views & reviews acute optic neuritis · acute optic neuritis unmet clinical needs and model for...

VIEWS amp REVIEWS

Steven L Galetta MDPablo Villoslada MDNetta Levin MD PhDKenneth Shindler MD

PhDHiroshi Ishikawa MDEdward Parr PhDDiego Cadavid MDLaura J Balcer MD

MSCE

Correspondence toDr Balcerlaurabalcernyumcorg

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

choriocapillaris layer GCL 5 ganglion cell layer ILM 5 inner limiting membrane INL 5 inner nuclear layer IPL 5 innerplexiform layer OLM 5 outer limiting membrane ONL 5 outer nuclear layer OPL 5 outer plexiform layer PL 5 photore-ceptor layer RNFL 5 retinal nerve fiber layer RPE 5 retinal pigment epithelium


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


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


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


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


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


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


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


October 2013ndashJanuary2016

MD1003 100 mg TID vs placebo Not specified High-contrast visualacuity (100 ETDRScharts)


March 2014ndashApril 2016 Amiloride hydrochlorothiazide100 mgd vs placebo

10 d RNFL thickness at24 wks


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


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


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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

Neurosurg Psychiatry 20017028ndash35

33 Hood DC Odel JG Winn BJ The multifocal visual

evoked potential J Neuroophthalmol 200323279ndash289

34 Jenkins T Ciccarelli O Toosy A et al Dissecting structure-

function interactions in acute optic neuritis to investigate

neuroplasticity Hum Brain Mapp 201031276ndash286

35 Klistorner A Arvind H Garrick R Graham SL

Paine M Yiannikas C Interrelationship of optical coher-

ence tomography and multifocal visual-evoked potentials

after optic neuritis Invest Ophthalmol Vis Sci 201051

2770ndash2777

36 Klistorner A Arvind H Nguyen T et al Axonal loss and

myelin in early ON loss in postacute optic neuritis Ann


37 Klistorner A Arvind H Nguyen T et al Multifocal VEP

and OCT in optic neuritis a topographical study of the

structure-function relationship Doc Ophthalmol 2009

118129ndash137


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


39 Cadavid D Levin N Costello F Rahilly A Klistorner A

Technical feasibility of implementing multifocal VEP for

multicenter clinical trials Neurology 201380P02245

40 Grossman RI Magnetization transfer in multiple sclerosis

Ann Neurol 199436(suppl)S97ndashS99

41 Le Bihan D Mangin JF Poupon C et al Diffusion tensor

imaging concepts and applications J Magn Reson Imag-

ing 200113534ndash546

42 Melzi L Rocca MA Marzoli SB et al A longitudinal

conventional and magnetization transfer magnetic reso-

nance imaging study of optic neuritis Mult Scler 2007

13265ndash268

43 Wang Y van der Walt A Paine M et al Optic nerve

magnetisation transfer ratio after acute optic neuritis predicts

axonal and visual outcomes PLoS One 20127e52291

44 Naismith RT Xu J Tutlam NT et al Disability in optic

neuritis correlates with diffusion tensor-derived directional

diffusivities Neurology 200972589ndash594

45 Naismith RT Xu J Tutlam NT et al Diffusion tensor

imaging in acute optic neuropathies predictor of clinical

outcomes Arch Neurol 20126965ndash71

46 Xu J Sun SW Naismith RT Snyder AZ Cross AH

Song SK Assessing optic nerve pathology with diffusion

MRI from mouse to human NMR Biomed 200821

928ndash940

47 Heesen C Boumlhm J Reich C Kasper J Goebel M

Gold SM Patient perception of bodily functions in mul-

tiple sclerosis gait and visual function are the most valu-

able Mult Scler 200814988ndash991

48 Schinzel J Zimmermann H Paul F et al Relations of low

contrast visual acuity quality of life and multiple sclerosis

functional composite a cross-sectional analysis BMC

Neurol 20141431

49 Mowry EM Loguidice MJ Daniels AB et al Vision

related quality of life in multiple sclerosis correlation with

new measures of low and high contrast letter acuity

J Neurol Neurosurg Psychiatry 200980767ndash772

50 Raz N Hallak M Ben-Hur T Levin N Dynamic visual

tests to identify and quantify visual damage and repair

following demyelination in optic neuritis patients J Vis

Exp Epub 2014 Apr 14 doi 10379151107

51 Raphael BA Galetta KM Jacobs DA et al Validation and

test characteristics of a 10-item neuro-ophthalmic supple-

ment to the NEI-VFQ-25 Am J Ophthalmol 2006142

1026ndash1035

52 Nolan RC Galetta KM Wilson JA et al Quality of life

after optic neuritis in MS new data for the 10-item neuro-

ophthalmic supplement to the NEI-VFQ-25 Poster pre-

sented at 40th Annual Meeting of the North American

Neuro-Ophthalmology Society March 1ndash6 2014 Rio

Grande Puerto Rico

53 Suumlhs KW Hein K Pehlke JR Kaumlsmann-Kellner B

Diem R Retinal nerve fibre layer thinning in patients with

clinically isolated optic neuritis and early treatment with

interferon-beta PLoS One 20127e51645

54 Balcer LJ Galetta SL Calabresi PA et al Natalizumab

reduces visual loss in patients with relapsing multiple scle-

rosis Neurology 2007681299ndash1304

