensitivity(5 ETDRS charts)
Completed None available NCT01337986
July 2011ndashDecember2012
Vitamin D 50000 unitswk vsvitamin withheld
Not applicable(preventionstudy)
RNFL thickness at10ndash32 d after opticneuritis
Unknown None available NCT01465893
November 2011ndashAugust2014
Phenytoin 15 mgkgd for 3 d then4 mgkgd for 13 wks vs placebo
14 d RNFL thickness at6 mo
Completedd Significantly lessRNFL thinning at6 mod
NCT01451593
March 2012ndashSeptember2014
Oral prednisone 1250 mg vsmethylprednisolone 1000 mg IV for3 d each
14 d VEP latency Unknown None available NCT01524250
December 2012ndashOctober2014
BIIB033 (anti-LINGO-1) 100 mgkgIV every 4 wks vs placebo
28 d VEP latency Completed None available NCT01721161
February 2013ndashFebruary2015
Amiloride 10 mg QD vs placebo for5 mo
28 d RNFL thickness at 6 mo12 mo
Recruiting None available NCT01802489
July 2013ndashJune 2016 Fingolimod 05 mg QD vs interferonb-1b
30 d VEP latency Recruiting None available NCT01647880
August 2013ndashMay 2014 Fingolimod 05 mg QD vs placebo Not specified RNFL thickness at18 wks
Completed None available NCT01757691
October 2013ndashJanuary2016
MD1003 100 mg TID vs placebo Not specified High-contrast visualacuity (100 ETDRScharts)
Recruiting None available NCT02220244
March 2014ndashApril 2016 Amiloride hydrochlorothiazide100 mgd vs placebo
10 d RNFL thickness at24 wks
Recruiting None available NCT01879527
November 2014ndashDecember 2018
Erythropoietin 33000 units IV for3 d vs placebo
10 d RNFL thickness at 6 mo Recruiting None available NCT01962571
Abbreviations ETDRS5 Early Treatment Diabetic Retinopathy Study RNFL5 retinal nerve fiber layer SC5 subcutaneous VEP5 visual-evoked potentiala From ClinicalTrialsgov except where indicated otherwiseb The Optic Neuritis Treatment Trial included a 15-year follow-up periodc Based on published resultd Reported at American Academy of Neurology 2015 Annual Meeting April 18ndash25 Washington DC
8 Neurology Neuroimmunology amp Neuroinflammation
clear that enrollment goals were met Another phaseIIIII study is under way but study results are not yetavailable (table)
Based on promising results from animal studiesand small clinical studies IV immunoglobulin wasinvestigated in patients with one or more episodesof typical ON and irreversible loss of visual acuitybut was terminated early due to negative results56
(table) Since that time various investigational ther-apies have shown promise in early preclinical andclinical studies and a number of phase II and IIIstudies have been completed or are under way Forexample in a placebo-controlled study of IV eryth-ropoietin for 3 days as an add-on to methylpredni-sone in patients with a first episode of ON withinthe previous 10 days those treated with erythropoi-etin demonstrated reduced RNFL thinning lessdecrease in optic nerve diameter and shorter VEPlatency57 Although the mechanism by which eryth-ropoietin may exert these effects is poorly under-stood it may involve the neuroprotective effectsof this hormone during acute inflammation Inanother placebo-controlled study in patients withsymptom duration of 4 weeks and reduced con-trast sensitivity simvastatin (a hypercholesterolemiamedication) narrowly missed significance on theprimary efficacy outcome (contrast sensitivity)but improvements were noted for VEP latencyand amplitude58 However imbalances in random-ization and technical issues may have contributed tothe observed effects59 A study in ON testing possibleneuroprotective effects of phenytoin an anticonvul-sant has recently completed and another study testingeffects of amiloride hydrochlorothiazide a diuretic iscurrently underway Nevertheless it is an open ques-tion whether a neuroprotective agent can domore thandelay degeneration of axons if they remain chronicallydemyelinated Finally BIIB033 a fully-human anti-body to LINGO-1 an inhibitor of myelination andneuroaxonal growth has shown promise in preclinicaland early clinical testing60 and a phase II study in ONwas recently completed
CONCLUSIONS It is now clear that recovery fromON is frequently incomplete which adversely affectsthe QOL of patients In addition there remain con-siderable gaps with respect to understanding assess-ing and treating this disease to prevent long-termdeficits Nevertheless ongoing work holds promisefor all of these areas The application of newertechnologies continues to provide new insight intothe underlying disease processes and increasedappreciation of the injury that occurs followingON The development of these new tools mayincrease the ability to detect meaningful changes invision with therapeutic intervention and study
results suggest that timing is critical Developmentof guidelines to ensure consistency in theirapplication should also improve interpretation offindings and thereby improve the quality ofassessments Finally several therapies have shownpromise in preclinical and early clinical testingTherefore there is reason to be optimistic thatstrategies may soon be identified to improve theprognosis for patients with ON Given therelationship between ON and MS it seems likelythat any such developments for ON may havesubstantial implications for understanding assessingand treating MS as well
AUTHOR CONTRIBUTIONSAll authors participated in the conception of the article interpretation of
the data and revision of the manuscript and they approved the final ver-
sion Biogen provided funding for writing and editorial support in the
development of this paper and they reviewed and provided feedback
on the paper to the authors The authors had full editorial control of
the paper and provided their final approval of all content
ACKNOWLEDGMENTThe authors thank Dr Elena H Martinez-Lapiscina Dr Santiago Ortiz-
Perez and Dr Ana Tercero from the Center of Neuroimmunology Insti-
tute of Biomedical Research August Pi SunyerHospital Clinic Barcelona
University of Barcelona for creating figures 1 2B and 3 respectively
Lauren Nagy of Excel Scientific Solutions copyedited and styled the man-
uscript per journal requirements and this editorial support was funded by
Biogen
STUDY FUNDINGWriting and editorial support was funded by Biogen
DISCLOSURESL Galetta has received consulting honoraria and travel fundingspeaker
honoraria from Genzyme and Biogen and is on the editorial board for
Neurology and Journal of Neuro-Ophthalmology P Villoslada serves on
advisory boards for Novartis Roche Neurotec Pharma and Bionure
Pharma has consulted for Novartis Roche TFS Heidelberg Engineer-
ing MedImmune Diagna Biotec and Neurotec Pharma is an academic
editor for PLoSONE is on the editorial board for Neurology amp Therapy
and Current Treatment Options in Neurology has received research sup-
port from European Commission Genzyme Biogen Instituto Salud
Carlos III Marato TV3 Novartis and Roche and holds patents and
owns stocksstock options with Bionure Pharma N Levin receives
research support from National Multiple Sclerosis Foundation
K Shindler received research support from the FM Kirby Foundation
Harbor Therapeutics National Eye Institute National Multiple Sclerosis
Foundation Research to Prevent Blindness Sirtris Pharmaceuticals
ITMAT and Stemnion Inc has received speaker honoraria from Med-
ical College of Wisconsin and Temple University is an associate editor
for Frontiers in Neurology Neuro-Ophthalmology receives publishing roy-
alties from UpToDate and Oakstone Publishing and has consulted for
medical-legal cases H Ishikawa received research support from the NIH
E Parr is a full-time employee of Excel Scientific Solutions who were
funded by Biogen to provide editorial and writing support for this paper
D Cadavid is a full-time employee of Biogen owns stock options in
Biogen and has patent applications pending related to the use of drugs
that block LINGO-1 to treat demyelination in multiple sclerosis LJ
Balcer received consulting fees from Acorda Biogen Genzyme Novartis
Questcor and Vaccinexe serves on a clinical trial advisory board for
Biogen and serves on a scientific advisory board for Genzyme Go to
Neurologyorgnn for full disclosure forms
Received February 12 2015 Accepted in final form May 13 2015
Neurology Neuroimmunology amp Neuroinflammation 9
REFERENCES1 Toosy AT Mason DF Miller DH Optic neuritis Lancet
Neurol 20141383ndash99
2 Beck RW Cleary PA Anderson MM Jr et al Optic Neu-
ritis Study Group A randomized controlled trial of cor-
ticosteroids in the treatment of acute optic neuritis N
Engl J Med 1992326581ndash588
3 Cole SR Beck RW Moke PS Gal RL Long DT Optic
Neuritis Study Group The National Eye Institute Visual
Function Questionnaire experience of the ONTT Invest
Ophthalmol Vis Sci 2000411017ndash1021
4 Beck RW Cleary PA Backlund JC The course of visual
recovery after optic neuritis Experience of the Optic
Neuritis Treatment Trial Ophthalmology 1994101
1771ndash1778
5 Costello F Hodge W Pan YI Eggenberger E Coupland S
Kardon RH Tracking retinal nerve fiber layer loss after
optic neuritis a prospective study using optical coherence
tomography Mult Scler 200814893ndash905
6 Brusa A Jones SJ Plant GT Long-term remyelination
after optic neuritis a 2-year visual evoked potential and
psychophysical serial study Brain 2001124468ndash479
7 Malik MT Healy BC Benson LA et al Factors associated
with recovery from acute optic neuritis in patients with
multiple sclerosis Neurology 2014822173ndash2179
8 Raz N Dotan S Chokron S Ben-Hur T Levin N Demy-
elination affects temporal aspects of perception an optic
neuritis study Ann Neurol 201271531ndash538
9 Leat SJ Legge GE Bullimore MA What is low vision A re-
evaluation of definitions Optom Vis Sci 199976198ndash211
10 Martiacutenez-Lapiscina EH Ortiz-Peacuterez S Fraga-Pumar E et al
Colour vision impairment is associated with disease severity
in multiple sclerosis Mult Scler 2014201207ndash1216
11 Raz N Dotan S Benoliel T Chokron S Ben-Hur T
Levin N Sustained motion perception deficit following
optic neuritis behavioral and cortical evidence Neurology
2011762103ndash2111
12 Pineles SL Birch EE Talman LS et al One eye or two a
comparison of binocular and monocular low-contrast acu-
ity testing in multiple sclerosis Am J Ophthalmol 2011
152133ndash140
13 Gabriele ML Wollstein G Ishikawa H et al Optical
coherence tomography history current status and lab-
oratory work Invest Ophthalmol Vis Sci 201152
2425ndash2436
14 Henderson AP Altmann DR Trip AS et al A serial study
of retinal changes following optic neuritis with sample size
estimates for acute neuroprotection trials Brain 2010133
2592ndash2602
15 Petzold A de Boer JF Schippling S et al Optical coher-
ence tomography in multiple sclerosis a systematic review
and meta-analysis Lancet Neurol 20109921ndash932
16 Gabilondo I Martiacutenez-Lapiscina EH Fraga-Pumar E
et al Dynamics of retinal injury after acute optic neuritis
Ann Neurol 201577517ndash528
17 Huang-Link Y-M Al-Hawasi A Lindehammar H Acute
optic neuritis retinal ganglion cell loss precedes retinal
nerve fiber thinning Neurol Sci 201536617ndash620
18 Trip SA Schlottmann PG Jones SJ et al Retinal nerve
fiber layer axonal loss and visual dysfunction in optic neu-
ritis Ann Neurol 200558383ndash391
19 Henderson AP Altmann DR Trip SA et al Early factors
associated with axonal loss after optic neuritis Ann Neurol
201170955ndash963
20 Costello F Coupland S Hodge W et al Quantifying
axonal loss after optic neuritis with optical coherence
tomography Ann Neurol 200659963ndash969
21 Hood DC Anderson SC Wall M Kardon RH Structure
versus function in glaucoma an application of a linear
model Invest Ophthalmol Vis Sci 2007483662ndash3668
22 Balk LJ Steenwijk MD Tewarie P et al Bidirectional
trans-synaptic axonal degeneration in the visual pathway
in multiple sclerosis J Neurol Neurosurg Psychiatry 2014
86419ndash424
23 Gabilondo I Martiacutenez-Lapiscina EH Martiacutenez-Heras E
et al Trans-synaptic axonal degeneration in the visual path-
way in multiple sclerosis Ann Neurol 20147598ndash107
24 Alshowaeir D Yiannikas C Garrick R et al Latency of
multifocal visual evoked potentials in nonoptic neuritis eyes
of multiple sclerosis patients associated with optic radiation
lesions Invest Ophthalmol Vis Sci 2014553758ndash3764
25 Sakai RE Feller DJ Galetta KM Galetta SL Balcer LJ
Vision in multiple sclerosis the story structure-function cor-
relations and models for neuroprotection J Neuroophthalmol
201131362ndash373
26 Walter SD Ishikawa H Galetta KM et al Ganglion cell
loss in relation to visual disability in multiple sclerosis
Ophthalmology 20121191250ndash1257
27 Di Maggio G Santangelo R Guerrieri S et al Optical
coherence tomography and visual evoked potentials which
is more sensitive in multiple sclerosis Mult Scler 201420
1342ndash1347
28 Naismith RT Tutlam NT Xu J et al Optical coherence
tomography is less sensitive than visual evoked potentials
in optic neuritis Neurology 20097346ndash52
29 Araie M Test-retest variability in structural parameters
measured with glaucoma imaging devices Jpn J Ophthal-
mol 2013571ndash24
30 Watson GM Keltner JL Chin EK Harvey D Nguyen A
Park SS Comparison of retinal nerve fiber layer and cen-
tral macular thickness measurements among five different
optical coherence tomography instruments in patients with
multiple sclerosis and optic neuritis J Neuroophthalmol
201131110ndash116
31 Schippling S Balk L Costello F et al Quality control for
retinal OCT in multiple sclerosis validation of the
OSCAR-IB criteria Mult Scler 201521163ndash170
32 Rinalduzzi S Brusa A Jones SJ Variation of visual evoked
potential delay to stimulation of central nasal and tem-
poral regions of the macula in optic neuritis J Neurol
httpnnneurologyorgcgicollectionmultiple_sclerosisMultiple sclerosisfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2015 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
retinal nerve fiber layer (RNFL) is composed ofunmyelinated optic nerve axons RNFL thinningdetected by OCT is directly interpretable asneuroaxonal degeneration More modern systemsusing spectral-domain OCT (SD-OCT) provideconsiderably improved resolution and speed and canbe used to generate 3-dimensional images formeasurements of thickness of neuronal layers
Acute ON often results in inflammatory swellingof the RNFL of the affected eye The inflammatoryswelling generally resolves within 3 months14 and isaccompanied by a period of RNFL thinning thatcontinues for up to 7ndash12 months but is most prom-inent in the first 6 months after acute ON onset515
The initial period of swelling prevents examination ofthe timing of axonal loss in the RNFL withTD-OCT In contrast the thickness of the retinalganglion cell layer (RGCL) appears to be less affectedby edema1617 so the more detailed resolution withSD-OCT may allow for a better assessment of thetiming of thinning in reference to acute ON Recentstudies suggest that thinning of the RGCL startswithin several weeks after an episode of ON andmay precede RNFL thinning1617 Ultimately RNFLthinning in affected eyes correlates with visual acuitylow-contrast letter acuity visual field color vision andVEPs (see also below)1819 thereby supporting itsfunctional relevance and RNFL thickness 75 mmhas been shown to predict reduced visual field func-tion520 Although it is not yet clear whether prevent-ing RNFL thickness from crossing that threshold canreduce the extent of associated visual deficits it isworth noting that it is also near the lower limit ofRNFL thickness when virtually all retinal ganglioncell (RGC) axons have been lost (20ndash40 mm)21
Thinning of the RNFL following an episode ofON is thought to result from axonal loss subsequentto axonal injury during the inflammatory demyelinat-ing lesion of the affected optic nerve However it isnoteworthy that detectable RNFL thinning and asso-ciated visual deficits are also observed in unaffectedeyes of patients with MS in the absence of historyof ON15 One possibility is that some ldquomildrdquo attacksare not reported or do not result in deficits that are
Figure 1 Evolution of visual function after acute optic neuritis
Figure shows the measurement of high-contrast visual acuity (VA) using the Early TreatmentDiabetic Retinopathy Study (ETDRS) charts (A) the 25 and 125 low-contrast VA using
Sloan charts (B C) and color vision using the Hardy-Rand-Rittler (HRR) pseudoisochromatic plates (D) in a cohort of37 patients with acute optic neuritis (AON) and visual assess-ment at baseline (presentation) and months 2 4 and 6 afteronset (data fromGabilondo I et al 201516) Each colored lineis data from an individual patient the solid black line repre-sents the mean from all patients and the dashed black lineshows the normal values for healthy individuals for binoculartesting (ETDRS 5 70 25 low-contrast VA 5 43 125low-contrast VA5 34 HRR5 36) Reprinted with permissionfrom Elena H Martinez-Lapiscina
Neurology Neuroimmunology amp Neuroinflammation 3
immediately evident to patients Thus in nonacuteON eyes there is a component of RNFL thinning thatmay be attributable to other causes such as subclin-ical optic nerve inflammation neurodegenerationwithin normal-appearing white matter or transsyn-aptic degeneration associated with lesions elsewherein the visual pathway22ndash24
The increased resolution of SD-OCT and the useof segmentation algorithms have allowed a moredetailed analysis of the effects of ON and MS on ret-inal structure25 (figure 2) These studies found thatRNFL thinning associated with MS with or withoutON is not confined to the peripapillary region butalso affects the macula In addition a similar pattern
Figure 2 Optical coherence tomography of the human retina
A) Detailed retinal segmentation sample on spectral-domain optical coherence tomography (OCT) image Six intraretinallayer borders can be automatically segmented (B) Correlation of anatomy with OCT for the human retina On the left is ahematoxylin amp eosin stain of the human retina in the center is a schematic representation of the cell composition of thehuman retina and on the right is a magnification of the image obtained with spectral-domain OCT (bottom) with indicationsof the retina layers identified Figure 2B reprinted with permission from Santiago Ortiz-Perez BM5 Bruch membrane CC5
of thinning is observed for the ganglion cell layerinner plexiform layers (GCL 1 IPL) in the peripap-illary region and macula A recent study in patientswith ON found that decreases of$45 mm in GCL1
IPL thickness after 1 month predicted low-contrastvisual acuity dysfunction at 6 months whereas de-creases of $7 mm predicted visual field and colorvision deficits16 In another study in patients withMS with or without a history of ON thinning of
GCL 1 IPL was most closely associated with visualfunction and vision-specific QOL26 Results of thesestudies suggest that degeneration associated with ONand MS is widespread in the RGCL
Together these studies provide compelling evi-dence for structural damage from acute ON and theyalso provide a powerful demonstration of the poten-tial for SD-OCT as a tool to assess neurodegenerativechanges in acute ON However both TD-OCT and
Figure 3 Multifocal visual-evoked potentials in optic neuritis
Figure shows the visual-evoked potentials (VEPs) in 52 sectors of the retina (A B) A case of acute optic neuritis with diffuse impairment of the VEPs in theaffected eye (A) compared with the unaffected eye (B) with significant impairment of the latencies and amplitudes (B C) After recovery from the acute opticneuritis the VEPs show a significant decrease of amplitude and latencies in most of the sectors of the affected eye (C) compared with the unaffected eye (D)Reprinted with permission from Ana Tercero
Neurology Neuroimmunology amp Neuroinflammation 5
SD-OCT appear to be less sensitive than VEPs for as-sessing the clinical and subclinical effects of ON2728
so interpretation of OCT may require complemen-tary assessments using functional techniques Fur-thermore improvements are needed to standardizeand reduce test-retest variability in SD-OCT sys-tems29 Given the rapid evolution of the technologythe technical expertise required and differencesbetween commercially available instruments30 it isalso important that criteria be established to ensurequality control for OCT as a validated outcome mea-sure a process that is under way31
VEPs Standard VEPs elicited by visual stimuli andmeasured in the occipital cortex can be used to detectfunctional changes in the visual pathway includingthe optic nerve32 In multifocal VEPs (mfVEPs)visual stimuli are provided independently to localizedregions of a wider visual field (48deg) and responses tothe stimuli are measured individually33 allowing for amore detailed analysis of visual function covering amuch larger area of the visual pathway than standardVEPs (figure 3)
The severity of an attack of ON and the extent ofinflammation are correlated with an acute reductionin the amplitude of VEPs34 Reduction in VEP ampli-tude is thought to reflect functional impairment ofaxonal conduction either transiently (eg due toacute inflammation or demyelination) or persistently(due to axonal loss) Within 3ndash4 months after theacute episode the amplitude generally shows somerecovery reflecting resolution of edema and thewaveform of the VEP is well-preserved but thelatency is significantly increased This residual latencydelay is thought to result from demyelination of sur-viving axons which interferes with saltatory conduc-tion of the action potential along the optic nervelesion Some investigators have reported subsequentimprovement in latency for up to 2 years6 whereasothers have reported no further recovery after 4months8 Prolongation of latency is most evident inthe central visual field perhaps indicating that thecentral (macular) region of the optic nerve is moresusceptible to demyelination or resistant to remyeli-nation32 The central region of the optic nerve con-tains the greatest density of parvocellular fibers thatconvey static information (eg form and color) butVEP latency in patients with ON correlates morestrongly with dynamic functions (eg motion detec-tion) than with static functions This may suggestmore specific effects on magnocellular fibers orgreater vulnerability of fibers required for accuratesignal timing8
Effects of ON on VEPs have also been shown toreflect structural changes in the RNFL In a studyof 21 patients following a first episode of unilateral
ON VEP latency prolongations and amplitude re-ductions of affected eyes at baseline and 3 monthsafter onset were associated with RNFL thinning19
suggesting a relationship between the initial structuralloss and residual functional impairment In a separatestudy of 25 patients with ON with incomplete recov-ery after 1 year similar relationships between VEPlatencyamplitude and RNFL thinning were still evi-dent18 further supporting the clinical relevance ofthis technique
mfVEPs have been used in a growing number ofsmall studies to examine the pathology of ON ingreater detail35ndash38 mfVEPs detect functional changesassociated with onset and evolution of acute ON38
and may be particularly useful to assess treatmentoutcomes in clinical trials as it appears to be morereproducible than standard VEPs39 One study of 25patients with ON between 6 and 12 months afteronset found an apparent discrepancy between struc-tural and functional measures in these patients35 AsRNFL thinning progressed in the affected eyes overthis time period the mfVEP amplitude partiallyrecovered suggesting that functional recovery maybe due in part to remyelination andor neuronalplasticity
Functional data provided by VEPs and mfVEPsmake an ideal counterpart to structural retinal assess-ments using OCT However as with OCT criterianeed to be established to ensure reproducibility andvalidity of VEP results Furthermore larger-scalestudies are needed to confirm the results of currentsmaller studies
MRI Nonconventional MRI techniques offer noveltools to examine the structure of CNS tissues indetail For example magnetization transfer (MT)imaging exploits the difference in resonance in freeprotons and protons associated with macromolecules(eg myelin) the ratio of which may provide a mea-sure of myelin content40 Diffusion tensor imaging(DTI) can be used to measure asymmetric radial dif-fusivity (RD) axial diffusivity (AD) or fractionalanisotropy (FA) of water as a gauge of tissue in majornerve tracts (eg optic nerve and optic radiations)41
A small number of studies have provided supportfor use of these techniques to assess pathologicchanges in ON For example in an MT study in11 patients with ON MT ratios of affected opticnerves closely followed the course of the disease theywere significantly higher at baseline (within 8 days ofonset) but were reduced at months 3 and 642 In aseparate study in 37 patients with ON MT ratios ofaffected optic nerves were not found to be differentfrom those of unaffected nerves until 3 months afteronset43 In that study ON-associated alterations inMT ratios at 3 months correlated with high- and
6 Neurology Neuroimmunology amp Neuroinflammation
low-contrast visual deficits and with VEP latency at 6months as well as with RNFL thinning at 12 months
In a study of DTI performed within 30 days ofonset and after 1 year in 12 patients with ON FAof affected optic nerves (which is also considered apotential measure of myelination) was the onlyparameter correlated with vision at onset but didnot correlate with the extent of recovery of visual acu-ity or contrast sensitivity at 1 or 3 months44 The AD(considered a measure of axonal integrity) was theonly parameter that was correlated with worse con-trast sensitivity at 1 and 3 months This was con-firmed in a follow-up study in 25 patients in whicha lower baseline AD was also found to be correlatedwith the extent of RNFL thinning and with VEPamplitude and latency45 These were small studiesand should be interpreted with caution as eye motionmakes imaging of the optic nerve by MT ratio andDTI challenging but they do not seem to support amodel in which the extent of neurodegeneration isdetermined solely by chronic demyelination Ratherthey suggest that the initial neuroaxonal effects of theacute inflammatory injury may be more important
Although these ldquononconventionalrdquo MRI techni-ques hold promise as a tool to investigate underlyingprocesses and assess recovery in ON there are substan-tial challenges to widespread use For example theacquisition times are frequently longer than is practical
for routine human studies and imaging is complicatedby motion artifacts caused by moving the eye orhead46 In addition there is no consensus on sequencesand protocols for their application in ON These fac-tors have limited widespread adoption of these ap-proaches and have likely contributed to theinconsistencies in findings Thus further technologicalimprovements and standardization of techniques forimaging of ON lesions will be required before theycan be considered as reliable measures of outcomesin clinical trials
QOL Visual deficits in patients with ON are likely tohave a marked impact on daily activities and QOLPatients frequently rate vision among the mostimportant physical functions affected by MS47 How-ever vision is poorly or insufficiently represented onstandard objective measures of physical functionsuch as the Expanded Disability Status Scale andfunctional assessment instruments such as the Mul-tiple Sclerosis Functional Composite (MSFC) Addi-tion of SLCLA charts to the MSFC has been reportedto better capture MS-related disability48 One patient-reported outcome instrument the 25-item NationalEye Institute Visual Functioning Questionnaire(NEI-VFQ-25) has become a commonly usedmeasurement of vision-specific health-related QOLWhen administered to patients from the ONTT 5ndash8years after the episode of acute ON scores on the NEI-VFQ-25 were lower than for an older disease-freecohort3 In patients with MS correlations with NEI-VFQ-25 scores have been demonstrated for low-contrast visual acuity49 binocular summation12
motion perception50 and loss of RGCs25 (figure 4)Moreover a 10-item supplement has been developedto better capture aspects more relevant to neuro-ophthalmology such as double vision and difficultieswith viewing motion51 A follow-up study has alsoreported its ability to distinguish patients with MSwith a history of ON52
TREATMENTS An important unmet need withrespect to ON is the availability of effective treatmentsto prevent or reverse long-term visual dysfunctionGiven the narrow window of time during whichmost recovery occurs it seems reasonable to suggestthat an effective treatment be initiated as soon aspossible after ON onset with the aim of promotingRGC survival and either extending the window forremyelination or accelerating the rate and extent towhich it occurs Data emerging from OCT studiessuggest that RGC loss may begin within weeks ofthe event thereby narrowing the time to initiateneuroprotective therapy
Despite the lack of long-term benefits of high-dosecorticosteroids patients with acute ON are frequently
Figure 4 Relationship of thickness of retinal layers to quality of life and low-contrast visual acuity
Scatter plot and fitted linear regression line showing relationships of ganglion cell layer plusinner plexiform layer (GCL 1 IPL) thickness to 25-item National Eye Institute Visual Func-tioning Questionnaire (NEI-VFQ-25) composite scores and low-contrast visual acuity at25 level The regression lines represent fitted values for mean GCL 1 IPL thickness foreach value of NEI-VFQ-25 or low-contrast visual acuity the gray shaded areas show the95 confidence intervals from the SEs of the predictions for the fitted lines Linear corre-lations were significant QOL5 quality of life Reprinted from Ophthalmology 119(6) WalterSD et al Ganglion cell loss in relation to visual disability in multiple sclerosis 1250ndash12572012 with permission from Elsevier26
Neurology Neuroimmunology amp Neuroinflammation 7
provided these drugs as symptomatic treatment tospeed resolution of acute inflammation Patients areoften assessed by MRI to determine their risk forMS but it is not clear that disease-modifying thera-pies for relapsing forms of MS are effective to preventneurodegeneration when ON occurs while receivingthese treatments For example interferon b was not
found to prevent RFNL thinning in patients withON53 Natalizumab has been shown to reduce lossof vision54 and improve VEPs55 in patients withrelapsing-remitting MS but there are no data toindicate treatment benefits specifically in patientswith ON A phase II study of fingolimod in acutedemyelinating ON is complete although it is not
Table Phase II and III studies in typical optic neuritis
Startend datesa Treatment
Time from eventto studyinitiation Primary endpoint Statusa
Primary efficacyresults Study numbera
July 1988b (end datenot provided)
Oral prednisone 1 mgkg for 14 d vsmethylprednisolone 1000 mg IV for3 d then oral prednisone 1 mgkgfor 11 d vs placebo
8 d Visual field and contrastsensitivity over 6 mo
Completedc No significanteffect2
NCT00000146
August 1995ndashDecember1997
Immunoglobulin 04 gkg IV QD for3 d then 3 infusionsmo for 3 mo vsplacebo
$6 mo High-contrast visualacuity (100 ETDRScharts)
Completed No significanteffect56
NCT00000117
August 2006ndashJuly 2011 Erythropoietin 33000 units IV for3 d vs placebo
10 d RNFL thickness at 4 8and 16 wks
Completed Significantly lessRNFL thinning at 16wk57
NCT00355095
September 2006ndashMay2011
Simvastatin 80 mg QD PO vsplacebo
4 wk Contrast sensitivity at3 mo
Completedc No significanteffect58
NCT00261326
March 2008ndashJanuary2011
Atacicept 150 mg SC weekly vsplacebo
Not specified RNFL thickness up to48 wks
Terminated None available NCT00624468
February 2009ndashFebruary2011
Glatiramer acetate 20 mg SC QD vsplacebo
Not specified RNFL thickness at 6 mo Completed None available NCT00856635
February 2010ndashJanuary2013
Minocycline 100 mg BID vs notreatment
30 d RNFL thickness every3 mo for 9 mo
Terminated None available NCT01073813
May 2010ndashMarch 2013 Visual reconstitution therapy vssaccadic eye movement training
60ndash80 d or 12mo
Visual field at 6 mo Completed None available NCT01274702
May 2011ndashDecember2013
Dalfampridine 10mg BID vs placebo $12 mo Contrast sensitivity(5 ETDRS charts)
Completed None available NCT01337986
July 2011ndashDecember2012
Vitamin D 50000 unitswk vsvitamin withheld
Not applicable(preventionstudy)
RNFL thickness at10ndash32 d after opticneuritis
Unknown None available NCT01465893
November 2011ndashAugust2014
Phenytoin 15 mgkgd for 3 d then4 mgkgd for 13 wks vs placebo
14 d RNFL thickness at6 mo
Completedd Significantly lessRNFL thinning at6 mod
NCT01451593
March 2012ndashSeptember2014
Oral prednisone 1250 mg vsmethylprednisolone 1000 mg IV for3 d each
14 d VEP latency Unknown None available NCT01524250
December 2012ndashOctober2014
BIIB033 (anti-LINGO-1) 100 mgkgIV every 4 wks vs placebo
28 d VEP latency Completed None available NCT01721161
February 2013ndashFebruary2015
Amiloride 10 mg QD vs placebo for5 mo
28 d RNFL thickness at 6 mo12 mo
Recruiting None available NCT01802489
July 2013ndashJune 2016 Fingolimod 05 mg QD vs interferonb-1b
30 d VEP latency Recruiting None available NCT01647880
August 2013ndashMay 2014 Fingolimod 05 mg QD vs placebo Not specified RNFL thickness at18 wks
Completed None available NCT01757691
October 2013ndashJanuary2016
MD1003 100 mg TID vs placebo Not specified High-contrast visualacuity (100 ETDRScharts)
Recruiting None available NCT02220244
March 2014ndashApril 2016 Amiloride hydrochlorothiazide100 mgd vs placebo
10 d RNFL thickness at24 wks
Recruiting None available NCT01879527
November 2014ndashDecember 2018
Erythropoietin 33000 units IV for3 d vs placebo
10 d RNFL thickness at 6 mo Recruiting None available NCT01962571
Abbreviations ETDRS5 Early Treatment Diabetic Retinopathy Study RNFL5 retinal nerve fiber layer SC5 subcutaneous VEP5 visual-evoked potentiala From ClinicalTrialsgov except where indicated otherwiseb The Optic Neuritis Treatment Trial included a 15-year follow-up periodc Based on published resultd Reported at American Academy of Neurology 2015 Annual Meeting April 18ndash25 Washington DC
8 Neurology Neuroimmunology amp Neuroinflammation
clear that enrollment goals were met Another phaseIIIII study is under way but study results are not yetavailable (table)
Based on promising results from animal studiesand small clinical studies IV immunoglobulin wasinvestigated in patients with one or more episodesof typical ON and irreversible loss of visual acuitybut was terminated early due to negative results56
(table) Since that time various investigational ther-apies have shown promise in early preclinical andclinical studies and a number of phase II and IIIstudies have been completed or are under way Forexample in a placebo-controlled study of IV eryth-ropoietin for 3 days as an add-on to methylpredni-sone in patients with a first episode of ON withinthe previous 10 days those treated with erythropoi-etin demonstrated reduced RNFL thinning lessdecrease in optic nerve diameter and shorter VEPlatency57 Although the mechanism by which eryth-ropoietin may exert these effects is poorly under-stood it may involve the neuroprotective effectsof this hormone during acute inflammation Inanother placebo-controlled study in patients withsymptom duration of 4 weeks and reduced con-trast sensitivity simvastatin (a hypercholesterolemiamedication) narrowly missed significance on theprimary efficacy outcome (contrast sensitivity)but improvements were noted for VEP latencyand amplitude58 However imbalances in random-ization and technical issues may have contributed tothe observed effects59 A study in ON testing possibleneuroprotective effects of phenytoin an anticonvul-sant has recently completed and another study testingeffects of amiloride hydrochlorothiazide a diuretic iscurrently underway Nevertheless it is an open ques-tion whether a neuroprotective agent can domore thandelay degeneration of axons if they remain chronicallydemyelinated Finally BIIB033 a fully-human anti-body to LINGO-1 an inhibitor of myelination andneuroaxonal growth has shown promise in preclinicaland early clinical testing60 and a phase II study in ONwas recently completed
CONCLUSIONS It is now clear that recovery fromON is frequently incomplete which adversely affectsthe QOL of patients In addition there remain con-siderable gaps with respect to understanding assess-ing and treating this disease to prevent long-termdeficits Nevertheless ongoing work holds promisefor all of these areas The application of newertechnologies continues to provide new insight intothe underlying disease processes and increasedappreciation of the injury that occurs followingON The development of these new tools mayincrease the ability to detect meaningful changes invision with therapeutic intervention and study
results suggest that timing is critical Developmentof guidelines to ensure consistency in theirapplication should also improve interpretation offindings and thereby improve the quality ofassessments Finally several therapies have shownpromise in preclinical and early clinical testingTherefore there is reason to be optimistic thatstrategies may soon be identified to improve theprognosis for patients with ON Given therelationship between ON and MS it seems likelythat any such developments for ON may havesubstantial implications for understanding assessingand treating MS as well
AUTHOR CONTRIBUTIONSAll authors participated in the conception of the article interpretation of
the data and revision of the manuscript and they approved the final ver-
sion Biogen provided funding for writing and editorial support in the
development of this paper and they reviewed and provided feedback
on the paper to the authors The authors had full editorial control of
the paper and provided their final approval of all content
ACKNOWLEDGMENTThe authors thank Dr Elena H Martinez-Lapiscina Dr Santiago Ortiz-
Perez and Dr Ana Tercero from the Center of Neuroimmunology Insti-
tute of Biomedical Research August Pi SunyerHospital Clinic Barcelona
University of Barcelona for creating figures 1 2B and 3 respectively
Lauren Nagy of Excel Scientific Solutions copyedited and styled the man-
uscript per journal requirements and this editorial support was funded by
Biogen
STUDY FUNDINGWriting and editorial support was funded by Biogen
DISCLOSURESL Galetta has received consulting honoraria and travel fundingspeaker
honoraria from Genzyme and Biogen and is on the editorial board for
Neurology and Journal of Neuro-Ophthalmology P Villoslada serves on
advisory boards for Novartis Roche Neurotec Pharma and Bionure
Pharma has consulted for Novartis Roche TFS Heidelberg Engineer-
ing MedImmune Diagna Biotec and Neurotec Pharma is an academic
editor for PLoSONE is on the editorial board for Neurology amp Therapy
and Current Treatment Options in Neurology has received research sup-
port from European Commission Genzyme Biogen Instituto Salud
Carlos III Marato TV3 Novartis and Roche and holds patents and
owns stocksstock options with Bionure Pharma N Levin receives
research support from National Multiple Sclerosis Foundation
K Shindler received research support from the FM Kirby Foundation
Harbor Therapeutics National Eye Institute National Multiple Sclerosis
Foundation Research to Prevent Blindness Sirtris Pharmaceuticals
ITMAT and Stemnion Inc has received speaker honoraria from Med-
ical College of Wisconsin and Temple University is an associate editor
for Frontiers in Neurology Neuro-Ophthalmology receives publishing roy-
alties from UpToDate and Oakstone Publishing and has consulted for
medical-legal cases H Ishikawa received research support from the NIH
E Parr is a full-time employee of Excel Scientific Solutions who were
funded by Biogen to provide editorial and writing support for this paper
D Cadavid is a full-time employee of Biogen owns stock options in
Biogen and has patent applications pending related to the use of drugs
that block LINGO-1 to treat demyelination in multiple sclerosis LJ
Balcer received consulting fees from Acorda Biogen Genzyme Novartis
Questcor and Vaccinexe serves on a clinical trial advisory board for
Biogen and serves on a scientific advisory board for Genzyme Go to
Neurologyorgnn for full disclosure forms
Received February 12 2015 Accepted in final form May 13 2015
Neurology Neuroimmunology amp Neuroinflammation 9
REFERENCES1 Toosy AT Mason DF Miller DH Optic neuritis Lancet
Neurol 20141383ndash99
2 Beck RW Cleary PA Anderson MM Jr et al Optic Neu-
ritis Study Group A randomized controlled trial of cor-
ticosteroids in the treatment of acute optic neuritis N
Engl J Med 1992326581ndash588
3 Cole SR Beck RW Moke PS Gal RL Long DT Optic
Neuritis Study Group The National Eye Institute Visual
Function Questionnaire experience of the ONTT Invest
Ophthalmol Vis Sci 2000411017ndash1021
4 Beck RW Cleary PA Backlund JC The course of visual
recovery after optic neuritis Experience of the Optic
Neuritis Treatment Trial Ophthalmology 1994101
1771ndash1778
5 Costello F Hodge W Pan YI Eggenberger E Coupland S
Kardon RH Tracking retinal nerve fiber layer loss after
optic neuritis a prospective study using optical coherence
tomography Mult Scler 200814893ndash905
6 Brusa A Jones SJ Plant GT Long-term remyelination
after optic neuritis a 2-year visual evoked potential and
psychophysical serial study Brain 2001124468ndash479
7 Malik MT Healy BC Benson LA et al Factors associated
with recovery from acute optic neuritis in patients with
multiple sclerosis Neurology 2014822173ndash2179
8 Raz N Dotan S Chokron S Ben-Hur T Levin N Demy-
elination affects temporal aspects of perception an optic
neuritis study Ann Neurol 201271531ndash538
9 Leat SJ Legge GE Bullimore MA What is low vision A re-
evaluation of definitions Optom Vis Sci 199976198ndash211
10 Martiacutenez-Lapiscina EH Ortiz-Peacuterez S Fraga-Pumar E et al
Colour vision impairment is associated with disease severity
in multiple sclerosis Mult Scler 2014201207ndash1216
11 Raz N Dotan S Benoliel T Chokron S Ben-Hur T
Levin N Sustained motion perception deficit following
optic neuritis behavioral and cortical evidence Neurology
2011762103ndash2111
12 Pineles SL Birch EE Talman LS et al One eye or two a
comparison of binocular and monocular low-contrast acu-
ity testing in multiple sclerosis Am J Ophthalmol 2011
152133ndash140
13 Gabriele ML Wollstein G Ishikawa H et al Optical
coherence tomography history current status and lab-
oratory work Invest Ophthalmol Vis Sci 201152
2425ndash2436
14 Henderson AP Altmann DR Trip AS et al A serial study
of retinal changes following optic neuritis with sample size
estimates for acute neuroprotection trials Brain 2010133
2592ndash2602
15 Petzold A de Boer JF Schippling S et al Optical coher-
ence tomography in multiple sclerosis a systematic review
and meta-analysis Lancet Neurol 20109921ndash932
16 Gabilondo I Martiacutenez-Lapiscina EH Fraga-Pumar E
et al Dynamics of retinal injury after acute optic neuritis
Ann Neurol 201577517ndash528
17 Huang-Link Y-M Al-Hawasi A Lindehammar H Acute
optic neuritis retinal ganglion cell loss precedes retinal
nerve fiber thinning Neurol Sci 201536617ndash620
18 Trip SA Schlottmann PG Jones SJ et al Retinal nerve
fiber layer axonal loss and visual dysfunction in optic neu-
ritis Ann Neurol 200558383ndash391
19 Henderson AP Altmann DR Trip SA et al Early factors
associated with axonal loss after optic neuritis Ann Neurol
201170955ndash963
20 Costello F Coupland S Hodge W et al Quantifying
axonal loss after optic neuritis with optical coherence
tomography Ann Neurol 200659963ndash969
21 Hood DC Anderson SC Wall M Kardon RH Structure
versus function in glaucoma an application of a linear
model Invest Ophthalmol Vis Sci 2007483662ndash3668
22 Balk LJ Steenwijk MD Tewarie P et al Bidirectional
trans-synaptic axonal degeneration in the visual pathway
in multiple sclerosis J Neurol Neurosurg Psychiatry 2014
86419ndash424
23 Gabilondo I Martiacutenez-Lapiscina EH Martiacutenez-Heras E
et al Trans-synaptic axonal degeneration in the visual path-
way in multiple sclerosis Ann Neurol 20147598ndash107
24 Alshowaeir D Yiannikas C Garrick R et al Latency of
multifocal visual evoked potentials in nonoptic neuritis eyes
of multiple sclerosis patients associated with optic radiation
lesions Invest Ophthalmol Vis Sci 2014553758ndash3764
25 Sakai RE Feller DJ Galetta KM Galetta SL Balcer LJ
Vision in multiple sclerosis the story structure-function cor-
relations and models for neuroprotection J Neuroophthalmol
201131362ndash373
26 Walter SD Ishikawa H Galetta KM et al Ganglion cell
loss in relation to visual disability in multiple sclerosis
Ophthalmology 20121191250ndash1257
27 Di Maggio G Santangelo R Guerrieri S et al Optical
coherence tomography and visual evoked potentials which
is more sensitive in multiple sclerosis Mult Scler 201420
1342ndash1347
28 Naismith RT Tutlam NT Xu J et al Optical coherence
tomography is less sensitive than visual evoked potentials
in optic neuritis Neurology 20097346ndash52
29 Araie M Test-retest variability in structural parameters
measured with glaucoma imaging devices Jpn J Ophthal-
mol 2013571ndash24
30 Watson GM Keltner JL Chin EK Harvey D Nguyen A
Park SS Comparison of retinal nerve fiber layer and cen-
tral macular thickness measurements among five different
optical coherence tomography instruments in patients with
multiple sclerosis and optic neuritis J Neuroophthalmol
201131110ndash116
31 Schippling S Balk L Costello F et al Quality control for
retinal OCT in multiple sclerosis validation of the
OSCAR-IB criteria Mult Scler 201521163ndash170
32 Rinalduzzi S Brusa A Jones SJ Variation of visual evoked
potential delay to stimulation of central nasal and tem-
poral regions of the macula in optic neuritis J Neurol
httpnnneurologyorgcgicollectionmultiple_sclerosisMultiple sclerosisfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2015 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
immediately evident to patients Thus in nonacuteON eyes there is a component of RNFL thinning thatmay be attributable to other causes such as subclin-ical optic nerve inflammation neurodegenerationwithin normal-appearing white matter or transsyn-aptic degeneration associated with lesions elsewherein the visual pathway22ndash24