55 Meuth SG Bittner S Seiler C Gobel K Wiendl H Na-

talizumab restores evoked potential abnormalities in pa-

tients with relapsing-remitting multiple sclerosis Mult

Scler 201117198ndash203

56 Noseworthy JH OrsquoBrien PC Petterson TM et al A random-

ized trial of intravenous immunoglobulin in inflammatory

demyelinating optic neuritis Neurology 2001561514ndash1522

57 Suumlhs KW Hein K Saumlttler MB et al A randomized

double-blind phase 2 study of erythropoietin in optic

neuritis Ann Neurol 201272199ndash210

58 Tsakiri A Kallenbach K Fugloslash D Wanscher B

Larsson H Frederiksen J Simvastatin improves final visual

outcome in acute optic neuritis a randomized study Mult


59 Johnson MA Cadavid D Simvastatin in acute optic neu-

ritis Mult Scler 2012181657 author reply 1658

60 Tran JQ Rana J Barkhof F et al Randomized phase I trials

of the safetytolerability of anti-LINGO-1 monoclonal anti-

body BIIB033 Neurol Neuroimmunol Neuroinflamm

20141e18 doi 101212NXI0000000000000018


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

References httpnnneurologyorgcontent24e135fullhtmlref-list-1

This article cites 57 articles 8 of which you can access for free at

Subspecialty Collections

httpnnneurologyorgcgicollectionvisual_lossVisual loss

httpnnneurologyorgcgicollectionvisual_fieldsVisual fields

httpnnneurologyorgcgicollectionoptic_neuritisOptic neuritis see Neuro-ophthalmologyOptic Nerve

httpnnneurologyorgcgicollectionoptic_nerveOptic nerve

httpnnneurologyorgcgicollectionmultiple_sclerosisMultiple sclerosisfollowing collection(s) This article along with others on similar topics appears in the

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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

























































NCT00000146





NCT00000117




NCT00355095





NCT00261326













60ndash80 d or 12mo














NCT01451593











































Biogen














































1771ndash1778






















2011762103ndash2111




152133ndash140




2425ndash2436




2592ndash2602















201170955ndash963










86419ndash424











201131362ndash373







1342ndash1347






mol 2013571ndash24






201131110ndash116

















2770ndash2777







118129ndash137













ing 200113534ndash546




13265ndash268













928ndash940








Neurol 20141431








Exp Epub 2014 Apr 14 doi 10379151107




1026ndash1035






Grande Puerto Rico



























20141e18 doi 101212NXI0000000000000018

















Reprints



























































NCT00000146





NCT00000117




NCT00355095





NCT00261326













60ndash80 d or 12mo














NCT01451593











































Biogen














































1771ndash1778






















2011762103ndash2111




152133ndash140




2425ndash2436




2592ndash2602















201170955ndash963










86419ndash424











201131362ndash373







1342ndash1347






mol 2013571ndash24






201131110ndash116

















2770ndash2777







118129ndash137













ing 200113534ndash546




13265ndash268













928ndash940








Neurol 20141431








Exp Epub 2014 Apr 14 doi 10379151107




1026ndash1035






Grande Puerto Rico



























20141e18 doi 101212NXI0000000000000018

















Reprints





















Biogen














































1771ndash1778






















2011762103ndash2111




152133ndash140




2425ndash2436




2592ndash2602















201170955ndash963










86419ndash424











201131362ndash373







1342ndash1347






mol 2013571ndash24






201131110ndash116

















2770ndash2777







118129ndash137













ing 200113534ndash546




13265ndash268













928ndash940








Neurol 20141431








Exp Epub 2014 Apr 14 doi 10379151107




1026ndash1035






Grande Puerto Rico



























20141e18 doi 101212NXI0000000000000018

















Reprints

















1771ndash1778






















2011762103ndash2111




152133ndash140




2425ndash2436




2592ndash2602















201170955ndash963










86419ndash424











201131362ndash373







1342ndash1347






mol 2013571ndash24






201131110ndash116

















2770ndash2777







118129ndash137













ing 200113534ndash546




13265ndash268













928ndash940








Neurol 20141431








Exp Epub 2014 Apr 14 doi 10379151107




1026ndash1035






Grande Puerto Rico



























20141e18 doi 101212NXI0000000000000018

















Reprints















ing 200113534ndash546




13265ndash268













928ndash940








Neurol 20141431








Exp Epub 2014 Apr 14 doi 10379151107




1026ndash1035






Grande Puerto Rico



























20141e18 doi 101212NXI0000000000000018

















Reprints



















Reprints




views & reviews acute optic neuritis · acute optic neuritis unmet clinical needs and model for...

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