The increased resolution of SD-OCT and the useof segmentation algorithms have allowed a moredetailed analysis of the effects of ON and MS on ret-inal structure25 (figure 2) These studies found thatRNFL thinning associated with MS with or withoutON is not confined to the peripapillary region butalso affects the macula In addition a similar pattern
Figure 2 Optical coherence tomography of the human retina
A) Detailed retinal segmentation sample on spectral-domain optical coherence tomography (OCT) image Six intraretinallayer borders can be automatically segmented (B) Correlation of anatomy with OCT for the human retina On the left is ahematoxylin amp eosin stain of the human retina in the center is a schematic representation of the cell composition of thehuman retina and on the right is a magnification of the image obtained with spectral-domain OCT (bottom) with indicationsof the retina layers identified Figure 2B reprinted with permission from Santiago Ortiz-Perez BM5 Bruch membrane CC5
of thinning is observed for the ganglion cell layerinner plexiform layers (GCL 1 IPL) in the peripap-illary region and macula A recent study in patientswith ON found that decreases of$45 mm in GCL1
IPL thickness after 1 month predicted low-contrastvisual acuity dysfunction at 6 months whereas de-creases of $7 mm predicted visual field and colorvision deficits16 In another study in patients withMS with or without a history of ON thinning of
GCL 1 IPL was most closely associated with visualfunction and vision-specific QOL26 Results of thesestudies suggest that degeneration associated with ONand MS is widespread in the RGCL
Together these studies provide compelling evi-dence for structural damage from acute ON and theyalso provide a powerful demonstration of the poten-tial for SD-OCT as a tool to assess neurodegenerativechanges in acute ON However both TD-OCT and
Figure 3 Multifocal visual-evoked potentials in optic neuritis
Figure shows the visual-evoked potentials (VEPs) in 52 sectors of the retina (A B) A case of acute optic neuritis with diffuse impairment of the VEPs in theaffected eye (A) compared with the unaffected eye (B) with significant impairment of the latencies and amplitudes (B C) After recovery from the acute opticneuritis the VEPs show a significant decrease of amplitude and latencies in most of the sectors of the affected eye (C) compared with the unaffected eye (D)Reprinted with permission from Ana Tercero
Neurology Neuroimmunology amp Neuroinflammation 5
SD-OCT appear to be less sensitive than VEPs for as-sessing the clinical and subclinical effects of ON2728
so interpretation of OCT may require complemen-tary assessments using functional techniques Fur-thermore improvements are needed to standardizeand reduce test-retest variability in SD-OCT sys-tems29 Given the rapid evolution of the technologythe technical expertise required and differencesbetween commercially available instruments30 it isalso important that criteria be established to ensurequality control for OCT as a validated outcome mea-sure a process that is under way31
VEPs Standard VEPs elicited by visual stimuli andmeasured in the occipital cortex can be used to detectfunctional changes in the visual pathway includingthe optic nerve32 In multifocal VEPs (mfVEPs)visual stimuli are provided independently to localizedregions of a wider visual field (48deg) and responses tothe stimuli are measured individually33 allowing for amore detailed analysis of visual function covering amuch larger area of the visual pathway than standardVEPs (figure 3)
The severity of an attack of ON and the extent ofinflammation are correlated with an acute reductionin the amplitude of VEPs34 Reduction in VEP ampli-tude is thought to reflect functional impairment ofaxonal conduction either transiently (eg due toacute inflammation or demyelination) or persistently(due to axonal loss) Within 3ndash4 months after theacute episode the amplitude generally shows somerecovery reflecting resolution of edema and thewaveform of the VEP is well-preserved but thelatency is significantly increased This residual latencydelay is thought to result from demyelination of sur-viving axons which interferes with saltatory conduc-tion of the action potential along the optic nervelesion Some investigators have reported subsequentimprovement in latency for up to 2 years6 whereasothers have reported no further recovery after 4months8 Prolongation of latency is most evident inthe central visual field perhaps indicating that thecentral (macular) region of the optic nerve is moresusceptible to demyelination or resistant to remyeli-nation32 The central region of the optic nerve con-tains the greatest density of parvocellular fibers thatconvey static information (eg form and color) butVEP latency in patients with ON correlates morestrongly with dynamic functions (eg motion detec-tion) than with static functions This may suggestmore specific effects on magnocellular fibers orgreater vulnerability of fibers required for accuratesignal timing8
Effects of ON on VEPs have also been shown toreflect structural changes in the RNFL In a studyof 21 patients following a first episode of unilateral
ON VEP latency prolongations and amplitude re-ductions of affected eyes at baseline and 3 monthsafter onset were associated with RNFL thinning19
suggesting a relationship between the initial structuralloss and residual functional impairment In a separatestudy of 25 patients with ON with incomplete recov-ery after 1 year similar relationships between VEPlatencyamplitude and RNFL thinning were still evi-dent18 further supporting the clinical relevance ofthis technique
mfVEPs have been used in a growing number ofsmall studies to examine the pathology of ON ingreater detail35ndash38 mfVEPs detect functional changesassociated with onset and evolution of acute ON38
and may be particularly useful to assess treatmentoutcomes in clinical trials as it appears to be morereproducible than standard VEPs39 One study of 25patients with ON between 6 and 12 months afteronset found an apparent discrepancy between struc-tural and functional measures in these patients35 AsRNFL thinning progressed in the affected eyes overthis time period the mfVEP amplitude partiallyrecovered suggesting that functional recovery maybe due in part to remyelination andor neuronalplasticity
Functional data provided by VEPs and mfVEPsmake an ideal counterpart to structural retinal assess-ments using OCT However as with OCT criterianeed to be established to ensure reproducibility andvalidity of VEP results Furthermore larger-scalestudies are needed to confirm the results of currentsmaller studies
MRI Nonconventional MRI techniques offer noveltools to examine the structure of CNS tissues indetail For example magnetization transfer (MT)imaging exploits the difference in resonance in freeprotons and protons associated with macromolecules(eg myelin) the ratio of which may provide a mea-sure of myelin content40 Diffusion tensor imaging(DTI) can be used to measure asymmetric radial dif-fusivity (RD) axial diffusivity (AD) or fractionalanisotropy (FA) of water as a gauge of tissue in majornerve tracts (eg optic nerve and optic radiations)41
A small number of studies have provided supportfor use of these techniques to assess pathologicchanges in ON For example in an MT study in11 patients with ON MT ratios of affected opticnerves closely followed the course of the disease theywere significantly higher at baseline (within 8 days ofonset) but were reduced at months 3 and 642 In aseparate study in 37 patients with ON MT ratios ofaffected optic nerves were not found to be differentfrom those of unaffected nerves until 3 months afteronset43 In that study ON-associated alterations inMT ratios at 3 months correlated with high- and
6 Neurology Neuroimmunology amp Neuroinflammation
low-contrast visual deficits and with VEP latency at 6months as well as with RNFL thinning at 12 months
In a study of DTI performed within 30 days ofonset and after 1 year in 12 patients with ON FAof affected optic nerves (which is also considered apotential measure of myelination) was the onlyparameter correlated with vision at onset but didnot correlate with the extent of recovery of visual acu-ity or contrast sensitivity at 1 or 3 months44 The AD(considered a measure of axonal integrity) was theonly parameter that was correlated with worse con-trast sensitivity at 1 and 3 months This was con-firmed in a follow-up study in 25 patients in whicha lower baseline AD was also found to be correlatedwith the extent of RNFL thinning and with VEPamplitude and latency45 These were small studiesand should be interpreted with caution as eye motionmakes imaging of the optic nerve by MT ratio andDTI challenging but they do not seem to support amodel in which the extent of neurodegeneration isdetermined solely by chronic demyelination Ratherthey suggest that the initial neuroaxonal effects of theacute inflammatory injury may be more important
Although these ldquononconventionalrdquo MRI techni-ques hold promise as a tool to investigate underlyingprocesses and assess recovery in ON there are substan-tial challenges to widespread use For example theacquisition times are frequently longer than is practical
for routine human studies and imaging is complicatedby motion artifacts caused by moving the eye orhead46 In addition there is no consensus on sequencesand protocols for their application in ON These fac-tors have limited widespread adoption of these ap-proaches and have likely contributed to theinconsistencies in findings Thus further technologicalimprovements and standardization of techniques forimaging of ON lesions will be required before theycan be considered as reliable measures of outcomesin clinical trials
QOL Visual deficits in patients with ON are likely tohave a marked impact on daily activities and QOLPatients frequently rate vision among the mostimportant physical functions affected by MS47 How-ever vision is poorly or insufficiently represented onstandard objective measures of physical functionsuch as the Expanded Disability Status Scale andfunctional assessment instruments such as the Mul-tiple Sclerosis Functional Composite (MSFC) Addi-tion of SLCLA charts to the MSFC has been reportedto better capture MS-related disability48 One patient-reported outcome instrument the 25-item NationalEye Institute Visual Functioning Questionnaire(NEI-VFQ-25) has become a commonly usedmeasurement of vision-specific health-related QOLWhen administered to patients from the ONTT 5ndash8years after the episode of acute ON scores on the NEI-VFQ-25 were lower than for an older disease-freecohort3 In patients with MS correlations with NEI-VFQ-25 scores have been demonstrated for low-contrast visual acuity49 binocular summation12
motion perception50 and loss of RGCs25 (figure 4)Moreover a 10-item supplement has been developedto better capture aspects more relevant to neuro-ophthalmology such as double vision and difficultieswith viewing motion51 A follow-up study has alsoreported its ability to distinguish patients with MSwith a history of ON52
TREATMENTS An important unmet need withrespect to ON is the availability of effective treatmentsto prevent or reverse long-term visual dysfunctionGiven the narrow window of time during whichmost recovery occurs it seems reasonable to suggestthat an effective treatment be initiated as soon aspossible after ON onset with the aim of promotingRGC survival and either extending the window forremyelination or accelerating the rate and extent towhich it occurs Data emerging from OCT studiessuggest that RGC loss may begin within weeks ofthe event thereby narrowing the time to initiateneuroprotective therapy
Despite the lack of long-term benefits of high-dosecorticosteroids patients with acute ON are frequently
Figure 4 Relationship of thickness of retinal layers to quality of life and low-contrast visual acuity
Scatter plot and fitted linear regression line showing relationships of ganglion cell layer plusinner plexiform layer (GCL 1 IPL) thickness to 25-item National Eye Institute Visual Func-tioning Questionnaire (NEI-VFQ-25) composite scores and low-contrast visual acuity at25 level The regression lines represent fitted values for mean GCL 1 IPL thickness foreach value of NEI-VFQ-25 or low-contrast visual acuity the gray shaded areas show the95 confidence intervals from the SEs of the predictions for the fitted lines Linear corre-lations were significant QOL5 quality of life Reprinted from Ophthalmology 119(6) WalterSD et al Ganglion cell loss in relation to visual disability in multiple sclerosis 1250ndash12572012 with permission from Elsevier26
Neurology Neuroimmunology amp Neuroinflammation 7
provided these drugs as symptomatic treatment tospeed resolution of acute inflammation Patients areoften assessed by MRI to determine their risk forMS but it is not clear that disease-modifying thera-pies for relapsing forms of MS are effective to preventneurodegeneration when ON occurs while receivingthese treatments For example interferon b was not
found to prevent RFNL thinning in patients withON53 Natalizumab has been shown to reduce lossof vision54 and improve VEPs55 in patients withrelapsing-remitting MS but there are no data toindicate treatment benefits specifically in patientswith ON A phase II study of fingolimod in acutedemyelinating ON is complete although it is not
Table Phase II and III studies in typical optic neuritis
Startend datesa Treatment
Time from eventto studyinitiation Primary endpoint Statusa
Primary efficacyresults Study numbera
July 1988b (end datenot provided)
Oral prednisone 1 mgkg for 14 d vsmethylprednisolone 1000 mg IV for3 d then oral prednisone 1 mgkgfor 11 d vs placebo
8 d Visual field and contrastsensitivity over 6 mo
Completedc No significanteffect2
NCT00000146
August 1995ndashDecember1997
Immunoglobulin 04 gkg IV QD for3 d then 3 infusionsmo for 3 mo vsplacebo
$6 mo High-contrast visualacuity (100 ETDRScharts)
Completed No significanteffect56
NCT00000117
August 2006ndashJuly 2011 Erythropoietin 33000 units IV for3 d vs placebo
10 d RNFL thickness at 4 8and 16 wks
Completed Significantly lessRNFL thinning at 16wk57
NCT00355095
September 2006ndashMay2011
Simvastatin 80 mg QD PO vsplacebo
4 wk Contrast sensitivity at3 mo
Completedc No significanteffect58
NCT00261326
March 2008ndashJanuary2011
Atacicept 150 mg SC weekly vsplacebo
Not specified RNFL thickness up to48 wks
Terminated None available NCT00624468
February 2009ndashFebruary2011
Glatiramer acetate 20 mg SC QD vsplacebo
Not specified RNFL thickness at 6 mo Completed None available NCT00856635
February 2010ndashJanuary2013
Minocycline 100 mg BID vs notreatment
30 d RNFL thickness every3 mo for 9 mo
Terminated None available NCT01073813
May 2010ndashMarch 2013 Visual reconstitution therapy vssaccadic eye movement training
60ndash80 d or 12mo
Visual field at 6 mo Completed None available NCT01274702
May 2011ndashDecember2013
Dalfampridine 10mg BID vs placebo $12 mo Contrast sensitivity(5 ETDRS charts)
Completed None available NCT01337986
July 2011ndashDecember2012
Vitamin D 50000 unitswk vsvitamin withheld
Not applicable(preventionstudy)
RNFL thickness at10ndash32 d after opticneuritis
Unknown None available NCT01465893
November 2011ndashAugust2014
Phenytoin 15 mgkgd for 3 d then4 mgkgd for 13 wks vs placebo
14 d RNFL thickness at6 mo
Completedd Significantly lessRNFL thinning at6 mod
NCT01451593
March 2012ndashSeptember2014
Oral prednisone 1250 mg vsmethylprednisolone 1000 mg IV for3 d each
14 d VEP latency Unknown None available NCT01524250
December 2012ndashOctober2014
BIIB033 (anti-LINGO-1) 100 mgkgIV every 4 wks vs placebo
28 d VEP latency Completed None available NCT01721161
February 2013ndashFebruary2015
Amiloride 10 mg QD vs placebo for5 mo
28 d RNFL thickness at 6 mo12 mo
Recruiting None available NCT01802489
July 2013ndashJune 2016 Fingolimod 05 mg QD vs interferonb-1b
30 d VEP latency Recruiting None available NCT01647880
August 2013ndashMay 2014 Fingolimod 05 mg QD vs placebo Not specified RNFL thickness at18 wks
Completed None available NCT01757691
October 2013ndashJanuary2016
MD1003 100 mg TID vs placebo Not specified High-contrast visualacuity (100 ETDRScharts)
Recruiting None available NCT02220244
March 2014ndashApril 2016 Amiloride hydrochlorothiazide100 mgd vs placebo
10 d RNFL thickness at24 wks
Recruiting None available NCT01879527
November 2014ndashDecember 2018
Erythropoietin 33000 units IV for3 d vs placebo
10 d RNFL thickness at 6 mo Recruiting None available NCT01962571
Abbreviations ETDRS5 Early Treatment Diabetic Retinopathy Study RNFL5 retinal nerve fiber layer SC5 subcutaneous VEP5 visual-evoked potentiala From ClinicalTrialsgov except where indicated otherwiseb The Optic Neuritis Treatment Trial included a 15-year follow-up periodc Based on published resultd Reported at American Academy of Neurology 2015 Annual Meeting April 18ndash25 Washington DC
8 Neurology Neuroimmunology amp Neuroinflammation
clear that enrollment goals were met Another phaseIIIII study is under way but study results are not yetavailable (table)
Based on promising results from animal studiesand small clinical studies IV immunoglobulin wasinvestigated in patients with one or more episodesof typical ON and irreversible loss of visual acuitybut was terminated early due to negative results56
(table) Since that time various investigational ther-apies have shown promise in early preclinical andclinical studies and a number of phase II and IIIstudies have been completed or are under way Forexample in a placebo-controlled study of IV eryth-ropoietin for 3 days as an add-on to methylpredni-sone in patients with a first episode of ON withinthe previous 10 days those treated with erythropoi-etin demonstrated reduced RNFL thinning lessdecrease in optic nerve diameter and shorter VEPlatency57 Although the mechanism by which eryth-ropoietin may exert these effects is poorly under-stood it may involve the neuroprotective effectsof this hormone during acute inflammation Inanother placebo-controlled study in patients withsymptom duration of 4 weeks and reduced con-trast sensitivity simvastatin (a hypercholesterolemiamedication) narrowly missed significance on theprimary efficacy outcome (contrast sensitivity)but improvements were noted for VEP latencyand amplitude58 However imbalances in random-ization and technical issues may have contributed tothe observed effects59 A study in ON testing possibleneuroprotective effects of phenytoin an anticonvul-sant has recently completed and another study testingeffects of amiloride hydrochlorothiazide a diuretic iscurrently underway Nevertheless it is an open ques-tion whether a neuroprotective agent can domore thandelay degeneration of axons if they remain chronicallydemyelinated Finally BIIB033 a fully-human anti-body to LINGO-1 an inhibitor of myelination andneuroaxonal growth has shown promise in preclinicaland early clinical testing60 and a phase II study in ONwas recently completed
CONCLUSIONS It is now clear that recovery fromON is frequently incomplete which adversely affectsthe QOL of patients In addition there remain con-siderable gaps with respect to understanding assess-ing and treating this disease to prevent long-termdeficits Nevertheless ongoing work holds promisefor all of these areas The application of newertechnologies continues to provide new insight intothe underlying disease processes and increasedappreciation of the injury that occurs followingON The development of these new tools mayincrease the ability to detect meaningful changes invision with therapeutic intervention and study
results suggest that timing is critical Developmentof guidelines to ensure consistency in theirapplication should also improve interpretation offindings and thereby improve the quality ofassessments Finally several therapies have shownpromise in preclinical and early clinical testingTherefore there is reason to be optimistic thatstrategies may soon be identified to improve theprognosis for patients with ON Given therelationship between ON and MS it seems likelythat any such developments for ON may havesubstantial implications for understanding assessingand treating MS as well
AUTHOR CONTRIBUTIONSAll authors participated in the conception of the article interpretation of
the data and revision of the manuscript and they approved the final ver-
sion Biogen provided funding for writing and editorial support in the
development of this paper and they reviewed and provided feedback
on the paper to the authors The authors had full editorial control of
the paper and provided their final approval of all content
ACKNOWLEDGMENTThe authors thank Dr Elena H Martinez-Lapiscina Dr Santiago Ortiz-
Perez and Dr Ana Tercero from the Center of Neuroimmunology Insti-
tute of Biomedical Research August Pi SunyerHospital Clinic Barcelona
University of Barcelona for creating figures 1 2B and 3 respectively
Lauren Nagy of Excel Scientific Solutions copyedited and styled the man-
uscript per journal requirements and this editorial support was funded by
Biogen
STUDY FUNDINGWriting and editorial support was funded by Biogen
DISCLOSURESL Galetta has received consulting honoraria and travel fundingspeaker
honoraria from Genzyme and Biogen and is on the editorial board for
Neurology and Journal of Neuro-Ophthalmology P Villoslada serves on
advisory boards for Novartis Roche Neurotec Pharma and Bionure
Pharma has consulted for Novartis Roche TFS Heidelberg Engineer-
ing MedImmune Diagna Biotec and Neurotec Pharma is an academic
editor for PLoSONE is on the editorial board for Neurology amp Therapy
and Current Treatment Options in Neurology has received research sup-
port from European Commission Genzyme Biogen Instituto Salud
Carlos III Marato TV3 Novartis and Roche and holds patents and
owns stocksstock options with Bionure Pharma N Levin receives
research support from National Multiple Sclerosis Foundation
K Shindler received research support from the FM Kirby Foundation
Harbor Therapeutics National Eye Institute National Multiple Sclerosis
Foundation Research to Prevent Blindness Sirtris Pharmaceuticals
ITMAT and Stemnion Inc has received speaker honoraria from Med-
ical College of Wisconsin and Temple University is an associate editor
for Frontiers in Neurology Neuro-Ophthalmology receives publishing roy-
alties from UpToDate and Oakstone Publishing and has consulted for
medical-legal cases H Ishikawa received research support from the NIH
E Parr is a full-time employee of Excel Scientific Solutions who were
funded by Biogen to provide editorial and writing support for this paper
D Cadavid is a full-time employee of Biogen owns stock options in
Biogen and has patent applications pending related to the use of drugs
that block LINGO-1 to treat demyelination in multiple sclerosis LJ
Balcer received consulting fees from Acorda Biogen Genzyme Novartis
Questcor and Vaccinexe serves on a clinical trial advisory board for
Biogen and serves on a scientific advisory board for Genzyme Go to
Neurologyorgnn for full disclosure forms
Received February 12 2015 Accepted in final form May 13 2015
Neurology Neuroimmunology amp Neuroinflammation 9
REFERENCES1 Toosy AT Mason DF Miller DH Optic neuritis Lancet
Neurol 20141383ndash99
2 Beck RW Cleary PA Anderson MM Jr et al Optic Neu-
ritis Study Group A randomized controlled trial of cor-
ticosteroids in the treatment of acute optic neuritis N
Engl J Med 1992326581ndash588
3 Cole SR Beck RW Moke PS Gal RL Long DT Optic
Neuritis Study Group The National Eye Institute Visual
Function Questionnaire experience of the ONTT Invest
Ophthalmol Vis Sci 2000411017ndash1021
4 Beck RW Cleary PA Backlund JC The course of visual
recovery after optic neuritis Experience of the Optic
Neuritis Treatment Trial Ophthalmology 1994101
1771ndash1778
5 Costello F Hodge W Pan YI Eggenberger E Coupland S
Kardon RH Tracking retinal nerve fiber layer loss after
optic neuritis a prospective study using optical coherence
tomography Mult Scler 200814893ndash905
6 Brusa A Jones SJ Plant GT Long-term remyelination
after optic neuritis a 2-year visual evoked potential and
psychophysical serial study Brain 2001124468ndash479
7 Malik MT Healy BC Benson LA et al Factors associated
with recovery from acute optic neuritis in patients with
multiple sclerosis Neurology 2014822173ndash2179
8 Raz N Dotan S Chokron S Ben-Hur T Levin N Demy-
elination affects temporal aspects of perception an optic
neuritis study Ann Neurol 201271531ndash538
9 Leat SJ Legge GE Bullimore MA What is low vision A re-
evaluation of definitions Optom Vis Sci 199976198ndash211
10 Martiacutenez-Lapiscina EH Ortiz-Peacuterez S Fraga-Pumar E et al
Colour vision impairment is associated with disease severity
in multiple sclerosis Mult Scler 2014201207ndash1216
11 Raz N Dotan S Benoliel T Chokron S Ben-Hur T
Levin N Sustained motion perception deficit following
optic neuritis behavioral and cortical evidence Neurology
2011762103ndash2111
12 Pineles SL Birch EE Talman LS et al One eye or two a
comparison of binocular and monocular low-contrast acu-
ity testing in multiple sclerosis Am J Ophthalmol 2011
152133ndash140
13 Gabriele ML Wollstein G Ishikawa H et al Optical
coherence tomography history current status and lab-
oratory work Invest Ophthalmol Vis Sci 201152
2425ndash2436
14 Henderson AP Altmann DR Trip AS et al A serial study
of retinal changes following optic neuritis with sample size
estimates for acute neuroprotection trials Brain 2010133
2592ndash2602
15 Petzold A de Boer JF Schippling S et al Optical coher-
ence tomography in multiple sclerosis a systematic review
and meta-analysis Lancet Neurol 20109921ndash932
16 Gabilondo I Martiacutenez-Lapiscina EH Fraga-Pumar E
et al Dynamics of retinal injury after acute optic neuritis
Ann Neurol 201577517ndash528
17 Huang-Link Y-M Al-Hawasi A Lindehammar H Acute
optic neuritis retinal ganglion cell loss precedes retinal
nerve fiber thinning Neurol Sci 201536617ndash620
18 Trip SA Schlottmann PG Jones SJ et al Retinal nerve
fiber layer axonal loss and visual dysfunction in optic neu-
ritis Ann Neurol 200558383ndash391
19 Henderson AP Altmann DR Trip SA et al Early factors
associated with axonal loss after optic neuritis Ann Neurol
201170955ndash963
20 Costello F Coupland S Hodge W et al Quantifying
axonal loss after optic neuritis with optical coherence
tomography Ann Neurol 200659963ndash969
21 Hood DC Anderson SC Wall M Kardon RH Structure
versus function in glaucoma an application of a linear
model Invest Ophthalmol Vis Sci 2007483662ndash3668
22 Balk LJ Steenwijk MD Tewarie P et al Bidirectional
trans-synaptic axonal degeneration in the visual pathway
in multiple sclerosis J Neurol Neurosurg Psychiatry 2014
86419ndash424
23 Gabilondo I Martiacutenez-Lapiscina EH Martiacutenez-Heras E
et al Trans-synaptic axonal degeneration in the visual path-
way in multiple sclerosis Ann Neurol 20147598ndash107
24 Alshowaeir D Yiannikas C Garrick R et al Latency of
multifocal visual evoked potentials in nonoptic neuritis eyes
of multiple sclerosis patients associated with optic radiation
lesions Invest Ophthalmol Vis Sci 2014553758ndash3764
25 Sakai RE Feller DJ Galetta KM Galetta SL Balcer LJ
Vision in multiple sclerosis the story structure-function cor-
relations and models for neuroprotection J Neuroophthalmol
201131362ndash373
26 Walter SD Ishikawa H Galetta KM et al Ganglion cell
loss in relation to visual disability in multiple sclerosis
Ophthalmology 20121191250ndash1257
27 Di Maggio G Santangelo R Guerrieri S et al Optical
coherence tomography and visual evoked potentials which
is more sensitive in multiple sclerosis Mult Scler 201420
1342ndash1347
28 Naismith RT Tutlam NT Xu J et al Optical coherence
tomography is less sensitive than visual evoked potentials
in optic neuritis Neurology 20097346ndash52
29 Araie M Test-retest variability in structural parameters
measured with glaucoma imaging devices Jpn J Ophthal-
mol 2013571ndash24
30 Watson GM Keltner JL Chin EK Harvey D Nguyen A
Park SS Comparison of retinal nerve fiber layer and cen-
tral macular thickness measurements among five different
optical coherence tomography instruments in patients with
multiple sclerosis and optic neuritis J Neuroophthalmol
201131110ndash116
31 Schippling S Balk L Costello F et al Quality control for
retinal OCT in multiple sclerosis validation of the
OSCAR-IB criteria Mult Scler 201521163ndash170
32 Rinalduzzi S Brusa A Jones SJ Variation of visual evoked
potential delay to stimulation of central nasal and tem-
poral regions of the macula in optic neuritis J Neurol
httpnnneurologyorgcgicollectionmultiple_sclerosisMultiple sclerosisfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2015 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
of thinning is observed for the ganglion cell layerinner plexiform layers (GCL 1 IPL) in the peripap-illary region and macula A recent study in patientswith ON found that decreases of$45 mm in GCL1
IPL thickness after 1 month predicted low-contrastvisual acuity dysfunction at 6 months whereas de-creases of $7 mm predicted visual field and colorvision deficits16 In another study in patients withMS with or without a history of ON thinning of
GCL 1 IPL was most closely associated with visualfunction and vision-specific QOL26 Results of thesestudies suggest that degeneration associated with ONand MS is widespread in the RGCL
Together these studies provide compelling evi-dence for structural damage from acute ON and theyalso provide a powerful demonstration of the poten-tial for SD-OCT as a tool to assess neurodegenerativechanges in acute ON However both TD-OCT and
Figure 3 Multifocal visual-evoked potentials in optic neuritis
Figure shows the visual-evoked potentials (VEPs) in 52 sectors of the retina (A B) A case of acute optic neuritis with diffuse impairment of the VEPs in theaffected eye (A) compared with the unaffected eye (B) with significant impairment of the latencies and amplitudes (B C) After recovery from the acute opticneuritis the VEPs show a significant decrease of amplitude and latencies in most of the sectors of the affected eye (C) compared with the unaffected eye (D)Reprinted with permission from Ana Tercero
Neurology Neuroimmunology amp Neuroinflammation 5
SD-OCT appear to be less sensitive than VEPs for as-sessing the clinical and subclinical effects of ON2728
so interpretation of OCT may require complemen-tary assessments using functional techniques Fur-thermore improvements are needed to standardizeand reduce test-retest variability in SD-OCT sys-tems29 Given the rapid evolution of the technologythe technical expertise required and differencesbetween commercially available instruments30 it isalso important that criteria be established to ensurequality control for OCT as a validated outcome mea-sure a process that is under way31
VEPs Standard VEPs elicited by visual stimuli andmeasured in the occipital cortex can be used to detectfunctional changes in the visual pathway includingthe optic nerve32 In multifocal VEPs (mfVEPs)visual stimuli are provided independently to localizedregions of a wider visual field (48deg) and responses tothe stimuli are measured individually33 allowing for amore detailed analysis of visual function covering amuch larger area of the visual pathway than standardVEPs (figure 3)
The severity of an attack of ON and the extent ofinflammation are correlated with an acute reductionin the amplitude of VEPs34 Reduction in VEP ampli-tude is thought to reflect functional impairment ofaxonal conduction either transiently (eg due toacute inflammation or demyelination) or persistently(due to axonal loss) Within 3ndash4 months after theacute episode the amplitude generally shows somerecovery reflecting resolution of edema and thewaveform of the VEP is well-preserved but thelatency is significantly increased This residual latencydelay is thought to result from demyelination of sur-viving axons which interferes with saltatory conduc-tion of the action potential along the optic nervelesion Some investigators have reported subsequentimprovement in latency for up to 2 years6 whereasothers have reported no further recovery after 4months8 Prolongation of latency is most evident inthe central visual field perhaps indicating that thecentral (macular) region of the optic nerve is moresusceptible to demyelination or resistant to remyeli-nation32 The central region of the optic nerve con-tains the greatest density of parvocellular fibers thatconvey static information (eg form and color) butVEP latency in patients with ON correlates morestrongly with dynamic functions (eg motion detec-tion) than with static functions This may suggestmore specific effects on magnocellular fibers orgreater vulnerability of fibers required for accuratesignal timing8
Effects of ON on VEPs have also been shown toreflect structural changes in the RNFL In a studyof 21 patients following a first episode of unilateral
ON VEP latency prolongations and amplitude re-ductions of affected eyes at baseline and 3 monthsafter onset were associated with RNFL thinning19
suggesting a relationship between the initial structuralloss and residual functional impairment In a separatestudy of 25 patients with ON with incomplete recov-ery after 1 year similar relationships between VEPlatencyamplitude and RNFL thinning were still evi-dent18 further supporting the clinical relevance ofthis technique
mfVEPs have been used in a growing number ofsmall studies to examine the pathology of ON ingreater detail35ndash38 mfVEPs detect functional changesassociated with onset and evolution of acute ON38
and may be particularly useful to assess treatmentoutcomes in clinical trials as it appears to be morereproducible than standard VEPs39 One study of 25patients with ON between 6 and 12 months afteronset found an apparent discrepancy between struc-tural and functional measures in these patients35 AsRNFL thinning progressed in the affected eyes overthis time period the mfVEP amplitude partiallyrecovered suggesting that functional recovery maybe due in part to remyelination andor neuronalplasticity
Functional data provided by VEPs and mfVEPsmake an ideal counterpart to structural retinal assess-ments using OCT However as with OCT criterianeed to be established to ensure reproducibility andvalidity of VEP results Furthermore larger-scalestudies are needed to confirm the results of currentsmaller studies
MRI Nonconventional MRI techniques offer noveltools to examine the structure of CNS tissues indetail For example magnetization transfer (MT)imaging exploits the difference in resonance in freeprotons and protons associated with macromolecules(eg myelin) the ratio of which may provide a mea-sure of myelin content40 Diffusion tensor imaging(DTI) can be used to measure asymmetric radial dif-fusivity (RD) axial diffusivity (AD) or fractionalanisotropy (FA) of water as a gauge of tissue in majornerve tracts (eg optic nerve and optic radiations)41
A small number of studies have provided supportfor use of these techniques to assess pathologicchanges in ON For example in an MT study in11 patients with ON MT ratios of affected opticnerves closely followed the course of the disease theywere significantly higher at baseline (within 8 days ofonset) but were reduced at months 3 and 642 In aseparate study in 37 patients with ON MT ratios ofaffected optic nerves were not found to be differentfrom those of unaffected nerves until 3 months afteronset43 In that study ON-associated alterations inMT ratios at 3 months correlated with high- and
6 Neurology Neuroimmunology amp Neuroinflammation
low-contrast visual deficits and with VEP latency at 6months as well as with RNFL thinning at 12 months
In a study of DTI performed within 30 days ofonset and after 1 year in 12 patients with ON FAof affected optic nerves (which is also considered apotential measure of myelination) was the onlyparameter correlated with vision at onset but didnot correlate with the extent of recovery of visual acu-ity or contrast sensitivity at 1 or 3 months44 The AD(considered a measure of axonal integrity) was theonly parameter that was correlated with worse con-trast sensitivity at 1 and 3 months This was con-firmed in a follow-up study in 25 patients in whicha lower baseline AD was also found to be correlatedwith the extent of RNFL thinning and with VEPamplitude and latency45 These were small studiesand should be interpreted with caution as eye motionmakes imaging of the optic nerve by MT ratio andDTI challenging but they do not seem to support amodel in which the extent of neurodegeneration isdetermined solely by chronic demyelination Ratherthey suggest that the initial neuroaxonal effects of theacute inflammatory injury may be more important
Although these ldquononconventionalrdquo MRI techni-ques hold promise as a tool to investigate underlyingprocesses and assess recovery in ON there are substan-tial challenges to widespread use For example theacquisition times are frequently longer than is practical
for routine human studies and imaging is complicatedby motion artifacts caused by moving the eye orhead46 In addition there is no consensus on sequencesand protocols for their application in ON These fac-tors have limited widespread adoption of these ap-proaches and have likely contributed to theinconsistencies in findings Thus further technologicalimprovements and standardization of techniques forimaging of ON lesions will be required before theycan be considered as reliable measures of outcomesin clinical trials
QOL Visual deficits in patients with ON are likely tohave a marked impact on daily activities and QOLPatients frequently rate vision among the mostimportant physical functions affected by MS47 How-ever vision is poorly or insufficiently represented onstandard objective measures of physical functionsuch as the Expanded Disability Status Scale andfunctional assessment instruments such as the Mul-tiple Sclerosis Functional Composite (MSFC) Addi-tion of SLCLA charts to the MSFC has been reportedto better capture MS-related disability48 One patient-reported outcome instrument the 25-item NationalEye Institute Visual Functioning Questionnaire(NEI-VFQ-25) has become a commonly usedmeasurement of vision-specific health-related QOLWhen administered to patients from the ONTT 5ndash8years after the episode of acute ON scores on the NEI-VFQ-25 were lower than for an older disease-freecohort3 In patients with MS correlations with NEI-VFQ-25 scores have been demonstrated for low-contrast visual acuity49 binocular summation12
motion perception50 and loss of RGCs25 (figure 4)Moreover a 10-item supplement has been developedto better capture aspects more relevant to neuro-ophthalmology such as double vision and difficultieswith viewing motion51 A follow-up study has alsoreported its ability to distinguish patients with MSwith a history of ON52
TREATMENTS An important unmet need withrespect to ON is the availability of effective treatmentsto prevent or reverse long-term visual dysfunctionGiven the narrow window of time during whichmost recovery occurs it seems reasonable to suggestthat an effective treatment be initiated as soon aspossible after ON onset with the aim of promotingRGC survival and either extending the window forremyelination or accelerating the rate and extent towhich it occurs Data emerging from OCT studiessuggest that RGC loss may begin within weeks ofthe event thereby narrowing the time to initiateneuroprotective therapy
Despite the lack of long-term benefits of high-dosecorticosteroids patients with acute ON are frequently
Figure 4 Relationship of thickness of retinal layers to quality of life and low-contrast visual acuity
Scatter plot and fitted linear regression line showing relationships of ganglion cell layer plusinner plexiform layer (GCL 1 IPL) thickness to 25-item National Eye Institute Visual Func-tioning Questionnaire (NEI-VFQ-25) composite scores and low-contrast visual acuity at25 level The regression lines represent fitted values for mean GCL 1 IPL thickness foreach value of NEI-VFQ-25 or low-contrast visual acuity the gray shaded areas show the95 confidence intervals from the SEs of the predictions for the fitted lines Linear corre-lations were significant QOL5 quality of life Reprinted from Ophthalmology 119(6) WalterSD et al Ganglion cell loss in relation to visual disability in multiple sclerosis 1250ndash12572012 with permission from Elsevier26
Neurology Neuroimmunology amp Neuroinflammation 7
provided these drugs as symptomatic treatment tospeed resolution of acute inflammation Patients areoften assessed by MRI to determine their risk forMS but it is not clear that disease-modifying thera-pies for relapsing forms of MS are effective to preventneurodegeneration when ON occurs while receivingthese treatments For example interferon b was not
found to prevent RFNL thinning in patients withON53 Natalizumab has been shown to reduce lossof vision54 and improve VEPs55 in patients withrelapsing-remitting MS but there are no data toindicate treatment benefits specifically in patientswith ON A phase II study of fingolimod in acutedemyelinating ON is complete although it is not
Table Phase II and III studies in typical optic neuritis
Startend datesa Treatment
Time from eventto studyinitiation Primary endpoint Statusa
Primary efficacyresults Study numbera
July 1988b (end datenot provided)
Oral prednisone 1 mgkg for 14 d vsmethylprednisolone 1000 mg IV for3 d then oral prednisone 1 mgkgfor 11 d vs placebo
8 d Visual field and contrastsensitivity over 6 mo
Completedc No significanteffect2
NCT00000146
August 1995ndashDecember1997
Immunoglobulin 04 gkg IV QD for3 d then 3 infusionsmo for 3 mo vsplacebo
$6 mo High-contrast visualacuity (100 ETDRScharts)
Completed No significanteffect56
NCT00000117
August 2006ndashJuly 2011 Erythropoietin 33000 units IV for3 d vs placebo
10 d RNFL thickness at 4 8and 16 wks
Completed Significantly lessRNFL thinning at 16wk57
NCT00355095
September 2006ndashMay2011
Simvastatin 80 mg QD PO vsplacebo
4 wk Contrast sensitivity at3 mo
Completedc No significanteffect58
NCT00261326
March 2008ndashJanuary2011
Atacicept 150 mg SC weekly vsplacebo
Not specified RNFL thickness up to48 wks
Terminated None available NCT00624468
February 2009ndashFebruary2011
Glatiramer acetate 20 mg SC QD vsplacebo
Not specified RNFL thickness at 6 mo Completed None available NCT00856635
February 2010ndashJanuary2013
Minocycline 100 mg BID vs notreatment
30 d RNFL thickness every3 mo for 9 mo
Terminated None available NCT01073813
May 2010ndashMarch 2013 Visual reconstitution therapy vssaccadic eye movement training
60ndash80 d or 12mo
Visual field at 6 mo Completed None available NCT01274702
May 2011ndashDecember2013
Dalfampridine 10mg BID vs placebo $12 mo Contrast sensitivity(5 ETDRS charts)
Completed None available NCT01337986
July 2011ndashDecember2012
Vitamin D 50000 unitswk vsvitamin withheld
Not applicable(preventionstudy)
RNFL thickness at10ndash32 d after opticneuritis
Unknown None available NCT01465893
November 2011ndashAugust2014
Phenytoin 15 mgkgd for 3 d then4 mgkgd for 13 wks vs placebo
14 d RNFL thickness at6 mo
Completedd Significantly lessRNFL thinning at6 mod
NCT01451593
March 2012ndashSeptember2014
Oral prednisone 1250 mg vsmethylprednisolone 1000 mg IV for3 d each
14 d VEP latency Unknown None available NCT01524250
December 2012ndashOctober2014
BIIB033 (anti-LINGO-1) 100 mgkgIV every 4 wks vs placebo
28 d VEP latency Completed None available NCT01721161
February 2013ndashFebruary2015
Amiloride 10 mg QD vs placebo for5 mo
28 d RNFL thickness at 6 mo12 mo
Recruiting None available NCT01802489
July 2013ndashJune 2016 Fingolimod 05 mg QD vs interferonb-1b
30 d VEP latency Recruiting None available NCT01647880
August 2013ndashMay 2014 Fingolimod 05 mg QD vs placebo Not specified RNFL thickness at18 wks
Completed None available NCT01757691
October 2013ndashJanuary2016
MD1003 100 mg TID vs placebo Not specified High-contrast visualacuity (100 ETDRScharts)
Recruiting None available NCT02220244
March 2014ndashApril 2016 Amiloride hydrochlorothiazide100 mgd vs placebo
10 d RNFL thickness at24 wks
Recruiting None available NCT01879527
November 2014ndashDecember 2018
Erythropoietin 33000 units IV for3 d vs placebo
10 d RNFL thickness at 6 mo Recruiting None available NCT01962571
Abbreviations ETDRS5 Early Treatment Diabetic Retinopathy Study RNFL5 retinal nerve fiber layer SC5 subcutaneous VEP5 visual-evoked potentiala From ClinicalTrialsgov except where indicated otherwiseb The Optic Neuritis Treatment Trial included a 15-year follow-up periodc Based on published resultd Reported at American Academy of Neurology 2015 Annual Meeting April 18ndash25 Washington DC
8 Neurology Neuroimmunology amp Neuroinflammation
clear that enrollment goals were met Another phaseIIIII study is under way but study results are not yetavailable (table)
Based on promising results from animal studiesand small clinical studies IV immunoglobulin wasinvestigated in patients with one or more episodesof typical ON and irreversible loss of visual acuitybut was terminated early due to negative results56
(table) Since that time various investigational ther-apies have shown promise in early preclinical andclinical studies and a number of phase II and IIIstudies have been completed or are under way Forexample in a placebo-controlled study of IV eryth-ropoietin for 3 days as an add-on to methylpredni-sone in patients with a first episode of ON withinthe previous 10 days those treated with erythropoi-etin demonstrated reduced RNFL thinning lessdecrease in optic nerve diameter and shorter VEPlatency57 Although the mechanism by which eryth-ropoietin may exert these effects is poorly under-stood it may involve the neuroprotective effectsof this hormone during acute inflammation Inanother placebo-controlled study in patients withsymptom duration of 4 weeks and reduced con-trast sensitivity simvastatin (a hypercholesterolemiamedication) narrowly missed significance on theprimary efficacy outcome (contrast sensitivity)but improvements were noted for VEP latencyand amplitude58 However imbalances in random-ization and technical issues may have contributed tothe observed effects59 A study in ON testing possibleneuroprotective effects of phenytoin an anticonvul-sant has recently completed and another study testingeffects of amiloride hydrochlorothiazide a diuretic iscurrently underway Nevertheless it is an open ques-tion whether a neuroprotective agent can domore thandelay degeneration of axons if they remain chronicallydemyelinated Finally BIIB033 a fully-human anti-body to LINGO-1 an inhibitor of myelination andneuroaxonal growth has shown promise in preclinicaland early clinical testing60 and a phase II study in ONwas recently completed
CONCLUSIONS It is now clear that recovery fromON is frequently incomplete which adversely affectsthe QOL of patients In addition there remain con-siderable gaps with respect to understanding assess-ing and treating this disease to prevent long-termdeficits Nevertheless ongoing work holds promisefor all of these areas The application of newertechnologies continues to provide new insight intothe underlying disease processes and increasedappreciation of the injury that occurs followingON The development of these new tools mayincrease the ability to detect meaningful changes invision with therapeutic intervention and study
results suggest that timing is critical Developmentof guidelines to ensure consistency in theirapplication should also improve interpretation offindings and thereby improve the quality ofassessments Finally several therapies have shownpromise in preclinical and early clinical testingTherefore there is reason to be optimistic thatstrategies may soon be identified to improve theprognosis for patients with ON Given therelationship between ON and MS it seems likelythat any such developments for ON may havesubstantial implications for understanding assessingand treating MS as well
AUTHOR CONTRIBUTIONSAll authors participated in the conception of the article interpretation of
the data and revision of the manuscript and they approved the final ver-
sion Biogen provided funding for writing and editorial support in the
development of this paper and they reviewed and provided feedback
on the paper to the authors The authors had full editorial control of
the paper and provided their final approval of all content
ACKNOWLEDGMENTThe authors thank Dr Elena H Martinez-Lapiscina Dr Santiago Ortiz-
Perez and Dr Ana Tercero from the Center of Neuroimmunology Insti-
tute of Biomedical Research August Pi SunyerHospital Clinic Barcelona
University of Barcelona for creating figures 1 2B and 3 respectively
Lauren Nagy of Excel Scientific Solutions copyedited and styled the man-
uscript per journal requirements and this editorial support was funded by
Biogen
STUDY FUNDINGWriting and editorial support was funded by Biogen
DISCLOSURESL Galetta has received consulting honoraria and travel fundingspeaker
honoraria from Genzyme and Biogen and is on the editorial board for
Neurology and Journal of Neuro-Ophthalmology P Villoslada serves on
advisory boards for Novartis Roche Neurotec Pharma and Bionure
Pharma has consulted for Novartis Roche TFS Heidelberg Engineer-
ing MedImmune Diagna Biotec and Neurotec Pharma is an academic
editor for PLoSONE is on the editorial board for Neurology amp Therapy
and Current Treatment Options in Neurology has received research sup-
port from European Commission Genzyme Biogen Instituto Salud
Carlos III Marato TV3 Novartis and Roche and holds patents and
owns stocksstock options with Bionure Pharma N Levin receives
research support from National Multiple Sclerosis Foundation
K Shindler received research support from the FM Kirby Foundation
Harbor Therapeutics National Eye Institute National Multiple Sclerosis
Foundation Research to Prevent Blindness Sirtris Pharmaceuticals
ITMAT and Stemnion Inc has received speaker honoraria from Med-
ical College of Wisconsin and Temple University is an associate editor
for Frontiers in Neurology Neuro-Ophthalmology receives publishing roy-
alties from UpToDate and Oakstone Publishing and has consulted for
medical-legal cases H Ishikawa received research support from the NIH
E Parr is a full-time employee of Excel Scientific Solutions who were
funded by Biogen to provide editorial and writing support for this paper
D Cadavid is a full-time employee of Biogen owns stock options in
Biogen and has patent applications pending related to the use of drugs
that block LINGO-1 to treat demyelination in multiple sclerosis LJ
Balcer received consulting fees from Acorda Biogen Genzyme Novartis
Questcor and Vaccinexe serves on a clinical trial advisory board for
Biogen and serves on a scientific advisory board for Genzyme Go to
Neurologyorgnn for full disclosure forms
Received February 12 2015 Accepted in final form May 13 2015
Neurology Neuroimmunology amp Neuroinflammation 9
REFERENCES1 Toosy AT Mason DF Miller DH Optic neuritis Lancet
Neurol 20141383ndash99
2 Beck RW Cleary PA Anderson MM Jr et al Optic Neu-
ritis Study Group A randomized controlled trial of cor-
ticosteroids in the treatment of acute optic neuritis N
Engl J Med 1992326581ndash588
3 Cole SR Beck RW Moke PS Gal RL Long DT Optic
Neuritis Study Group The National Eye Institute Visual
Function Questionnaire experience of the ONTT Invest
Ophthalmol Vis Sci 2000411017ndash1021
4 Beck RW Cleary PA Backlund JC The course of visual
recovery after optic neuritis Experience of the Optic
Neuritis Treatment Trial Ophthalmology 1994101
1771ndash1778
5 Costello F Hodge W Pan YI Eggenberger E Coupland S
Kardon RH Tracking retinal nerve fiber layer loss after
optic neuritis a prospective study using optical coherence
tomography Mult Scler 200814893ndash905
6 Brusa A Jones SJ Plant GT Long-term remyelination
after optic neuritis a 2-year visual evoked potential and
psychophysical serial study Brain 2001124468ndash479
7 Malik MT Healy BC Benson LA et al Factors associated
with recovery from acute optic neuritis in patients with
multiple sclerosis Neurology 2014822173ndash2179
8 Raz N Dotan S Chokron S Ben-Hur T Levin N Demy-
elination affects temporal aspects of perception an optic
neuritis study Ann Neurol 201271531ndash538
9 Leat SJ Legge GE Bullimore MA What is low vision A re-
evaluation of definitions Optom Vis Sci 199976198ndash211
10 Martiacutenez-Lapiscina EH Ortiz-Peacuterez S Fraga-Pumar E et al
Colour vision impairment is associated with disease severity
in multiple sclerosis Mult Scler 2014201207ndash1216
11 Raz N Dotan S Benoliel T Chokron S Ben-Hur T
Levin N Sustained motion perception deficit following
optic neuritis behavioral and cortical evidence Neurology
2011762103ndash2111
12 Pineles SL Birch EE Talman LS et al One eye or two a
comparison of binocular and monocular low-contrast acu-
ity testing in multiple sclerosis Am J Ophthalmol 2011
152133ndash140
13 Gabriele ML Wollstein G Ishikawa H et al Optical
coherence tomography history current status and lab-
oratory work Invest Ophthalmol Vis Sci 201152
2425ndash2436
14 Henderson AP Altmann DR Trip AS et al A serial study
of retinal changes following optic neuritis with sample size
estimates for acute neuroprotection trials Brain 2010133
2592ndash2602
15 Petzold A de Boer JF Schippling S et al Optical coher-
ence tomography in multiple sclerosis a systematic review
and meta-analysis Lancet Neurol 20109921ndash932
16 Gabilondo I Martiacutenez-Lapiscina EH Fraga-Pumar E
et al Dynamics of retinal injury after acute optic neuritis
Ann Neurol 201577517ndash528
17 Huang-Link Y-M Al-Hawasi A Lindehammar H Acute
optic neuritis retinal ganglion cell loss precedes retinal
nerve fiber thinning Neurol Sci 201536617ndash620
18 Trip SA Schlottmann PG Jones SJ et al Retinal nerve
fiber layer axonal loss and visual dysfunction in optic neu-
ritis Ann Neurol 200558383ndash391
19 Henderson AP Altmann DR Trip SA et al Early factors
associated with axonal loss after optic neuritis Ann Neurol
201170955ndash963
20 Costello F Coupland S Hodge W et al Quantifying
axonal loss after optic neuritis with optical coherence
tomography Ann Neurol 200659963ndash969
21 Hood DC Anderson SC Wall M Kardon RH Structure
versus function in glaucoma an application of a linear
model Invest Ophthalmol Vis Sci 2007483662ndash3668
22 Balk LJ Steenwijk MD Tewarie P et al Bidirectional
trans-synaptic axonal degeneration in the visual pathway
in multiple sclerosis J Neurol Neurosurg Psychiatry 2014
86419ndash424
23 Gabilondo I Martiacutenez-Lapiscina EH Martiacutenez-Heras E
et al Trans-synaptic axonal degeneration in the visual path-
way in multiple sclerosis Ann Neurol 20147598ndash107
24 Alshowaeir D Yiannikas C Garrick R et al Latency of
multifocal visual evoked potentials in nonoptic neuritis eyes
of multiple sclerosis patients associated with optic radiation
lesions Invest Ophthalmol Vis Sci 2014553758ndash3764
25 Sakai RE Feller DJ Galetta KM Galetta SL Balcer LJ
Vision in multiple sclerosis the story structure-function cor-
relations and models for neuroprotection J Neuroophthalmol
201131362ndash373
26 Walter SD Ishikawa H Galetta KM et al Ganglion cell
loss in relation to visual disability in multiple sclerosis
Ophthalmology 20121191250ndash1257
27 Di Maggio G Santangelo R Guerrieri S et al Optical
coherence tomography and visual evoked potentials which
is more sensitive in multiple sclerosis Mult Scler 201420
1342ndash1347
28 Naismith RT Tutlam NT Xu J et al Optical coherence
tomography is less sensitive than visual evoked potentials
in optic neuritis Neurology 20097346ndash52
29 Araie M Test-retest variability in structural parameters
measured with glaucoma imaging devices Jpn J Ophthal-
mol 2013571ndash24
30 Watson GM Keltner JL Chin EK Harvey D Nguyen A
Park SS Comparison of retinal nerve fiber layer and cen-
tral macular thickness measurements among five different
optical coherence tomography instruments in patients with
multiple sclerosis and optic neuritis J Neuroophthalmol
201131110ndash116
31 Schippling S Balk L Costello F et al Quality control for
retinal OCT in multiple sclerosis validation of the
OSCAR-IB criteria Mult Scler 201521163ndash170
32 Rinalduzzi S Brusa A Jones SJ Variation of visual evoked
potential delay to stimulation of central nasal and tem-
poral regions of the macula in optic neuritis J Neurol
httpnnneurologyorgcgicollectionmultiple_sclerosisMultiple sclerosisfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2015 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
SD-OCT appear to be less sensitive than VEPs for as-sessing the clinical and subclinical effects of ON2728
so interpretation of OCT may require complemen-tary assessments using functional techniques Fur-thermore improvements are needed to standardizeand reduce test-retest variability in SD-OCT sys-tems29 Given the rapid evolution of the technologythe technical expertise required and differencesbetween commercially available instruments30 it isalso important that criteria be established to ensurequality control for OCT as a validated outcome mea-sure a process that is under way31
VEPs Standard VEPs elicited by visual stimuli andmeasured in the occipital cortex can be used to detectfunctional changes in the visual pathway includingthe optic nerve32 In multifocal VEPs (mfVEPs)visual stimuli are provided independently to localizedregions of a wider visual field (48deg) and responses tothe stimuli are measured individually33 allowing for amore detailed analysis of visual function covering amuch larger area of the visual pathway than standardVEPs (figure 3)
The severity of an attack of ON and the extent ofinflammation are correlated with an acute reductionin the amplitude of VEPs34 Reduction in VEP ampli-tude is thought to reflect functional impairment ofaxonal conduction either transiently (eg due toacute inflammation or demyelination) or persistently(due to axonal loss) Within 3ndash4 months after theacute episode the amplitude generally shows somerecovery reflecting resolution of edema and thewaveform of the VEP is well-preserved but thelatency is significantly increased This residual latencydelay is thought to result from demyelination of sur-viving axons which interferes with saltatory conduc-tion of the action potential along the optic nervelesion Some investigators have reported subsequentimprovement in latency for up to 2 years6 whereasothers have reported no further recovery after 4months8 Prolongation of latency is most evident inthe central visual field perhaps indicating that thecentral (macular) region of the optic nerve is moresusceptible to demyelination or resistant to remyeli-nation32 The central region of the optic nerve con-tains the greatest density of parvocellular fibers thatconvey static information (eg form and color) butVEP latency in patients with ON correlates morestrongly with dynamic functions (eg motion detec-tion) than with static functions This may suggestmore specific effects on magnocellular fibers orgreater vulnerability of fibers required for accuratesignal timing8
Effects of ON on VEPs have also been shown toreflect structural changes in the RNFL In a studyof 21 patients following a first episode of unilateral
ON VEP latency prolongations and amplitude re-ductions of affected eyes at baseline and 3 monthsafter onset were associated with RNFL thinning19
suggesting a relationship between the initial structuralloss and residual functional impairment In a separatestudy of 25 patients with ON with incomplete recov-ery after 1 year similar relationships between VEPlatencyamplitude and RNFL thinning were still evi-dent18 further supporting the clinical relevance ofthis technique
mfVEPs have been used in a growing number ofsmall studies to examine the pathology of ON ingreater detail35ndash38 mfVEPs detect functional changesassociated with onset and evolution of acute ON38
and may be particularly useful to assess treatmentoutcomes in clinical trials as it appears to be morereproducible than standard VEPs39 One study of 25patients with ON between 6 and 12 months afteronset found an apparent discrepancy between struc-tural and functional measures in these patients35 AsRNFL thinning progressed in the affected eyes overthis time period the mfVEP amplitude partiallyrecovered suggesting that functional recovery maybe due in part to remyelination andor neuronalplasticity
Functional data provided by VEPs and mfVEPsmake an ideal counterpart to structural retinal assess-ments using OCT However as with OCT criterianeed to be established to ensure reproducibility andvalidity of VEP results Furthermore larger-scalestudies are needed to confirm the results of currentsmaller studies
MRI Nonconventional MRI techniques offer noveltools to examine the structure of CNS tissues indetail For example magnetization transfer (MT)imaging exploits the difference in resonance in freeprotons and protons associated with macromolecules(eg myelin) the ratio of which may provide a mea-sure of myelin content40 Diffusion tensor imaging(DTI) can be used to measure asymmetric radial dif-fusivity (RD) axial diffusivity (AD) or fractionalanisotropy (FA) of water as a gauge of tissue in majornerve tracts (eg optic nerve and optic radiations)41
A small number of studies have provided supportfor use of these techniques to assess pathologicchanges in ON For example in an MT study in11 patients with ON MT ratios of affected opticnerves closely followed the course of the disease theywere significantly higher at baseline (within 8 days ofonset) but were reduced at months 3 and 642 In aseparate study in 37 patients with ON MT ratios ofaffected optic nerves were not found to be differentfrom those of unaffected nerves until 3 months afteronset43 In that study ON-associated alterations inMT ratios at 3 months correlated with high- and
6 Neurology Neuroimmunology amp Neuroinflammation
low-contrast visual deficits and with VEP latency at 6months as well as with RNFL thinning at 12 months
In a study of DTI performed within 30 days ofonset and after 1 year in 12 patients with ON FAof affected optic nerves (which is also considered apotential measure of myelination) was the onlyparameter correlated with vision at onset but didnot correlate with the extent of recovery of visual acu-ity or contrast sensitivity at 1 or 3 months44 The AD(considered a measure of axonal integrity) was theonly parameter that was correlated with worse con-trast sensitivity at 1 and 3 months This was con-firmed in a follow-up study in 25 patients in whicha lower baseline AD was also found to be correlatedwith the extent of RNFL thinning and with VEPamplitude and latency45 These were small studiesand should be interpreted with caution as eye motionmakes imaging of the optic nerve by MT ratio andDTI challenging but they do not seem to support amodel in which the extent of neurodegeneration isdetermined solely by chronic demyelination Ratherthey suggest that the initial neuroaxonal effects of theacute inflammatory injury may be more important
Although these ldquononconventionalrdquo MRI techni-ques hold promise as a tool to investigate underlyingprocesses and assess recovery in ON there are substan-tial challenges to widespread use For example theacquisition times are frequently longer than is practical
for routine human studies and imaging is complicatedby motion artifacts caused by moving the eye orhead46 In addition there is no consensus on sequencesand protocols for their application in ON These fac-tors have limited widespread adoption of these ap-proaches and have likely contributed to theinconsistencies in findings Thus further technologicalimprovements and standardization of techniques forimaging of ON lesions will be required before theycan be considered as reliable measures of outcomesin clinical trials
QOL Visual deficits in patients with ON are likely tohave a marked impact on daily activities and QOLPatients frequently rate vision among the mostimportant physical functions affected by MS47 How-ever vision is poorly or insufficiently represented onstandard objective measures of physical functionsuch as the Expanded Disability Status Scale andfunctional assessment instruments such as the Mul-tiple Sclerosis Functional Composite (MSFC) Addi-tion of SLCLA charts to the MSFC has been reportedto better capture MS-related disability48 One patient-reported outcome instrument the 25-item NationalEye Institute Visual Functioning Questionnaire(NEI-VFQ-25) has become a commonly usedmeasurement of vision-specific health-related QOLWhen administered to patients from the ONTT 5ndash8years after the episode of acute ON scores on the NEI-VFQ-25 were lower than for an older disease-freecohort3 In patients with MS correlations with NEI-VFQ-25 scores have been demonstrated for low-contrast visual acuity49 binocular summation12
motion perception50 and loss of RGCs25 (figure 4)Moreover a 10-item supplement has been developedto better capture aspects more relevant to neuro-ophthalmology such as double vision and difficultieswith viewing motion51 A follow-up study has alsoreported its ability to distinguish patients with MSwith a history of ON52
TREATMENTS An important unmet need withrespect to ON is the availability of effective treatmentsto prevent or reverse long-term visual dysfunctionGiven the narrow window of time during whichmost recovery occurs it seems reasonable to suggestthat an effective treatment be initiated as soon aspossible after ON onset with the aim of promotingRGC survival and either extending the window forremyelination or accelerating the rate and extent towhich it occurs Data emerging from OCT studiessuggest that RGC loss may begin within weeks ofthe event thereby narrowing the time to initiateneuroprotective therapy
Despite the lack of long-term benefits of high-dosecorticosteroids patients with acute ON are frequently
Figure 4 Relationship of thickness of retinal layers to quality of life and low-contrast visual acuity
Scatter plot and fitted linear regression line showing relationships of ganglion cell layer plusinner plexiform layer (GCL 1 IPL) thickness to 25-item National Eye Institute Visual Func-tioning Questionnaire (NEI-VFQ-25) composite scores and low-contrast visual acuity at25 level The regression lines represent fitted values for mean GCL 1 IPL thickness foreach value of NEI-VFQ-25 or low-contrast visual acuity the gray shaded areas show the95 confidence intervals from the SEs of the predictions for the fitted lines Linear corre-lations were significant QOL5 quality of life Reprinted from Ophthalmology 119(6) WalterSD et al Ganglion cell loss in relation to visual disability in multiple sclerosis 1250ndash12572012 with permission from Elsevier26
Neurology Neuroimmunology amp Neuroinflammation 7
provided these drugs as symptomatic treatment tospeed resolution of acute inflammation Patients areoften assessed by MRI to determine their risk forMS but it is not clear that disease-modifying thera-pies for relapsing forms of MS are effective to preventneurodegeneration when ON occurs while receivingthese treatments For example interferon b was not
found to prevent RFNL thinning in patients withON53 Natalizumab has been shown to reduce lossof vision54 and improve VEPs55 in patients withrelapsing-remitting MS but there are no data toindicate treatment benefits specifically in patientswith ON A phase II study of fingolimod in acutedemyelinating ON is complete although it is not
Table Phase II and III studies in typical optic neuritis
Startend datesa Treatment
Time from eventto studyinitiation Primary endpoint Statusa
Primary efficacyresults Study numbera
July 1988b (end datenot provided)
Oral prednisone 1 mgkg for 14 d vsmethylprednisolone 1000 mg IV for3 d then oral prednisone 1 mgkgfor 11 d vs placebo
8 d Visual field and contrastsensitivity over 6 mo
Completedc No significanteffect2
NCT00000146
August 1995ndashDecember1997
Immunoglobulin 04 gkg IV QD for3 d then 3 infusionsmo for 3 mo vsplacebo
$6 mo High-contrast visualacuity (100 ETDRScharts)
Completed No significanteffect56
NCT00000117
August 2006ndashJuly 2011 Erythropoietin 33000 units IV for3 d vs placebo
10 d RNFL thickness at 4 8and 16 wks
Completed Significantly lessRNFL thinning at 16wk57
NCT00355095
September 2006ndashMay2011
Simvastatin 80 mg QD PO vsplacebo
4 wk Contrast sensitivity at3 mo
Completedc No significanteffect58
NCT00261326
March 2008ndashJanuary2011
Atacicept 150 mg SC weekly vsplacebo
Not specified RNFL thickness up to48 wks
Terminated None available NCT00624468
February 2009ndashFebruary2011
Glatiramer acetate 20 mg SC QD vsplacebo
Not specified RNFL thickness at 6 mo Completed None available NCT00856635
February 2010ndashJanuary2013
Minocycline 100 mg BID vs notreatment
30 d RNFL thickness every3 mo for 9 mo
Terminated None available NCT01073813
May 2010ndashMarch 2013 Visual reconstitution therapy vssaccadic eye movement training
60ndash80 d or 12mo
Visual field at 6 mo Completed None available NCT01274702
May 2011ndashDecember2013
Dalfampridine 10mg BID vs placebo $12 mo Contrast sensitivity(5 ETDRS charts)
Completed None available NCT01337986
July 2011ndashDecember2012
Vitamin D 50000 unitswk vsvitamin withheld
Not applicable(preventionstudy)
RNFL thickness at10ndash32 d after opticneuritis
Unknown None available NCT01465893
November 2011ndashAugust2014
Phenytoin 15 mgkgd for 3 d then4 mgkgd for 13 wks vs placebo
14 d RNFL thickness at6 mo
Completedd Significantly lessRNFL thinning at6 mod
NCT01451593
March 2012ndashSeptember2014
Oral prednisone 1250 mg vsmethylprednisolone 1000 mg IV for3 d each
14 d VEP latency Unknown None available NCT01524250
December 2012ndashOctober2014
BIIB033 (anti-LINGO-1) 100 mgkgIV every 4 wks vs placebo
28 d VEP latency Completed None available NCT01721161
February 2013ndashFebruary2015
Amiloride 10 mg QD vs placebo for5 mo
28 d RNFL thickness at 6 mo12 mo
Recruiting None available NCT01802489
July 2013ndashJune 2016 Fingolimod 05 mg QD vs interferonb-1b
30 d VEP latency Recruiting None available NCT01647880
August 2013ndashMay 2014 Fingolimod 05 mg QD vs placebo Not specified RNFL thickness at18 wks
Completed None available NCT01757691
October 2013ndashJanuary2016
MD1003 100 mg TID vs placebo Not specified High-contrast visualacuity (100 ETDRScharts)
Recruiting None available NCT02220244
March 2014ndashApril 2016 Amiloride hydrochlorothiazide100 mgd vs placebo
10 d RNFL thickness at24 wks
Recruiting None available NCT01879527
November 2014ndashDecember 2018
Erythropoietin 33000 units IV for3 d vs placebo
10 d RNFL thickness at 6 mo Recruiting None available NCT01962571
Abbreviations ETDRS5 Early Treatment Diabetic Retinopathy Study RNFL5 retinal nerve fiber layer SC5 subcutaneous VEP5 visual-evoked potentiala From ClinicalTrialsgov except where indicated otherwiseb The Optic Neuritis Treatment Trial included a 15-year follow-up periodc Based on published resultd Reported at American Academy of Neurology 2015 Annual Meeting April 18ndash25 Washington DC
8 Neurology Neuroimmunology amp Neuroinflammation
clear that enrollment goals were met Another phaseIIIII study is under way but study results are not yetavailable (table)
Based on promising results from animal studiesand small clinical studies IV immunoglobulin wasinvestigated in patients with one or more episodesof typical ON and irreversible loss of visual acuitybut was terminated early due to negative results56
(table) Since that time various investigational ther-apies have shown promise in early preclinical andclinical studies and a number of phase II and IIIstudies have been completed or are under way Forexample in a placebo-controlled study of IV eryth-ropoietin for 3 days as an add-on to methylpredni-sone in patients with a first episode of ON withinthe previous 10 days those treated with erythropoi-etin demonstrated reduced RNFL thinning lessdecrease in optic nerve diameter and shorter VEPlatency57 Although the mechanism by which eryth-ropoietin may exert these effects is poorly under-stood it may involve the neuroprotective effectsof this hormone during acute inflammation Inanother placebo-controlled study in patients withsymptom duration of 4 weeks and reduced con-trast sensitivity simvastatin (a hypercholesterolemiamedication) narrowly missed significance on theprimary efficacy outcome (contrast sensitivity)but improvements were noted for VEP latencyand amplitude58 However imbalances in random-ization and technical issues may have contributed tothe observed effects59 A study in ON testing possibleneuroprotective effects of phenytoin an anticonvul-sant has recently completed and another study testingeffects of amiloride hydrochlorothiazide a diuretic iscurrently underway Nevertheless it is an open ques-tion whether a neuroprotective agent can domore thandelay degeneration of axons if they remain chronicallydemyelinated Finally BIIB033 a fully-human anti-body to LINGO-1 an inhibitor of myelination andneuroaxonal growth has shown promise in preclinicaland early clinical testing60 and a phase II study in ONwas recently completed
CONCLUSIONS It is now clear that recovery fromON is frequently incomplete which adversely affectsthe QOL of patients In addition there remain con-siderable gaps with respect to understanding assess-ing and treating this disease to prevent long-termdeficits Nevertheless ongoing work holds promisefor all of these areas The application of newertechnologies continues to provide new insight intothe underlying disease processes and increasedappreciation of the injury that occurs followingON The development of these new tools mayincrease the ability to detect meaningful changes invision with therapeutic intervention and study
results suggest that timing is critical Developmentof guidelines to ensure consistency in theirapplication should also improve interpretation offindings and thereby improve the quality ofassessments Finally several therapies have shownpromise in preclinical and early clinical testingTherefore there is reason to be optimistic thatstrategies may soon be identified to improve theprognosis for patients with ON Given therelationship between ON and MS it seems likelythat any such developments for ON may havesubstantial implications for understanding assessingand treating MS as well
AUTHOR CONTRIBUTIONSAll authors participated in the conception of the article interpretation of
the data and revision of the manuscript and they approved the final ver-
sion Biogen provided funding for writing and editorial support in the
development of this paper and they reviewed and provided feedback
on the paper to the authors The authors had full editorial control of
the paper and provided their final approval of all content
ACKNOWLEDGMENTThe authors thank Dr Elena H Martinez-Lapiscina Dr Santiago Ortiz-
Perez and Dr Ana Tercero from the Center of Neuroimmunology Insti-
tute of Biomedical Research August Pi SunyerHospital Clinic Barcelona
University of Barcelona for creating figures 1 2B and 3 respectively
Lauren Nagy of Excel Scientific Solutions copyedited and styled the man-
uscript per journal requirements and this editorial support was funded by
Biogen
STUDY FUNDINGWriting and editorial support was funded by Biogen
DISCLOSURESL Galetta has received consulting honoraria and travel fundingspeaker
honoraria from Genzyme and Biogen and is on the editorial board for
Neurology and Journal of Neuro-Ophthalmology P Villoslada serves on
advisory boards for Novartis Roche Neurotec Pharma and Bionure
Pharma has consulted for Novartis Roche TFS Heidelberg Engineer-
ing MedImmune Diagna Biotec and Neurotec Pharma is an academic
editor for PLoSONE is on the editorial board for Neurology amp Therapy
and Current Treatment Options in Neurology has received research sup-
port from European Commission Genzyme Biogen Instituto Salud
Carlos III Marato TV3 Novartis and Roche and holds patents and
owns stocksstock options with Bionure Pharma N Levin receives
research support from National Multiple Sclerosis Foundation
K Shindler received research support from the FM Kirby Foundation
Harbor Therapeutics National Eye Institute National Multiple Sclerosis
Foundation Research to Prevent Blindness Sirtris Pharmaceuticals
ITMAT and Stemnion Inc has received speaker honoraria from Med-
ical College of Wisconsin and Temple University is an associate editor
for Frontiers in Neurology Neuro-Ophthalmology receives publishing roy-
alties from UpToDate and Oakstone Publishing and has consulted for
medical-legal cases H Ishikawa received research support from the NIH
E Parr is a full-time employee of Excel Scientific Solutions who were
funded by Biogen to provide editorial and writing support for this paper
D Cadavid is a full-time employee of Biogen owns stock options in
Biogen and has patent applications pending related to the use of drugs
that block LINGO-1 to treat demyelination in multiple sclerosis LJ
Balcer received consulting fees from Acorda Biogen Genzyme Novartis
Questcor and Vaccinexe serves on a clinical trial advisory board for
Biogen and serves on a scientific advisory board for Genzyme Go to
Neurologyorgnn for full disclosure forms
Received February 12 2015 Accepted in final form May 13 2015
Neurology Neuroimmunology amp Neuroinflammation 9
REFERENCES1 Toosy AT Mason DF Miller DH Optic neuritis Lancet
Neurol 20141383ndash99
2 Beck RW Cleary PA Anderson MM Jr et al Optic Neu-
ritis Study Group A randomized controlled trial of cor-
ticosteroids in the treatment of acute optic neuritis N
Engl J Med 1992326581ndash588
3 Cole SR Beck RW Moke PS Gal RL Long DT Optic
Neuritis Study Group The National Eye Institute Visual
Function Questionnaire experience of the ONTT Invest
Ophthalmol Vis Sci 2000411017ndash1021
4 Beck RW Cleary PA Backlund JC The course of visual
recovery after optic neuritis Experience of the Optic
Neuritis Treatment Trial Ophthalmology 1994101
1771ndash1778
5 Costello F Hodge W Pan YI Eggenberger E Coupland S
Kardon RH Tracking retinal nerve fiber layer loss after
optic neuritis a prospective study using optical coherence
tomography Mult Scler 200814893ndash905
6 Brusa A Jones SJ Plant GT Long-term remyelination
after optic neuritis a 2-year visual evoked potential and
psychophysical serial study Brain 2001124468ndash479
7 Malik MT Healy BC Benson LA et al Factors associated
with recovery from acute optic neuritis in patients with
multiple sclerosis Neurology 2014822173ndash2179
8 Raz N Dotan S Chokron S Ben-Hur T Levin N Demy-
elination affects temporal aspects of perception an optic
neuritis study Ann Neurol 201271531ndash538
9 Leat SJ Legge GE Bullimore MA What is low vision A re-
evaluation of definitions Optom Vis Sci 199976198ndash211
10 Martiacutenez-Lapiscina EH Ortiz-Peacuterez S Fraga-Pumar E et al
Colour vision impairment is associated with disease severity
in multiple sclerosis Mult Scler 2014201207ndash1216
11 Raz N Dotan S Benoliel T Chokron S Ben-Hur T
Levin N Sustained motion perception deficit following
optic neuritis behavioral and cortical evidence Neurology
2011762103ndash2111
12 Pineles SL Birch EE Talman LS et al One eye or two a
comparison of binocular and monocular low-contrast acu-
ity testing in multiple sclerosis Am J Ophthalmol 2011
152133ndash140
13 Gabriele ML Wollstein G Ishikawa H et al Optical
coherence tomography history current status and lab-
oratory work Invest Ophthalmol Vis Sci 201152
2425ndash2436
14 Henderson AP Altmann DR Trip AS et al A serial study
of retinal changes following optic neuritis with sample size
estimates for acute neuroprotection trials Brain 2010133
2592ndash2602
15 Petzold A de Boer JF Schippling S et al Optical coher-
ence tomography in multiple sclerosis a systematic review
and meta-analysis Lancet Neurol 20109921ndash932
16 Gabilondo I Martiacutenez-Lapiscina EH Fraga-Pumar E
et al Dynamics of retinal injury after acute optic neuritis
Ann Neurol 201577517ndash528
17 Huang-Link Y-M Al-Hawasi A Lindehammar H Acute
optic neuritis retinal ganglion cell loss precedes retinal
nerve fiber thinning Neurol Sci 201536617ndash620
18 Trip SA Schlottmann PG Jones SJ et al Retinal nerve
fiber layer axonal loss and visual dysfunction in optic neu-
ritis Ann Neurol 200558383ndash391
19 Henderson AP Altmann DR Trip SA et al Early factors
associated with axonal loss after optic neuritis Ann Neurol
201170955ndash963
20 Costello F Coupland S Hodge W et al Quantifying
axonal loss after optic neuritis with optical coherence
tomography Ann Neurol 200659963ndash969
21 Hood DC Anderson SC Wall M Kardon RH Structure
versus function in glaucoma an application of a linear
model Invest Ophthalmol Vis Sci 2007483662ndash3668
22 Balk LJ Steenwijk MD Tewarie P et al Bidirectional
trans-synaptic axonal degeneration in the visual pathway
in multiple sclerosis J Neurol Neurosurg Psychiatry 2014
86419ndash424
23 Gabilondo I Martiacutenez-Lapiscina EH Martiacutenez-Heras E
et al Trans-synaptic axonal degeneration in the visual path-
way in multiple sclerosis Ann Neurol 20147598ndash107
24 Alshowaeir D Yiannikas C Garrick R et al Latency of
multifocal visual evoked potentials in nonoptic neuritis eyes
of multiple sclerosis patients associated with optic radiation
lesions Invest Ophthalmol Vis Sci 2014553758ndash3764
25 Sakai RE Feller DJ Galetta KM Galetta SL Balcer LJ
Vision in multiple sclerosis the story structure-function cor-
relations and models for neuroprotection J Neuroophthalmol
201131362ndash373
26 Walter SD Ishikawa H Galetta KM et al Ganglion cell
loss in relation to visual disability in multiple sclerosis
Ophthalmology 20121191250ndash1257
27 Di Maggio G Santangelo R Guerrieri S et al Optical
coherence tomography and visual evoked potentials which
is more sensitive in multiple sclerosis Mult Scler 201420
1342ndash1347
28 Naismith RT Tutlam NT Xu J et al Optical coherence
tomography is less sensitive than visual evoked potentials
in optic neuritis Neurology 20097346ndash52
29 Araie M Test-retest variability in structural parameters
measured with glaucoma imaging devices Jpn J Ophthal-
mol 2013571ndash24
30 Watson GM Keltner JL Chin EK Harvey D Nguyen A
Park SS Comparison of retinal nerve fiber layer and cen-
tral macular thickness measurements among five different
optical coherence tomography instruments in patients with
multiple sclerosis and optic neuritis J Neuroophthalmol
201131110ndash116
31 Schippling S Balk L Costello F et al Quality control for
retinal OCT in multiple sclerosis validation of the
OSCAR-IB criteria Mult Scler 201521163ndash170
32 Rinalduzzi S Brusa A Jones SJ Variation of visual evoked
potential delay to stimulation of central nasal and tem-
poral regions of the macula in optic neuritis J Neurol
httpnnneurologyorgcgicollectionmultiple_sclerosisMultiple sclerosisfollowing collection(s) This article along with others on similar topics appears in the
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httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2015 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
low-contrast visual deficits and with VEP latency at 6months as well as with RNFL thinning at 12 months
In a study of DTI performed within 30 days ofonset and after 1 year in 12 patients with ON FAof affected optic nerves (which is also considered apotential measure of myelination) was the onlyparameter correlated with vision at onset but didnot correlate with the extent of recovery of visual acu-ity or contrast sensitivity at 1 or 3 months44 The AD(considered a measure of axonal integrity) was theonly parameter that was correlated with worse con-trast sensitivity at 1 and 3 months This was con-firmed in a follow-up study in 25 patients in whicha lower baseline AD was also found to be correlatedwith the extent of RNFL thinning and with VEPamplitude and latency45 These were small studiesand should be interpreted with caution as eye motionmakes imaging of the optic nerve by MT ratio andDTI challenging but they do not seem to support amodel in which the extent of neurodegeneration isdetermined solely by chronic demyelination Ratherthey suggest that the initial neuroaxonal effects of theacute inflammatory injury may be more important
Although these ldquononconventionalrdquo MRI techni-ques hold promise as a tool to investigate underlyingprocesses and assess recovery in ON there are substan-tial challenges to widespread use For example theacquisition times are frequently longer than is practical
for routine human studies and imaging is complicatedby motion artifacts caused by moving the eye orhead46 In addition there is no consensus on sequencesand protocols for their application in ON These fac-tors have limited widespread adoption of these ap-proaches and have likely contributed to theinconsistencies in findings Thus further technologicalimprovements and standardization of techniques forimaging of ON lesions will be required before theycan be considered as reliable measures of outcomesin clinical trials
QOL Visual deficits in patients with ON are likely tohave a marked impact on daily activities and QOLPatients frequently rate vision among the mostimportant physical functions affected by MS47 How-ever vision is poorly or insufficiently represented onstandard objective measures of physical functionsuch as the Expanded Disability Status Scale andfunctional assessment instruments such as the Mul-tiple Sclerosis Functional Composite (MSFC) Addi-tion of SLCLA charts to the MSFC has been reportedto better capture MS-related disability48 One patient-reported outcome instrument the 25-item NationalEye Institute Visual Functioning Questionnaire(NEI-VFQ-25) has become a commonly usedmeasurement of vision-specific health-related QOLWhen administered to patients from the ONTT 5ndash8years after the episode of acute ON scores on the NEI-VFQ-25 were lower than for an older disease-freecohort3 In patients with MS correlations with NEI-VFQ-25 scores have been demonstrated for low-contrast visual acuity49 binocular summation12
motion perception50 and loss of RGCs25 (figure 4)Moreover a 10-item supplement has been developedto better capture aspects more relevant to neuro-ophthalmology such as double vision and difficultieswith viewing motion51 A follow-up study has alsoreported its ability to distinguish patients with MSwith a history of ON52
TREATMENTS An important unmet need withrespect to ON is the availability of effective treatmentsto prevent or reverse long-term visual dysfunctionGiven the narrow window of time during whichmost recovery occurs it seems reasonable to suggestthat an effective treatment be initiated as soon aspossible after ON onset with the aim of promotingRGC survival and either extending the window forremyelination or accelerating the rate and extent towhich it occurs Data emerging from OCT studiessuggest that RGC loss may begin within weeks ofthe event thereby narrowing the time to initiateneuroprotective therapy
Despite the lack of long-term benefits of high-dosecorticosteroids patients with acute ON are frequently
Figure 4 Relationship of thickness of retinal layers to quality of life and low-contrast visual acuity
Scatter plot and fitted linear regression line showing relationships of ganglion cell layer plusinner plexiform layer (GCL 1 IPL) thickness to 25-item National Eye Institute Visual Func-tioning Questionnaire (NEI-VFQ-25) composite scores and low-contrast visual acuity at25 level The regression lines represent fitted values for mean GCL 1 IPL thickness foreach value of NEI-VFQ-25 or low-contrast visual acuity the gray shaded areas show the95 confidence intervals from the SEs of the predictions for the fitted lines Linear corre-lations were significant QOL5 quality of life Reprinted from Ophthalmology 119(6) WalterSD et al Ganglion cell loss in relation to visual disability in multiple sclerosis 1250ndash12572012 with permission from Elsevier26
Neurology Neuroimmunology amp Neuroinflammation 7
provided these drugs as symptomatic treatment tospeed resolution of acute inflammation Patients areoften assessed by MRI to determine their risk forMS but it is not clear that disease-modifying thera-pies for relapsing forms of MS are effective to preventneurodegeneration when ON occurs while receivingthese treatments For example interferon b was not
found to prevent RFNL thinning in patients withON53 Natalizumab has been shown to reduce lossof vision54 and improve VEPs55 in patients withrelapsing-remitting MS but there are no data toindicate treatment benefits specifically in patientswith ON A phase II study of fingolimod in acutedemyelinating ON is complete although it is not
Table Phase II and III studies in typical optic neuritis
Startend datesa Treatment
Time from eventto studyinitiation Primary endpoint Statusa
Primary efficacyresults Study numbera
July 1988b (end datenot provided)
Oral prednisone 1 mgkg for 14 d vsmethylprednisolone 1000 mg IV for3 d then oral prednisone 1 mgkgfor 11 d vs placebo
8 d Visual field and contrastsensitivity over 6 mo
Completedc No significanteffect2
NCT00000146
August 1995ndashDecember1997
Immunoglobulin 04 gkg IV QD for3 d then 3 infusionsmo for 3 mo vsplacebo
$6 mo High-contrast visualacuity (100 ETDRScharts)
Completed No significanteffect56
NCT00000117
August 2006ndashJuly 2011 Erythropoietin 33000 units IV for3 d vs placebo
10 d RNFL thickness at 4 8and 16 wks
Completed Significantly lessRNFL thinning at 16wk57
NCT00355095
September 2006ndashMay2011
Simvastatin 80 mg QD PO vsplacebo
4 wk Contrast sensitivity at3 mo
Completedc No significanteffect58
NCT00261326
March 2008ndashJanuary2011
Atacicept 150 mg SC weekly vsplacebo
Not specified RNFL thickness up to48 wks
Terminated None available NCT00624468
February 2009ndashFebruary2011
Glatiramer acetate 20 mg SC QD vsplacebo
Not specified RNFL thickness at 6 mo Completed None available NCT00856635
February 2010ndashJanuary2013
Minocycline 100 mg BID vs notreatment
30 d RNFL thickness every3 mo for 9 mo
Terminated None available NCT01073813
May 2010ndashMarch 2013 Visual reconstitution therapy vssaccadic eye movement training
60ndash80 d or 12mo
Visual field at 6 mo Completed None available NCT01274702
May 2011ndashDecember2013
Dalfampridine 10mg BID vs placebo $12 mo Contrast sensitivity(5 ETDRS charts)
Completed None available NCT01337986
July 2011ndashDecember2012
Vitamin D 50000 unitswk vsvitamin withheld
Not applicable(preventionstudy)
RNFL thickness at10ndash32 d after opticneuritis
Unknown None available NCT01465893
November 2011ndashAugust2014
Phenytoin 15 mgkgd for 3 d then4 mgkgd for 13 wks vs placebo
14 d RNFL thickness at6 mo
Completedd Significantly lessRNFL thinning at6 mod
NCT01451593
March 2012ndashSeptember2014
Oral prednisone 1250 mg vsmethylprednisolone 1000 mg IV for3 d each
14 d VEP latency Unknown None available NCT01524250
December 2012ndashOctober2014
BIIB033 (anti-LINGO-1) 100 mgkgIV every 4 wks vs placebo
28 d VEP latency Completed None available NCT01721161
February 2013ndashFebruary2015
Amiloride 10 mg QD vs placebo for5 mo
28 d RNFL thickness at 6 mo12 mo
Recruiting None available NCT01802489
July 2013ndashJune 2016 Fingolimod 05 mg QD vs interferonb-1b
30 d VEP latency Recruiting None available NCT01647880
August 2013ndashMay 2014 Fingolimod 05 mg QD vs placebo Not specified RNFL thickness at18 wks
Completed None available NCT01757691
October 2013ndashJanuary2016
MD1003 100 mg TID vs placebo Not specified High-contrast visualacuity (100 ETDRScharts)
Recruiting None available NCT02220244
March 2014ndashApril 2016 Amiloride hydrochlorothiazide100 mgd vs placebo
10 d RNFL thickness at24 wks
Recruiting None available NCT01879527
November 2014ndashDecember 2018
Erythropoietin 33000 units IV for3 d vs placebo
10 d RNFL thickness at 6 mo Recruiting None available NCT01962571
Abbreviations ETDRS5 Early Treatment Diabetic Retinopathy Study RNFL5 retinal nerve fiber layer SC5 subcutaneous VEP5 visual-evoked potentiala From ClinicalTrialsgov except where indicated otherwiseb The Optic Neuritis Treatment Trial included a 15-year follow-up periodc Based on published resultd Reported at American Academy of Neurology 2015 Annual Meeting April 18ndash25 Washington DC
8 Neurology Neuroimmunology amp Neuroinflammation
clear that enrollment goals were met Another phaseIIIII study is under way but study results are not yetavailable (table)
Based on promising results from animal studiesand small clinical studies IV immunoglobulin wasinvestigated in patients with one or more episodesof typical ON and irreversible loss of visual acuitybut was terminated early due to negative results56
(table) Since that time various investigational ther-apies have shown promise in early preclinical andclinical studies and a number of phase II and IIIstudies have been completed or are under way Forexample in a placebo-controlled study of IV eryth-ropoietin for 3 days as an add-on to methylpredni-sone in patients with a first episode of ON withinthe previous 10 days those treated with erythropoi-etin demonstrated reduced RNFL thinning lessdecrease in optic nerve diameter and shorter VEPlatency57 Although the mechanism by which eryth-ropoietin may exert these effects is poorly under-stood it may involve the neuroprotective effectsof this hormone during acute inflammation Inanother placebo-controlled study in patients withsymptom duration of 4 weeks and reduced con-trast sensitivity simvastatin (a hypercholesterolemiamedication) narrowly missed significance on theprimary efficacy outcome (contrast sensitivity)but improvements were noted for VEP latencyand amplitude58 However imbalances in random-ization and technical issues may have contributed tothe observed effects59 A study in ON testing possibleneuroprotective effects of phenytoin an anticonvul-sant has recently completed and another study testingeffects of amiloride hydrochlorothiazide a diuretic iscurrently underway Nevertheless it is an open ques-tion whether a neuroprotective agent can domore thandelay degeneration of axons if they remain chronicallydemyelinated Finally BIIB033 a fully-human anti-body to LINGO-1 an inhibitor of myelination andneuroaxonal growth has shown promise in preclinicaland early clinical testing60 and a phase II study in ONwas recently completed
CONCLUSIONS It is now clear that recovery fromON is frequently incomplete which adversely affectsthe QOL of patients In addition there remain con-siderable gaps with respect to understanding assess-ing and treating this disease to prevent long-termdeficits Nevertheless ongoing work holds promisefor all of these areas The application of newertechnologies continues to provide new insight intothe underlying disease processes and increasedappreciation of the injury that occurs followingON The development of these new tools mayincrease the ability to detect meaningful changes invision with therapeutic intervention and study
results suggest that timing is critical Developmentof guidelines to ensure consistency in theirapplication should also improve interpretation offindings and thereby improve the quality ofassessments Finally several therapies have shownpromise in preclinical and early clinical testingTherefore there is reason to be optimistic thatstrategies may soon be identified to improve theprognosis for patients with ON Given therelationship between ON and MS it seems likelythat any such developments for ON may havesubstantial implications for understanding assessingand treating MS as well
AUTHOR CONTRIBUTIONSAll authors participated in the conception of the article interpretation of
the data and revision of the manuscript and they approved the final ver-
sion Biogen provided funding for writing and editorial support in the
development of this paper and they reviewed and provided feedback
on the paper to the authors The authors had full editorial control of
the paper and provided their final approval of all content
ACKNOWLEDGMENTThe authors thank Dr Elena H Martinez-Lapiscina Dr Santiago Ortiz-
Perez and Dr Ana Tercero from the Center of Neuroimmunology Insti-
tute of Biomedical Research August Pi SunyerHospital Clinic Barcelona
University of Barcelona for creating figures 1 2B and 3 respectively
Lauren Nagy of Excel Scientific Solutions copyedited and styled the man-
uscript per journal requirements and this editorial support was funded by
Biogen
STUDY FUNDINGWriting and editorial support was funded by Biogen
DISCLOSURESL Galetta has received consulting honoraria and travel fundingspeaker
honoraria from Genzyme and Biogen and is on the editorial board for
Neurology and Journal of Neuro-Ophthalmology P Villoslada serves on
advisory boards for Novartis Roche Neurotec Pharma and Bionure
Pharma has consulted for Novartis Roche TFS Heidelberg Engineer-
ing MedImmune Diagna Biotec and Neurotec Pharma is an academic
editor for PLoSONE is on the editorial board for Neurology amp Therapy
and Current Treatment Options in Neurology has received research sup-
port from European Commission Genzyme Biogen Instituto Salud
Carlos III Marato TV3 Novartis and Roche and holds patents and
owns stocksstock options with Bionure Pharma N Levin receives
research support from National Multiple Sclerosis Foundation
K Shindler received research support from the FM Kirby Foundation
Harbor Therapeutics National Eye Institute National Multiple Sclerosis
Foundation Research to Prevent Blindness Sirtris Pharmaceuticals
ITMAT and Stemnion Inc has received speaker honoraria from Med-
ical College of Wisconsin and Temple University is an associate editor
for Frontiers in Neurology Neuro-Ophthalmology receives publishing roy-
alties from UpToDate and Oakstone Publishing and has consulted for
medical-legal cases H Ishikawa received research support from the NIH
E Parr is a full-time employee of Excel Scientific Solutions who were
funded by Biogen to provide editorial and writing support for this paper
D Cadavid is a full-time employee of Biogen owns stock options in
Biogen and has patent applications pending related to the use of drugs
that block LINGO-1 to treat demyelination in multiple sclerosis LJ
Balcer received consulting fees from Acorda Biogen Genzyme Novartis
Questcor and Vaccinexe serves on a clinical trial advisory board for
Biogen and serves on a scientific advisory board for Genzyme Go to
Neurologyorgnn for full disclosure forms
Received February 12 2015 Accepted in final form May 13 2015
Neurology Neuroimmunology amp Neuroinflammation 9
REFERENCES1 Toosy AT Mason DF Miller DH Optic neuritis Lancet
Neurol 20141383ndash99
2 Beck RW Cleary PA Anderson MM Jr et al Optic Neu-
ritis Study Group A randomized controlled trial of cor-
ticosteroids in the treatment of acute optic neuritis N
Engl J Med 1992326581ndash588
3 Cole SR Beck RW Moke PS Gal RL Long DT Optic
Neuritis Study Group The National Eye Institute Visual
Function Questionnaire experience of the ONTT Invest
Ophthalmol Vis Sci 2000411017ndash1021
4 Beck RW Cleary PA Backlund JC The course of visual
recovery after optic neuritis Experience of the Optic
Neuritis Treatment Trial Ophthalmology 1994101
1771ndash1778
5 Costello F Hodge W Pan YI Eggenberger E Coupland S
Kardon RH Tracking retinal nerve fiber layer loss after
optic neuritis a prospective study using optical coherence
tomography Mult Scler 200814893ndash905
6 Brusa A Jones SJ Plant GT Long-term remyelination
after optic neuritis a 2-year visual evoked potential and
psychophysical serial study Brain 2001124468ndash479
7 Malik MT Healy BC Benson LA et al Factors associated
with recovery from acute optic neuritis in patients with
multiple sclerosis Neurology 2014822173ndash2179
8 Raz N Dotan S Chokron S Ben-Hur T Levin N Demy-
elination affects temporal aspects of perception an optic
neuritis study Ann Neurol 201271531ndash538
9 Leat SJ Legge GE Bullimore MA What is low vision A re-
evaluation of definitions Optom Vis Sci 199976198ndash211
10 Martiacutenez-Lapiscina EH Ortiz-Peacuterez S Fraga-Pumar E et al
Colour vision impairment is associated with disease severity
in multiple sclerosis Mult Scler 2014201207ndash1216
11 Raz N Dotan S Benoliel T Chokron S Ben-Hur T
Levin N Sustained motion perception deficit following
optic neuritis behavioral and cortical evidence Neurology
2011762103ndash2111
12 Pineles SL Birch EE Talman LS et al One eye or two a
comparison of binocular and monocular low-contrast acu-
ity testing in multiple sclerosis Am J Ophthalmol 2011
152133ndash140
13 Gabriele ML Wollstein G Ishikawa H et al Optical
coherence tomography history current status and lab-
oratory work Invest Ophthalmol Vis Sci 201152
2425ndash2436
14 Henderson AP Altmann DR Trip AS et al A serial study
of retinal changes following optic neuritis with sample size
estimates for acute neuroprotection trials Brain 2010133
2592ndash2602
15 Petzold A de Boer JF Schippling S et al Optical coher-
ence tomography in multiple sclerosis a systematic review
and meta-analysis Lancet Neurol 20109921ndash932
16 Gabilondo I Martiacutenez-Lapiscina EH Fraga-Pumar E
et al Dynamics of retinal injury after acute optic neuritis
Ann Neurol 201577517ndash528
17 Huang-Link Y-M Al-Hawasi A Lindehammar H Acute
optic neuritis retinal ganglion cell loss precedes retinal
nerve fiber thinning Neurol Sci 201536617ndash620
18 Trip SA Schlottmann PG Jones SJ et al Retinal nerve
fiber layer axonal loss and visual dysfunction in optic neu-
ritis Ann Neurol 200558383ndash391
19 Henderson AP Altmann DR Trip SA et al Early factors
associated with axonal loss after optic neuritis Ann Neurol
201170955ndash963
20 Costello F Coupland S Hodge W et al Quantifying
axonal loss after optic neuritis with optical coherence
tomography Ann Neurol 200659963ndash969
21 Hood DC Anderson SC Wall M Kardon RH Structure
versus function in glaucoma an application of a linear
model Invest Ophthalmol Vis Sci 2007483662ndash3668
22 Balk LJ Steenwijk MD Tewarie P et al Bidirectional
trans-synaptic axonal degeneration in the visual pathway
in multiple sclerosis J Neurol Neurosurg Psychiatry 2014
86419ndash424
23 Gabilondo I Martiacutenez-Lapiscina EH Martiacutenez-Heras E
et al Trans-synaptic axonal degeneration in the visual path-
way in multiple sclerosis Ann Neurol 20147598ndash107
24 Alshowaeir D Yiannikas C Garrick R et al Latency of
multifocal visual evoked potentials in nonoptic neuritis eyes
of multiple sclerosis patients associated with optic radiation
lesions Invest Ophthalmol Vis Sci 2014553758ndash3764
25 Sakai RE Feller DJ Galetta KM Galetta SL Balcer LJ
Vision in multiple sclerosis the story structure-function cor-
relations and models for neuroprotection J Neuroophthalmol
201131362ndash373
26 Walter SD Ishikawa H Galetta KM et al Ganglion cell
loss in relation to visual disability in multiple sclerosis
Ophthalmology 20121191250ndash1257
27 Di Maggio G Santangelo R Guerrieri S et al Optical
coherence tomography and visual evoked potentials which
is more sensitive in multiple sclerosis Mult Scler 201420
1342ndash1347
28 Naismith RT Tutlam NT Xu J et al Optical coherence
tomography is less sensitive than visual evoked potentials
in optic neuritis Neurology 20097346ndash52
29 Araie M Test-retest variability in structural parameters
measured with glaucoma imaging devices Jpn J Ophthal-
mol 2013571ndash24
30 Watson GM Keltner JL Chin EK Harvey D Nguyen A
Park SS Comparison of retinal nerve fiber layer and cen-
tral macular thickness measurements among five different
optical coherence tomography instruments in patients with
multiple sclerosis and optic neuritis J Neuroophthalmol
201131110ndash116
31 Schippling S Balk L Costello F et al Quality control for
retinal OCT in multiple sclerosis validation of the
OSCAR-IB criteria Mult Scler 201521163ndash170
32 Rinalduzzi S Brusa A Jones SJ Variation of visual evoked
potential delay to stimulation of central nasal and tem-
poral regions of the macula in optic neuritis J Neurol
httpnnneurologyorgcgicollectionmultiple_sclerosisMultiple sclerosisfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2015 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
provided these drugs as symptomatic treatment tospeed resolution of acute inflammation Patients areoften assessed by MRI to determine their risk forMS but it is not clear that disease-modifying thera-pies for relapsing forms of MS are effective to preventneurodegeneration when ON occurs while receivingthese treatments For example interferon b was not
found to prevent RFNL thinning in patients withON53 Natalizumab has been shown to reduce lossof vision54 and improve VEPs55 in patients withrelapsing-remitting MS but there are no data toindicate treatment benefits specifically in patientswith ON A phase II study of fingolimod in acutedemyelinating ON is complete although it is not
Table Phase II and III studies in typical optic neuritis
Startend datesa Treatment
Time from eventto studyinitiation Primary endpoint Statusa
Primary efficacyresults Study numbera
July 1988b (end datenot provided)
Oral prednisone 1 mgkg for 14 d vsmethylprednisolone 1000 mg IV for3 d then oral prednisone 1 mgkgfor 11 d vs placebo
8 d Visual field and contrastsensitivity over 6 mo
Completedc No significanteffect2
NCT00000146
August 1995ndashDecember1997
Immunoglobulin 04 gkg IV QD for3 d then 3 infusionsmo for 3 mo vsplacebo
$6 mo High-contrast visualacuity (100 ETDRScharts)
Completed No significanteffect56
NCT00000117
August 2006ndashJuly 2011 Erythropoietin 33000 units IV for3 d vs placebo
10 d RNFL thickness at 4 8and 16 wks
Completed Significantly lessRNFL thinning at 16wk57
NCT00355095
September 2006ndashMay2011
Simvastatin 80 mg QD PO vsplacebo
4 wk Contrast sensitivity at3 mo
Completedc No significanteffect58
NCT00261326
March 2008ndashJanuary2011
Atacicept 150 mg SC weekly vsplacebo
Not specified RNFL thickness up to48 wks
Terminated None available NCT00624468
February 2009ndashFebruary2011
Glatiramer acetate 20 mg SC QD vsplacebo
Not specified RNFL thickness at 6 mo Completed None available NCT00856635
February 2010ndashJanuary2013
Minocycline 100 mg BID vs notreatment
30 d RNFL thickness every3 mo for 9 mo
Terminated None available NCT01073813
May 2010ndashMarch 2013 Visual reconstitution therapy vssaccadic eye movement training
60ndash80 d or 12mo
Visual field at 6 mo Completed None available NCT01274702
May 2011ndashDecember2013
Dalfampridine 10mg BID vs placebo $12 mo Contrast sensitivity(5 ETDRS charts)
Completed None available NCT01337986
July 2011ndashDecember2012
Vitamin D 50000 unitswk vsvitamin withheld
Not applicable(preventionstudy)
RNFL thickness at10ndash32 d after opticneuritis
Unknown None available NCT01465893
November 2011ndashAugust2014
Phenytoin 15 mgkgd for 3 d then4 mgkgd for 13 wks vs placebo
14 d RNFL thickness at6 mo
Completedd Significantly lessRNFL thinning at6 mod
NCT01451593
March 2012ndashSeptember2014
Oral prednisone 1250 mg vsmethylprednisolone 1000 mg IV for3 d each
14 d VEP latency Unknown None available NCT01524250
December 2012ndashOctober2014
BIIB033 (anti-LINGO-1) 100 mgkgIV every 4 wks vs placebo
28 d VEP latency Completed None available NCT01721161
February 2013ndashFebruary2015
Amiloride 10 mg QD vs placebo for5 mo
28 d RNFL thickness at 6 mo12 mo
Recruiting None available NCT01802489
July 2013ndashJune 2016 Fingolimod 05 mg QD vs interferonb-1b
30 d VEP latency Recruiting None available NCT01647880
August 2013ndashMay 2014 Fingolimod 05 mg QD vs placebo Not specified RNFL thickness at18 wks
Completed None available NCT01757691
October 2013ndashJanuary2016
MD1003 100 mg TID vs placebo Not specified High-contrast visualacuity (100 ETDRScharts)
Recruiting None available NCT02220244
March 2014ndashApril 2016 Amiloride hydrochlorothiazide100 mgd vs placebo
10 d RNFL thickness at24 wks
Recruiting None available NCT01879527
November 2014ndashDecember 2018
Erythropoietin 33000 units IV for3 d vs placebo
10 d RNFL thickness at 6 mo Recruiting None available NCT01962571
Abbreviations ETDRS5 Early Treatment Diabetic Retinopathy Study RNFL5 retinal nerve fiber layer SC5 subcutaneous VEP5 visual-evoked potentiala From ClinicalTrialsgov except where indicated otherwiseb The Optic Neuritis Treatment Trial included a 15-year follow-up periodc Based on published resultd Reported at American Academy of Neurology 2015 Annual Meeting April 18ndash25 Washington DC
8 Neurology Neuroimmunology amp Neuroinflammation
clear that enrollment goals were met Another phaseIIIII study is under way but study results are not yetavailable (table)
Based on promising results from animal studiesand small clinical studies IV immunoglobulin wasinvestigated in patients with one or more episodesof typical ON and irreversible loss of visual acuitybut was terminated early due to negative results56
(table) Since that time various investigational ther-apies have shown promise in early preclinical andclinical studies and a number of phase II and IIIstudies have been completed or are under way Forexample in a placebo-controlled study of IV eryth-ropoietin for 3 days as an add-on to methylpredni-sone in patients with a first episode of ON withinthe previous 10 days those treated with erythropoi-etin demonstrated reduced RNFL thinning lessdecrease in optic nerve diameter and shorter VEPlatency57 Although the mechanism by which eryth-ropoietin may exert these effects is poorly under-stood it may involve the neuroprotective effectsof this hormone during acute inflammation Inanother placebo-controlled study in patients withsymptom duration of 4 weeks and reduced con-trast sensitivity simvastatin (a hypercholesterolemiamedication) narrowly missed significance on theprimary efficacy outcome (contrast sensitivity)but improvements were noted for VEP latencyand amplitude58 However imbalances in random-ization and technical issues may have contributed tothe observed effects59 A study in ON testing possibleneuroprotective effects of phenytoin an anticonvul-sant has recently completed and another study testingeffects of amiloride hydrochlorothiazide a diuretic iscurrently underway Nevertheless it is an open ques-tion whether a neuroprotective agent can domore thandelay degeneration of axons if they remain chronicallydemyelinated Finally BIIB033 a fully-human anti-body to LINGO-1 an inhibitor of myelination andneuroaxonal growth has shown promise in preclinicaland early clinical testing60 and a phase II study in ONwas recently completed
CONCLUSIONS It is now clear that recovery fromON is frequently incomplete which adversely affectsthe QOL of patients In addition there remain con-siderable gaps with respect to understanding assess-ing and treating this disease to prevent long-termdeficits Nevertheless ongoing work holds promisefor all of these areas The application of newertechnologies continues to provide new insight intothe underlying disease processes and increasedappreciation of the injury that occurs followingON The development of these new tools mayincrease the ability to detect meaningful changes invision with therapeutic intervention and study
results suggest that timing is critical Developmentof guidelines to ensure consistency in theirapplication should also improve interpretation offindings and thereby improve the quality ofassessments Finally several therapies have shownpromise in preclinical and early clinical testingTherefore there is reason to be optimistic thatstrategies may soon be identified to improve theprognosis for patients with ON Given therelationship between ON and MS it seems likelythat any such developments for ON may havesubstantial implications for understanding assessingand treating MS as well
AUTHOR CONTRIBUTIONSAll authors participated in the conception of the article interpretation of
the data and revision of the manuscript and they approved the final ver-
sion Biogen provided funding for writing and editorial support in the
development of this paper and they reviewed and provided feedback
on the paper to the authors The authors had full editorial control of
the paper and provided their final approval of all content
ACKNOWLEDGMENTThe authors thank Dr Elena H Martinez-Lapiscina Dr Santiago Ortiz-
Perez and Dr Ana Tercero from the Center of Neuroimmunology Insti-
tute of Biomedical Research August Pi SunyerHospital Clinic Barcelona
University of Barcelona for creating figures 1 2B and 3 respectively
Lauren Nagy of Excel Scientific Solutions copyedited and styled the man-
uscript per journal requirements and this editorial support was funded by
Biogen
STUDY FUNDINGWriting and editorial support was funded by Biogen
DISCLOSURESL Galetta has received consulting honoraria and travel fundingspeaker
honoraria from Genzyme and Biogen and is on the editorial board for
Neurology and Journal of Neuro-Ophthalmology P Villoslada serves on
advisory boards for Novartis Roche Neurotec Pharma and Bionure
Pharma has consulted for Novartis Roche TFS Heidelberg Engineer-
ing MedImmune Diagna Biotec and Neurotec Pharma is an academic
editor for PLoSONE is on the editorial board for Neurology amp Therapy
and Current Treatment Options in Neurology has received research sup-
port from European Commission Genzyme Biogen Instituto Salud
Carlos III Marato TV3 Novartis and Roche and holds patents and
owns stocksstock options with Bionure Pharma N Levin receives
research support from National Multiple Sclerosis Foundation
K Shindler received research support from the FM Kirby Foundation
Harbor Therapeutics National Eye Institute National Multiple Sclerosis
Foundation Research to Prevent Blindness Sirtris Pharmaceuticals
ITMAT and Stemnion Inc has received speaker honoraria from Med-
ical College of Wisconsin and Temple University is an associate editor
for Frontiers in Neurology Neuro-Ophthalmology receives publishing roy-
alties from UpToDate and Oakstone Publishing and has consulted for
medical-legal cases H Ishikawa received research support from the NIH
E Parr is a full-time employee of Excel Scientific Solutions who were
funded by Biogen to provide editorial and writing support for this paper
D Cadavid is a full-time employee of Biogen owns stock options in
Biogen and has patent applications pending related to the use of drugs
that block LINGO-1 to treat demyelination in multiple sclerosis LJ
Balcer received consulting fees from Acorda Biogen Genzyme Novartis
Questcor and Vaccinexe serves on a clinical trial advisory board for
Biogen and serves on a scientific advisory board for Genzyme Go to
Neurologyorgnn for full disclosure forms
Received February 12 2015 Accepted in final form May 13 2015
Neurology Neuroimmunology amp Neuroinflammation 9
REFERENCES1 Toosy AT Mason DF Miller DH Optic neuritis Lancet
Neurol 20141383ndash99
2 Beck RW Cleary PA Anderson MM Jr et al Optic Neu-
ritis Study Group A randomized controlled trial of cor-
ticosteroids in the treatment of acute optic neuritis N
Engl J Med 1992326581ndash588
3 Cole SR Beck RW Moke PS Gal RL Long DT Optic
Neuritis Study Group The National Eye Institute Visual
Function Questionnaire experience of the ONTT Invest
Ophthalmol Vis Sci 2000411017ndash1021
4 Beck RW Cleary PA Backlund JC The course of visual
recovery after optic neuritis Experience of the Optic
Neuritis Treatment Trial Ophthalmology 1994101
1771ndash1778
5 Costello F Hodge W Pan YI Eggenberger E Coupland S
Kardon RH Tracking retinal nerve fiber layer loss after
optic neuritis a prospective study using optical coherence
tomography Mult Scler 200814893ndash905
6 Brusa A Jones SJ Plant GT Long-term remyelination
after optic neuritis a 2-year visual evoked potential and
psychophysical serial study Brain 2001124468ndash479
7 Malik MT Healy BC Benson LA et al Factors associated
with recovery from acute optic neuritis in patients with
multiple sclerosis Neurology 2014822173ndash2179
8 Raz N Dotan S Chokron S Ben-Hur T Levin N Demy-
elination affects temporal aspects of perception an optic
neuritis study Ann Neurol 201271531ndash538
9 Leat SJ Legge GE Bullimore MA What is low vision A re-
evaluation of definitions Optom Vis Sci 199976198ndash211
10 Martiacutenez-Lapiscina EH Ortiz-Peacuterez S Fraga-Pumar E et al
Colour vision impairment is associated with disease severity
in multiple sclerosis Mult Scler 2014201207ndash1216
11 Raz N Dotan S Benoliel T Chokron S Ben-Hur T
Levin N Sustained motion perception deficit following
optic neuritis behavioral and cortical evidence Neurology
2011762103ndash2111
12 Pineles SL Birch EE Talman LS et al One eye or two a
comparison of binocular and monocular low-contrast acu-
ity testing in multiple sclerosis Am J Ophthalmol 2011
152133ndash140
13 Gabriele ML Wollstein G Ishikawa H et al Optical
coherence tomography history current status and lab-
oratory work Invest Ophthalmol Vis Sci 201152
2425ndash2436
14 Henderson AP Altmann DR Trip AS et al A serial study
of retinal changes following optic neuritis with sample size
estimates for acute neuroprotection trials Brain 2010133
2592ndash2602
15 Petzold A de Boer JF Schippling S et al Optical coher-
ence tomography in multiple sclerosis a systematic review
and meta-analysis Lancet Neurol 20109921ndash932
16 Gabilondo I Martiacutenez-Lapiscina EH Fraga-Pumar E
et al Dynamics of retinal injury after acute optic neuritis
Ann Neurol 201577517ndash528
17 Huang-Link Y-M Al-Hawasi A Lindehammar H Acute
optic neuritis retinal ganglion cell loss precedes retinal
nerve fiber thinning Neurol Sci 201536617ndash620
18 Trip SA Schlottmann PG Jones SJ et al Retinal nerve
fiber layer axonal loss and visual dysfunction in optic neu-
ritis Ann Neurol 200558383ndash391
19 Henderson AP Altmann DR Trip SA et al Early factors
associated with axonal loss after optic neuritis Ann Neurol
201170955ndash963
20 Costello F Coupland S Hodge W et al Quantifying
axonal loss after optic neuritis with optical coherence
tomography Ann Neurol 200659963ndash969
21 Hood DC Anderson SC Wall M Kardon RH Structure
versus function in glaucoma an application of a linear
model Invest Ophthalmol Vis Sci 2007483662ndash3668
22 Balk LJ Steenwijk MD Tewarie P et al Bidirectional
trans-synaptic axonal degeneration in the visual pathway
in multiple sclerosis J Neurol Neurosurg Psychiatry 2014
86419ndash424
23 Gabilondo I Martiacutenez-Lapiscina EH Martiacutenez-Heras E
et al Trans-synaptic axonal degeneration in the visual path-
way in multiple sclerosis Ann Neurol 20147598ndash107
24 Alshowaeir D Yiannikas C Garrick R et al Latency of
multifocal visual evoked potentials in nonoptic neuritis eyes
of multiple sclerosis patients associated with optic radiation
lesions Invest Ophthalmol Vis Sci 2014553758ndash3764
25 Sakai RE Feller DJ Galetta KM Galetta SL Balcer LJ
Vision in multiple sclerosis the story structure-function cor-
relations and models for neuroprotection J Neuroophthalmol
201131362ndash373
26 Walter SD Ishikawa H Galetta KM et al Ganglion cell
loss in relation to visual disability in multiple sclerosis
Ophthalmology 20121191250ndash1257
27 Di Maggio G Santangelo R Guerrieri S et al Optical
coherence tomography and visual evoked potentials which
is more sensitive in multiple sclerosis Mult Scler 201420
1342ndash1347
28 Naismith RT Tutlam NT Xu J et al Optical coherence
tomography is less sensitive than visual evoked potentials
in optic neuritis Neurology 20097346ndash52
29 Araie M Test-retest variability in structural parameters
measured with glaucoma imaging devices Jpn J Ophthal-
mol 2013571ndash24
30 Watson GM Keltner JL Chin EK Harvey D Nguyen A
Park SS Comparison of retinal nerve fiber layer and cen-
tral macular thickness measurements among five different
optical coherence tomography instruments in patients with
multiple sclerosis and optic neuritis J Neuroophthalmol
201131110ndash116
31 Schippling S Balk L Costello F et al Quality control for
retinal OCT in multiple sclerosis validation of the
OSCAR-IB criteria Mult Scler 201521163ndash170
32 Rinalduzzi S Brusa A Jones SJ Variation of visual evoked
potential delay to stimulation of central nasal and tem-
poral regions of the macula in optic neuritis J Neurol
httpnnneurologyorgcgicollectionmultiple_sclerosisMultiple sclerosisfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2015 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
clear that enrollment goals were met Another phaseIIIII study is under way but study results are not yetavailable (table)
Based on promising results from animal studiesand small clinical studies IV immunoglobulin wasinvestigated in patients with one or more episodesof typical ON and irreversible loss of visual acuitybut was terminated early due to negative results56
(table) Since that time various investigational ther-apies have shown promise in early preclinical andclinical studies and a number of phase II and IIIstudies have been completed or are under way Forexample in a placebo-controlled study of IV eryth-ropoietin for 3 days as an add-on to methylpredni-sone in patients with a first episode of ON withinthe previous 10 days those treated with erythropoi-etin demonstrated reduced RNFL thinning lessdecrease in optic nerve diameter and shorter VEPlatency57 Although the mechanism by which eryth-ropoietin may exert these effects is poorly under-stood it may involve the neuroprotective effectsof this hormone during acute inflammation Inanother placebo-controlled study in patients withsymptom duration of 4 weeks and reduced con-trast sensitivity simvastatin (a hypercholesterolemiamedication) narrowly missed significance on theprimary efficacy outcome (contrast sensitivity)but improvements were noted for VEP latencyand amplitude58 However imbalances in random-ization and technical issues may have contributed tothe observed effects59 A study in ON testing possibleneuroprotective effects of phenytoin an anticonvul-sant has recently completed and another study testingeffects of amiloride hydrochlorothiazide a diuretic iscurrently underway Nevertheless it is an open ques-tion whether a neuroprotective agent can domore thandelay degeneration of axons if they remain chronicallydemyelinated Finally BIIB033 a fully-human anti-body to LINGO-1 an inhibitor of myelination andneuroaxonal growth has shown promise in preclinicaland early clinical testing60 and a phase II study in ONwas recently completed
CONCLUSIONS It is now clear that recovery fromON is frequently incomplete which adversely affectsthe QOL of patients In addition there remain con-siderable gaps with respect to understanding assess-ing and treating this disease to prevent long-termdeficits Nevertheless ongoing work holds promisefor all of these areas The application of newertechnologies continues to provide new insight intothe underlying disease processes and increasedappreciation of the injury that occurs followingON The development of these new tools mayincrease the ability to detect meaningful changes invision with therapeutic intervention and study
results suggest that timing is critical Developmentof guidelines to ensure consistency in theirapplication should also improve interpretation offindings and thereby improve the quality ofassessments Finally several therapies have shownpromise in preclinical and early clinical testingTherefore there is reason to be optimistic thatstrategies may soon be identified to improve theprognosis for patients with ON Given therelationship between ON and MS it seems likelythat any such developments for ON may havesubstantial implications for understanding assessingand treating MS as well
AUTHOR CONTRIBUTIONSAll authors participated in the conception of the article interpretation of
the data and revision of the manuscript and they approved the final ver-
sion Biogen provided funding for writing and editorial support in the
development of this paper and they reviewed and provided feedback
on the paper to the authors The authors had full editorial control of
the paper and provided their final approval of all content
ACKNOWLEDGMENTThe authors thank Dr Elena H Martinez-Lapiscina Dr Santiago Ortiz-
Perez and Dr Ana Tercero from the Center of Neuroimmunology Insti-
tute of Biomedical Research August Pi SunyerHospital Clinic Barcelona
University of Barcelona for creating figures 1 2B and 3 respectively
Lauren Nagy of Excel Scientific Solutions copyedited and styled the man-
uscript per journal requirements and this editorial support was funded by
Biogen
STUDY FUNDINGWriting and editorial support was funded by Biogen
DISCLOSURESL Galetta has received consulting honoraria and travel fundingspeaker
honoraria from Genzyme and Biogen and is on the editorial board for
Neurology and Journal of Neuro-Ophthalmology P Villoslada serves on
advisory boards for Novartis Roche Neurotec Pharma and Bionure
Pharma has consulted for Novartis Roche TFS Heidelberg Engineer-
ing MedImmune Diagna Biotec and Neurotec Pharma is an academic
editor for PLoSONE is on the editorial board for Neurology amp Therapy
and Current Treatment Options in Neurology has received research sup-
port from European Commission Genzyme Biogen Instituto Salud
Carlos III Marato TV3 Novartis and Roche and holds patents and
owns stocksstock options with Bionure Pharma N Levin receives
research support from National Multiple Sclerosis Foundation
K Shindler received research support from the FM Kirby Foundation
Harbor Therapeutics National Eye Institute National Multiple Sclerosis
Foundation Research to Prevent Blindness Sirtris Pharmaceuticals
ITMAT and Stemnion Inc has received speaker honoraria from Med-
ical College of Wisconsin and Temple University is an associate editor
for Frontiers in Neurology Neuro-Ophthalmology receives publishing roy-
alties from UpToDate and Oakstone Publishing and has consulted for
medical-legal cases H Ishikawa received research support from the NIH
E Parr is a full-time employee of Excel Scientific Solutions who were
funded by Biogen to provide editorial and writing support for this paper
D Cadavid is a full-time employee of Biogen owns stock options in
Biogen and has patent applications pending related to the use of drugs
that block LINGO-1 to treat demyelination in multiple sclerosis LJ
Balcer received consulting fees from Acorda Biogen Genzyme Novartis
Questcor and Vaccinexe serves on a clinical trial advisory board for
Biogen and serves on a scientific advisory board for Genzyme Go to
Neurologyorgnn for full disclosure forms
Received February 12 2015 Accepted in final form May 13 2015
Neurology Neuroimmunology amp Neuroinflammation 9
REFERENCES1 Toosy AT Mason DF Miller DH Optic neuritis Lancet
Neurol 20141383ndash99
2 Beck RW Cleary PA Anderson MM Jr et al Optic Neu-
ritis Study Group A randomized controlled trial of cor-
ticosteroids in the treatment of acute optic neuritis N
Engl J Med 1992326581ndash588
3 Cole SR Beck RW Moke PS Gal RL Long DT Optic
Neuritis Study Group The National Eye Institute Visual
Function Questionnaire experience of the ONTT Invest
Ophthalmol Vis Sci 2000411017ndash1021
4 Beck RW Cleary PA Backlund JC The course of visual
recovery after optic neuritis Experience of the Optic
Neuritis Treatment Trial Ophthalmology 1994101
1771ndash1778
5 Costello F Hodge W Pan YI Eggenberger E Coupland S
Kardon RH Tracking retinal nerve fiber layer loss after
optic neuritis a prospective study using optical coherence
tomography Mult Scler 200814893ndash905
6 Brusa A Jones SJ Plant GT Long-term remyelination
after optic neuritis a 2-year visual evoked potential and
psychophysical serial study Brain 2001124468ndash479
7 Malik MT Healy BC Benson LA et al Factors associated
with recovery from acute optic neuritis in patients with
multiple sclerosis Neurology 2014822173ndash2179
8 Raz N Dotan S Chokron S Ben-Hur T Levin N Demy-
elination affects temporal aspects of perception an optic
neuritis study Ann Neurol 201271531ndash538
9 Leat SJ Legge GE Bullimore MA What is low vision A re-
evaluation of definitions Optom Vis Sci 199976198ndash211
10 Martiacutenez-Lapiscina EH Ortiz-Peacuterez S Fraga-Pumar E et al
Colour vision impairment is associated with disease severity
in multiple sclerosis Mult Scler 2014201207ndash1216
11 Raz N Dotan S Benoliel T Chokron S Ben-Hur T
Levin N Sustained motion perception deficit following
optic neuritis behavioral and cortical evidence Neurology
2011762103ndash2111
12 Pineles SL Birch EE Talman LS et al One eye or two a
comparison of binocular and monocular low-contrast acu-
ity testing in multiple sclerosis Am J Ophthalmol 2011
152133ndash140
13 Gabriele ML Wollstein G Ishikawa H et al Optical
coherence tomography history current status and lab-
oratory work Invest Ophthalmol Vis Sci 201152
2425ndash2436
14 Henderson AP Altmann DR Trip AS et al A serial study
of retinal changes following optic neuritis with sample size
estimates for acute neuroprotection trials Brain 2010133
2592ndash2602
15 Petzold A de Boer JF Schippling S et al Optical coher-
ence tomography in multiple sclerosis a systematic review
and meta-analysis Lancet Neurol 20109921ndash932
16 Gabilondo I Martiacutenez-Lapiscina EH Fraga-Pumar E
et al Dynamics of retinal injury after acute optic neuritis
Ann Neurol 201577517ndash528
17 Huang-Link Y-M Al-Hawasi A Lindehammar H Acute
optic neuritis retinal ganglion cell loss precedes retinal
nerve fiber thinning Neurol Sci 201536617ndash620
18 Trip SA Schlottmann PG Jones SJ et al Retinal nerve
fiber layer axonal loss and visual dysfunction in optic neu-
ritis Ann Neurol 200558383ndash391
19 Henderson AP Altmann DR Trip SA et al Early factors
associated with axonal loss after optic neuritis Ann Neurol
201170955ndash963
20 Costello F Coupland S Hodge W et al Quantifying
axonal loss after optic neuritis with optical coherence
tomography Ann Neurol 200659963ndash969
21 Hood DC Anderson SC Wall M Kardon RH Structure
versus function in glaucoma an application of a linear
model Invest Ophthalmol Vis Sci 2007483662ndash3668
22 Balk LJ Steenwijk MD Tewarie P et al Bidirectional
trans-synaptic axonal degeneration in the visual pathway
in multiple sclerosis J Neurol Neurosurg Psychiatry 2014
86419ndash424
23 Gabilondo I Martiacutenez-Lapiscina EH Martiacutenez-Heras E
et al Trans-synaptic axonal degeneration in the visual path-
way in multiple sclerosis Ann Neurol 20147598ndash107
24 Alshowaeir D Yiannikas C Garrick R et al Latency of
multifocal visual evoked potentials in nonoptic neuritis eyes
of multiple sclerosis patients associated with optic radiation
lesions Invest Ophthalmol Vis Sci 2014553758ndash3764
25 Sakai RE Feller DJ Galetta KM Galetta SL Balcer LJ
Vision in multiple sclerosis the story structure-function cor-
relations and models for neuroprotection J Neuroophthalmol
201131362ndash373
26 Walter SD Ishikawa H Galetta KM et al Ganglion cell
loss in relation to visual disability in multiple sclerosis
Ophthalmology 20121191250ndash1257
27 Di Maggio G Santangelo R Guerrieri S et al Optical
coherence tomography and visual evoked potentials which
is more sensitive in multiple sclerosis Mult Scler 201420
1342ndash1347
28 Naismith RT Tutlam NT Xu J et al Optical coherence
tomography is less sensitive than visual evoked potentials
in optic neuritis Neurology 20097346ndash52
29 Araie M Test-retest variability in structural parameters
measured with glaucoma imaging devices Jpn J Ophthal-
mol 2013571ndash24
30 Watson GM Keltner JL Chin EK Harvey D Nguyen A
Park SS Comparison of retinal nerve fiber layer and cen-
tral macular thickness measurements among five different
optical coherence tomography instruments in patients with
multiple sclerosis and optic neuritis J Neuroophthalmol
201131110ndash116
31 Schippling S Balk L Costello F et al Quality control for
retinal OCT in multiple sclerosis validation of the
OSCAR-IB criteria Mult Scler 201521163ndash170
32 Rinalduzzi S Brusa A Jones SJ Variation of visual evoked
potential delay to stimulation of central nasal and tem-
poral regions of the macula in optic neuritis J Neurol
httpnnneurologyorgcgicollectionmultiple_sclerosisMultiple sclerosisfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2015 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
REFERENCES1 Toosy AT Mason DF Miller DH Optic neuritis Lancet
Neurol 20141383ndash99
2 Beck RW Cleary PA Anderson MM Jr et al Optic Neu-
ritis Study Group A randomized controlled trial of cor-
ticosteroids in the treatment of acute optic neuritis N
Engl J Med 1992326581ndash588
3 Cole SR Beck RW Moke PS Gal RL Long DT Optic
Neuritis Study Group The National Eye Institute Visual
Function Questionnaire experience of the ONTT Invest
Ophthalmol Vis Sci 2000411017ndash1021
4 Beck RW Cleary PA Backlund JC The course of visual
recovery after optic neuritis Experience of the Optic
Neuritis Treatment Trial Ophthalmology 1994101
1771ndash1778
5 Costello F Hodge W Pan YI Eggenberger E Coupland S
Kardon RH Tracking retinal nerve fiber layer loss after
optic neuritis a prospective study using optical coherence
tomography Mult Scler 200814893ndash905
6 Brusa A Jones SJ Plant GT Long-term remyelination
after optic neuritis a 2-year visual evoked potential and
psychophysical serial study Brain 2001124468ndash479
7 Malik MT Healy BC Benson LA et al Factors associated
with recovery from acute optic neuritis in patients with
multiple sclerosis Neurology 2014822173ndash2179
8 Raz N Dotan S Chokron S Ben-Hur T Levin N Demy-
elination affects temporal aspects of perception an optic
neuritis study Ann Neurol 201271531ndash538
9 Leat SJ Legge GE Bullimore MA What is low vision A re-
evaluation of definitions Optom Vis Sci 199976198ndash211
10 Martiacutenez-Lapiscina EH Ortiz-Peacuterez S Fraga-Pumar E et al
Colour vision impairment is associated with disease severity
in multiple sclerosis Mult Scler 2014201207ndash1216
11 Raz N Dotan S Benoliel T Chokron S Ben-Hur T
Levin N Sustained motion perception deficit following
optic neuritis behavioral and cortical evidence Neurology
2011762103ndash2111
12 Pineles SL Birch EE Talman LS et al One eye or two a
comparison of binocular and monocular low-contrast acu-
ity testing in multiple sclerosis Am J Ophthalmol 2011
152133ndash140
13 Gabriele ML Wollstein G Ishikawa H et al Optical
coherence tomography history current status and lab-
oratory work Invest Ophthalmol Vis Sci 201152
2425ndash2436
14 Henderson AP Altmann DR Trip AS et al A serial study
of retinal changes following optic neuritis with sample size
estimates for acute neuroprotection trials Brain 2010133
2592ndash2602
15 Petzold A de Boer JF Schippling S et al Optical coher-
ence tomography in multiple sclerosis a systematic review
and meta-analysis Lancet Neurol 20109921ndash932
16 Gabilondo I Martiacutenez-Lapiscina EH Fraga-Pumar E
et al Dynamics of retinal injury after acute optic neuritis
Ann Neurol 201577517ndash528
17 Huang-Link Y-M Al-Hawasi A Lindehammar H Acute
optic neuritis retinal ganglion cell loss precedes retinal
nerve fiber thinning Neurol Sci 201536617ndash620
18 Trip SA Schlottmann PG Jones SJ et al Retinal nerve
fiber layer axonal loss and visual dysfunction in optic neu-
ritis Ann Neurol 200558383ndash391
19 Henderson AP Altmann DR Trip SA et al Early factors
associated with axonal loss after optic neuritis Ann Neurol
201170955ndash963
20 Costello F Coupland S Hodge W et al Quantifying
axonal loss after optic neuritis with optical coherence
tomography Ann Neurol 200659963ndash969
21 Hood DC Anderson SC Wall M Kardon RH Structure
versus function in glaucoma an application of a linear
model Invest Ophthalmol Vis Sci 2007483662ndash3668
22 Balk LJ Steenwijk MD Tewarie P et al Bidirectional
trans-synaptic axonal degeneration in the visual pathway
in multiple sclerosis J Neurol Neurosurg Psychiatry 2014
86419ndash424
23 Gabilondo I Martiacutenez-Lapiscina EH Martiacutenez-Heras E
et al Trans-synaptic axonal degeneration in the visual path-
way in multiple sclerosis Ann Neurol 20147598ndash107
24 Alshowaeir D Yiannikas C Garrick R et al Latency of
multifocal visual evoked potentials in nonoptic neuritis eyes
of multiple sclerosis patients associated with optic radiation
lesions Invest Ophthalmol Vis Sci 2014553758ndash3764
25 Sakai RE Feller DJ Galetta KM Galetta SL Balcer LJ
Vision in multiple sclerosis the story structure-function cor-
relations and models for neuroprotection J Neuroophthalmol
201131362ndash373
26 Walter SD Ishikawa H Galetta KM et al Ganglion cell
loss in relation to visual disability in multiple sclerosis
Ophthalmology 20121191250ndash1257
27 Di Maggio G Santangelo R Guerrieri S et al Optical
coherence tomography and visual evoked potentials which
is more sensitive in multiple sclerosis Mult Scler 201420
1342ndash1347
28 Naismith RT Tutlam NT Xu J et al Optical coherence
tomography is less sensitive than visual evoked potentials
in optic neuritis Neurology 20097346ndash52
29 Araie M Test-retest variability in structural parameters
measured with glaucoma imaging devices Jpn J Ophthal-
mol 2013571ndash24
30 Watson GM Keltner JL Chin EK Harvey D Nguyen A
Park SS Comparison of retinal nerve fiber layer and cen-
tral macular thickness measurements among five different
optical coherence tomography instruments in patients with
multiple sclerosis and optic neuritis J Neuroophthalmol
201131110ndash116
31 Schippling S Balk L Costello F et al Quality control for
retinal OCT in multiple sclerosis validation of the
OSCAR-IB criteria Mult Scler 201521163ndash170
32 Rinalduzzi S Brusa A Jones SJ Variation of visual evoked
potential delay to stimulation of central nasal and tem-
poral regions of the macula in optic neuritis J Neurol
httpnnneurologyorgcgicollectionmultiple_sclerosisMultiple sclerosisfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2015 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
38 Yang EB Hood DC Rodarte C Zhang X Odel JG
Behrens MM Improvement in conduction velocity after
optic neuritis measured with the multifocal VEP Invest
Ophthalmol Vis Sci 200748692ndash698
39 Cadavid D Levin N Costello F Rahilly A Klistorner A
Technical feasibility of implementing multifocal VEP for
httpnnneurologyorgcgicollectionmultiple_sclerosisMultiple sclerosisfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2015 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
DOI 101212NXI000000000000013520152 Neurol Neuroimmunol Neuroinflamm
Steven L Galetta Pablo Villoslada Netta Levin et al Acute optic neuritis Unmet clinical needs and model for new therapies
This information is current as of July 23 2015
ServicesUpdated Information amp
httpnnneurologyorgcontent24e135fullhtmlincluding high resolution figures can be found at
httpnnneurologyorgcgicollectionmultiple_sclerosisMultiple sclerosisfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
2015 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm