doi:10.

1093/brain/awu335 BRAIN 2015: 138; 11–27 | 11

REVIEW ARTICLE
Vision and vision-related outcome measures
in multiple sclerosis
Laura J. Balcer,1 David H. Miller,2 Stephen C. Reingold3 and Jeffrey A. Cohen4

Visual impairment is a key manifestation of multiple sclerosis. Acute optic neuritis is a common, often presenting manifestation,
but visual deficits and structural loss of retinal axonal and neuronal integrity can occur even without a history of optic neuritis.
Interest in vision in multiple sclerosis is growing, partially in response to the development of sensitive visual function tests,
structural markers such as optical coherence tomography and magnetic resonance imaging, and quality of life measures that
give clinical meaning to the structure-function correlations that are unique to the afferent visual pathway. Abnormal eye move-
ments also are common in multiple sclerosis, but quantitative assessment methods that can be applied in practice and clinical trials
are not readily available. We summarize here a comprehensive literature search and the discussion at a recent international meeting
of investigators involved in the development and study of visual outcomes in multiple sclerosis, which had, as its overriding goals,

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to review the state of the field and identify areas for future research. We review data and principles to help us understand the
importance of vision as a model for outcomes assessment in clinical practice and therapeutic trials in multiple sclerosis.

1 Departments of Neurology, Ophthalmology and Population Health, New York University School of Medicine, NY 10016, USA
2 Queen Square MS Centre, UCL Institute of Neurology, London, WC1N 3BG, UK
3 Scientific and Clinical Review Associates, LLC, CT 06068, USA
4 Neurological Institute, Cleveland Clinic, OH 44195, USA
Correspondence to: Jeffrey A. Cohen, M.D.,
Mellen Centre for MS Treatment and Research,
Neurological Institute, Cleveland Clinic, 9500 Euclid Avenue,
Cleveland, OH 44195, USA
E-mail: [email protected]

Keywords: multiple sclerosis; optic neuritis; vision; neuro-ophthalmology; clinical trials methodology
Abbreviations: EDSS = Expanded Disability Status Scale; GCL = ganglion cell layer; HCVA = high contrast visual acuity;
IPL = inner plexiform layer; LCLA = low-contrast letter acuity; MSFC = Multiple Sclerosis Functional Composite; OCT = optical
coherence tomography; RNFL = retinal nerve fibre layer; VEP = visual-evoked potential

coherence tomography (OCT). Together, these factors

Introduction have led to rapid accumulation of knowledge about
Historically, multiple sclerosis clinical trials have lacked visual impairment in optic neuritis and multiple sclerosis.
sensitive, vision-specific outcome measures. Low-contrast The additional availability of MRI to provide further
letter acuity (LCLA) has emerged as the leading candidate structural information and electrophysiological measures
to measure visual impairment in multiple sclerosis. It cor- [visual-evoked potentials (VEPs) and electroretinography]
relates with vision-specific quality of life measures, provid- make the afferent visual pathway a useful model system
ing information on clinical meaningfulness, and with the to elucidate inflammatory and neurodegenerative mechan-
structural integrity of the retina measured by optical isms in the CNS and to test novel agents for

Received September 10, 2014. Revised October 14, 2014. Accepted October 29, 2014. Advance Access publication November 29, 2014
ß The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits
non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected]
12 | BRAIN 2015: 138; 11–27 L. J. Balcer et al.

neuroprotection and repair in multiple sclerosis (Frohman Structural measures assessed by OCT, retinal nerve fibre
et al., 2008a, b). layer (RNFL) thickness (Parisi et al., 1999; Trip et al.,
An international group of over 60 investigators in mul- 2005; Fisher et al., 2006; Sepulcre et al., 2007; Petzold
tiple sclerosis, neuro-ophthalmology, clinical trial design, et al., 2010; Saidha et al., 2013), macular volume (Trip
and evaluation of clinical outcome measures from Europe, et al., 2005; Burkholder et al., 2009), and retinal ganglion
North America, Asia, and Australia met on 21–23 cell/inner plexiform layer (GCL + IPL) thickness (Chen and
November 2013 in Dublin, Ireland (see Supplementary ma- Gordon, 2005; Graves and Balcer, 2010; Saidha et al.,
terial for a list of attendees). This meeting was convened by 2011; Sakai et al., 2011; Walter et al., 2012; Costello,
the International Advisory Committee on Clinical Trials in 2013; Oberwahrenbrock et al., 2013) are affected in mul-
Multiple Sclerosis and sponsored by the European tiple sclerosis. Changes in optic nerve diffusion tensor ima-
Committee on Treatment and Research in Multiple ging and other MRI measures are associated with multiple
Sclerosis (ECTRIMS) and the US National Multiple sclerosis-related visual dysfunction (Smith et al., 2011;
Sclerosis Society. Overriding goals were to review the Naismith et al., 2012). Visual manifestations in multiple
state of the field of vision in multiple sclerosis and to iden- sclerosis also may be captured by VEPs (Diem et al.,
tify areas for future research. The discussions focused on 2003), electroretinography (Rodriguez-Mena et al., 2013),
evaluating visual manifestations in multiple sclerosis and and electrophysiological recordings of eye movements
their impact on those with the disease, providing informa- (Tilikete et al., 2011).
tion to physicians for incorporating vision assessment into Visual manifestations occur in the setting of acute optic
multiple sclerosis clinical practice, developing consensus on neuritis, but may be present without a history of acute
the design and administrative structure of multicentre mul- optic neuritis. As recovery following acute optic neuritis
tiple sclerosis clinical trials incorporating visual outcomes, often is incomplete, with residual deficits in low-contrast
and identifying priorities for vision research in multiple vision, colour vision, vision-specific quality of life, and
sclerosis. sometimes high-contrast visual acuity (HCVA) (Cole
This review is based on discussions at that meeting and a et al., 2000; Optic Neuritis Study Group, 2004, 2008b),

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comprehensive search of the literature (PubMed search of more effective treatment of optic neuritis is itself an area
English language publications, using search terms ‘vision’, of unmet need in multiple sclerosis therapeutics.
‘visual outcomes’, ‘specific visual measures’, and ‘multiple
sclerosis’). We summarize the evolution of the role of vision
assessment in multiple sclerosis and provide principles that
help us understand the importance of vision as a model for Afferent visual manifesta-
outcomes assessment in the next generation of therapeutic
trials.
tions in optic neuritis and
multiple sclerosis
Overview Optic neuritis associated with
Inflammatory, demyelinating, and neurodegenerative path-
multiple sclerosis
ology in multiple sclerosis affects both afferent and efferent In adults, optic neuritis typically is unilateral, with visual
visual function. The incidence of optic neuritis in Europe loss evolving over several days, reaching a nadir within 2
and North America has been estimated at 5 cases per 100 weeks, and frequently associated with peri-orbital pain exa-
000 person-years and may be increasing (Martinez- cerbated by eye movements (Toosy et al., 2014). Reduction
Lapiscina et al., 2014). About 20% of patients with mul- in HCVA ranges from minimal to severe, although com-
tiple sclerosis present with optic neuritis (Costello, 2013). plete loss (no light perception) is uncommon. In addition to
One study estimated that one-third have persistent visual decreased visual acuity resulting from central depression of
symptoms (Jasse et al., 2013), but the proportion may be the visual field, examination characteristically demonstrates
higher. Resulting impairment and disability lead to reduc- a relative afferent pupillary defect in the affected eye or, in
tions in vision-related quality of life (Mowry et al., 2009; the case of bilateral optic neuritis, the more severely af-
Garcia-Martin et al., 2013; Salter et al., 2013). The 25-Item fected eye. Typically, colour vision and LCLA are more
National Eye Institute Visual Functioning Questionnaire severely affected than is HCVA. In two-thirds of adult pa-
(NEI-VFQ-25) and a 10-Item Neuro-Ophthalmic tients with optic neuritis, the optic disc appears normal on
Supplement capture the most common symptoms, which direct ophthalmoscopy during the acute phase; however,
include decreases in visual acuity and contrast sensitivity OCT reveals that many of these affected eyes have subclin-
(Balcer and Frohman, 2010), defects in binocular vision, ical disc oedema (Kupersmith et al., 2012). When visible,
visual field abnormalities (Nakajima et al., 2010), reduced optic disc swelling typically is mild, without evidence of
colour vision (Villoslada et al., 2012), blurred vision and haemorrhages or macular exudates. Such atypical findings
diplopia. indicate low risk for subsequent development of clinically
Assessing vision in multiple sclerosis BRAIN 2015: 138; 11–27 | 13

definite multiple sclerosis, especially if the brain MRI is synchronicity of input and, thereby, aid binocular vision.
normal (Optic Neuritis Study Group, 2004, 2008a, b). Binocular inhibition, the reduction in binocular vision com-
Improvement of vision after acute optic neuritis typically pared to the better eye alone, has been observed in patients
begins within 1 month following onset of visual symptoms. with multiple sclerosis and a history of acute unilateral
While patients with optic neuritis often are said to have optic neuritis (Pineles et al., 2011).
‘good recovery,’ with 95% of eyes achieving 20/40 or Abnormalities of the retinal layers other than the RNFL
better HCVA, more sensitive measures indicate that visual have been observed in post-mortem specimens from pa-
recovery often is incomplete. Most patients have persistent tients with multiple sclerosis (Green et al., 2010), where
deficits in vision-related quality of life 5–8 years later (Cole 79% of eyes exhibited ganglion cell loss and 40%
et al., 2000), likely related to the substantial thinning of showed amacrine and bipolar cell loss in the inner nuclear
RNFL and GCL + IPL detectable by OCT. The median loss layer. These findings have been corroborated in vivo by
of peripapillary RNFL is 20–40%, with most thinning OCT, demonstrating thinning of the GCL + IPL, and asso-
occurring by 3 months and the full extent by 6 months ciated with reductions in visual function and vision-specific
(Costello et al., 2006, 2008; Henderson et al., 2010). The quality of life (Syc et al., 2012; Walter et al., 2012). These
10–15% of patients with severe persistent visual deficits retinal findings demonstrated by OCT also correlate with
tend to have more severe RNFL loss (Costello et al., 2012). more general clinical and imaging measures of multiple
Although acute optic neuritis is often treated with a short sclerosis disease activity and severity (Ratchford et al.,
course of high-dose intravenous methylprednisolone, which 2013; Saidha et al., 2013).
may speed visual recovery (Beck et al., 1992), there are no About 5% of patients with early multiple sclerosis have
treatments that improve visual outcomes in general. Two evidence of microcystic macular oedema or thickening of
small, uncontrolled studies of patients with optic neuritis the inner nuclear layer on OCT (Gelfand et al., 2012;
and poor vision in spite of steroid therapy reported visual Saidha et al., 2012). Microcystic macular oedema and
improvement in 70% of cases following a course of plasma inner nuclear layer thickening also occur in other inflam-
exchange (Ruprecht et al., 2004; Roesner et al., 2012). matory disorders associated with optic neuritis (Kaufhold

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Conflicting outcomes were reported in two trials investigat- et al., 2013) and do not appear merely to be due to vitre-
ing intravenous immunoglobulin for optic neuritis with ous traction (Brandt et al., 2014). In multiple sclerosis, the
poor visual recovery (Noseworthy et al., 2001; Tselis presence of microcystic macular oedema and inner nuclear
et al., 2008). This unmet need for treatment of optic neur- layer thickening are associated with increased inflammatory
itis itself, the wide range of available functional measures, disease activity, including gadolinium-enhancing lesions
and the structure-function correlations afforded by OCT and new T2 lesions on brain MRI (Saidha et al., 2012).
make acute optic neuritis an attractive model system to Because the retinal layers do not contain myelin, these ob-
test new therapies for neuroprotection and repair in mul- servations suggest the inflammatory process in multiple
tiple sclerosis. sclerosis is not limited to myelinated CNS structures.
However, the occurrence of microcystic macular oedema
in non-inflammatory optic neuropathies (Burggraaff et al.,
Retinal findings and other afferent 2014) indicates other mechanisms also may be involved.
visual manifestations of multiple Approximately 10% of patients with multiple sclerosis
have predominantly macular thinning and relative preser-
sclerosis vation of other retinal layers on OCT (Saidha et al., 2011;
Some patients with previous optic neuritis or multiple scler- Winges et al., 2013). Associated symptoms include photo-
osis experience transient visual blurring associated with in- phobia, excessive glare, visual fading, and photopsias,
crease in body temperature with exercise, a hot bath, or which can occur with optic neuritis but are not typical.
fever—so-called Uhthoff phenomenon (Fraser et al., 2012). In one study, macular thinning was associated with a
This symptom is caused by a temporary impairment of more rapidly disabling form of multiple sclerosis and
conduction by demyelinated axons in the afferent visual hypothesized to reflect a primary neurodegenerative process
pathway. A similar phenomenon can affect other sensory (Saidha et al., 2011). These findings, however, were not
and motor pathways. reproduced in another series (Brandt et al., 2011).
Despite recovery of static measures of visual function, Approximately 10% of patients with multiple sclerosis
there may be impaired motion perception following optic have retinal periphlebitis, the presence of which is asso-
neuritis—clinically known as the Pulfrich phenomenon. ciated with increased disease activity (Sepulcre et al.,
This symptom has been related to a sustained deficit in 2007; Ortiz-Perez et al., 2013). Multiple sclerosis is asso-
functional MRI during tasks that require motion perception ciated with uveitis or pars planitis in up to 15–20% of
(Raz et al., 2011). Development of a delayed latency VEP cases (Lightman et al., 1987; Biousse et al., 1999;
response in the clinically unaffected fellow eye following Donaldson et al., 2007). These intraocular inflammatory
optic neuritis is associated with improvement in time- conditions should be considered when chronic pain and
constrained binocular perception (Raz et al., 2013), sug- photophobia are present. Non-inflammatory visual loss in
gesting an adaptive cortical response to improve multiple sclerosis may be a manifestation of comorbid
14 | BRAIN 2015: 138; 11–27 L. J. Balcer et al.

ocular disease. In the NARCOMS registry, a large-scale Functional outcomes: high- and
questionnaire study of people in North America with mul-
tiple sclerosis, comorbid conditions, including refractive low-contrast visual acuity
error, cataracts, strabismus, and glaucoma, were a The visual functional system component of the EDSS does
common cause of visual dysfunction and reduced visual not capture visual dysfunction optimally. This and other
quality of life (Salter et al., 2013). The relative frequency shortcomings of the EDSS were the main impetus for de-
of these comorbid conditions in patients with velopment of the Multiple Sclerosis Functional Composite
multiple sclerosis compared to the general population is (MSFC) as an alternative disability measure for multiple
uncertain. sclerosis clinical trials. However, the measures of vision
available in the clinical trial data sets used to develop the
MSFC were limited to non-standardized tests of HCVA
Efferent visual manifestations of (Rudick et al., 1996, 1997). In the evaluation of candidate
MSFC visual components in those data sets, Snellen-for-
multiple sclerosis matted HCVA did not change over time or demonstrate
Abnormalities of ocular motility are common in multiple concurrent changes with EDSS scores (Rudick et al.,
sclerosis and can lead to transient or persistent impairment 1997). Therefore, the initial version of the MSFC did not
independent of or in addition to afferent visual pathway include a vision test.
dysfunction. Efferent visual abnormalities are more Measures of low-contrast (grey- rather than black-on-
common in progressive than relapsing multiple sclerosis white) vision, tested by line gratings and letter charts in
and can be an indicator of posterior fossa lesions and multiple sclerosis, and by Pelli-Robson charts in the
worse neurologic prognosis. Visuomotor abnormalities North American Optic Neuritis Treatment Trial, were
most often are reported by patients as diplopia, oscillopsia, shown to be sensitive to visual impairment even among
and blurred or ‘confused’ vision. Abnormal eye movements patients with Snellen acuities of 20/20 or better
can be detected readily at the bedside but are not captured (Ashworth et al., 1989; Bodis-Wollner and Brannan,

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well by the standard multiple sclerosis disability rating 1997; Mowry et al., 2009; Balcer and Frohman, 2010;
scales such as the Expanded Disability Status Scale Bock et al., 2012; Costello, 2013; Garcia-Martin et al.,
(EDSS); more detailed quantitative characterization requires 2013; Jasse et al., 2013; Salter et al., 2013). In addition,
sophisticated eye movement recording and analysis. Fatigue measures of low-contrast vision predicted ‘real-world’
of adducting saccades in internuclear ophthalmoparesis in visual impairment of reading, facial recognition, and driv-
multiple sclerosis and improvement with dalfampridine ing (Leat et al., 1999). Binocular LCLA testing with Sloan
have been demonstrated using such technology (Serra letter charts (Balcer et al., 2000) (Fig. 1) was incorporated
et al., 2014). Interestingly, abnormalities of saccades ap- as an exploratory outcome in several Phase 3 trials, includ-
peared to be associated with generalized fatigue in patients ing the AFFIRM trial of natalizumab versus placebo for
with multiple sclerosis (Finke et al., 2012). relapsing-remitting multiple sclerosis (Table 1). Here,
The King-Devick Test, a brief rapid number-naming test LCLA demonstrated changes over time and treatment ef-
new to the multiple sclerosis field, is a potential quantita- fects manifested as reduced likelihood of sustained visual
tive bedside performance measure of efferent visual dys- loss (Balcer et al., 2007) and greater likelihood of sustained
function (Moster et al., 2014). This test takes 52 min to visual improvement (Balcer et al., 2012) in the active treat-
complete and is sensitive to dysfunction of saccadic and ment group. In contrast, HCVA did not detect sustained
other eye movements; time scores are higher (worse) visual loss or improvement over time, or differences be-
among patients with multiple sclerosis compared to dis- tween treatment groups, similar to the analyses of the
ease-free controls. Further studies of this and other efferent pooled data set used to develop the MSFC (Rudick et al.,
visual function tests in multiple sclerosis are needed to 1997). Based on these observations, LCLA shows promise
bring assessment of this aspect of vision to the level of as a vision-related outcome for multiple sclerosis clinical
afferent system investigation. trials and as an additional component test for the MSFC.
Technical factors that can affect LCLA assessment in-
clude optimal refraction of the study participant and lumi-
Measurement of vision in multiple nance of the testing environment. Similarly, there are
relative advantages and disadvantages of monocular
sclerosis trials versus binocular testing. Testing each eye individually
Ideally, visual measures used in multiple sclerosis clinical would be expected to be more sensitive to monocular def-
trials should be standardized, reliable, practical, tolerated icits and to relate to other monocular measures such as
by study participants, and applicable for both adult and OCT but is more time-consuming. Conversely, binocular
paediatric populations. Aspects include visual function, testing takes less time and is more analogous to visual func-
vision-specific quality of life, structural markers, and elec- tion in the natural environment, but potentially could mask
trophysiological tools. monocular deficits due to binocular summation.
Assessing vision in multiple sclerosis BRAIN 2015: 138; 11–27 | 15

Change in LCLA by seven letters was used in a longitudinal

study of vision in multiple sclerosis (Talman et al., 2010)
and as the criterion for confirmed improvement in the
AFFIRM clinical trial (Balcer et al., 2012). Further valid-
ation of the definition of clinically meaningful worsening
and improvement in vision is needed and must be accom-
panied by discussion with regulatory agencies.

Vision-specific quality of life and

patient-reported outcomes
Patient-reported outcomes related to visual function are im-
Figure 1 Low-contrast Sloan letter chart (Precision Vision). portant as, ultimately, the clinical relevance of measures of
These charts have a standardized format based on Early Treatment visual function, structure, and electrophysiology will be
Diabetic Retinopathy Study visual acuity charts, the standard used in
determined by how they relate to or predict measures of
ophthalmology clinical trials, and have several advantages over
vision-specific quality of life. Scores for the NEI-VFQ-25,
standard Snellen charts or near vision testing cards as traditionally
used in multiple sclerosis trials: (i) letters (Sloan letters) are de- the most widely used and validated measure of vision-spe-
signed to be equally detectable for normal observers; (ii) each line cific quality of life (Mangione et al., 2001), are reduced in
has an equal number of letters (five per line); (iii) spacing between patients with multiple sclerosis (Mowry et al., 2009). A 10-
letters and lines is proportional to the letter size; (iv) change in Item Neuro-Ophthalmic Supplement to the NEI-VFQ-25
visual acuity from one line to another occurs in equal logarithmic was designed using multiple sclerosis cohorts to capture
steps (change of three lines constitutes a doubling of the visual symptoms relevant to neurologic disease in a more sensitive
angle); and (v) visual acuity [for high-contrast (black letters on manner (Ma et al., 2002; Raphael et al., 2006). The Impact
white) chart] may be specified by Snellen notation for descriptive of Visual Impairment Scale, a component of the Multiple

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purposes (i.e. 20/20), by the number of letters identified correctly.
Sclerosis Quality of Life Inventory (Fischer et al., 1999),
This figure shows the 25% contrast level for purposes of illustrating
also has shown association of reduced scores with worse
format; the actual contrast levels used in these trials, 2.5% and
1.25%, have substantially lighter grey letters. The charts measure
performance on LCLA testing (Mowry et al., 2009).
14  14 inches for easy use and portability in the multiple sclerosis Collectively, data from these outcomes demonstrate that
clinical trial setting; charts may also be mounted on a retro-illumi- LCLA testing provides information on clinically relevant
nated cabinet, thus eliminating the need for standardization of room aspects of vision.
lighting levels. Reprinted with permission (Balcer et al., 2007). In considering use of patient-reported outcomes as thera-
peutic trial outcomes, attention must be paid to participant
fatigue during the study visit, the currently limited avail-
ability of normative longitudinal data, and the differential
Interestingly, in some patients with a history of unilateral
sensitivity of the outcomes to treatment effects on decreased
optic neuritis, binocular vision scores are worse than the
worsening versus augmented improvement. Vision-related
better seeing eye, a phenomenon known as binocular inhib-
patient-reported outcomes potentially are susceptible to
ition. Testing both monocular and binocular vision is of
context effects from co-existing damage from multiple scler-
value in this setting. A final consideration is the relative
osis, cognitive impairment, comorbid medical conditions,
advantages of using 2.5% versus 1.25% contrast Sloan
depression, personality traits, dependence on vision, and
charts and potential ceiling and floor effects. The extent
the availability of social support (Submacular Surgery
to which these factors need to be controlled depends on
Trials Research Group, 2007; Wieder et al., 2013).
the study design and priority of visual assessment as an
endpoint.
An additional issue is the magnitude of worsening of Structural assessment: optical
LCLA using Sloan charts that is appropriate as a clinical
trial endpoint. Mowry and colleagues (2009) reported that
coherence tomography
worsening by two lines (10 letters) is associated with a Confirmation that LCLA reflects visual pathway structure
clinically meaningful decrease in vision-related quality of and disease burden was most firmly provided by the intro-
life. Worsening by two lines (10 letters) confirmed at 3 duction of OCT to the multiple sclerosis field (Parisi et al.,
months was used as the criterion for sustained worsening 1999). Studies of binocular LCLA had showed associations
of LCLA in the AFFIRM clinical trial (Balcer et al., 2007). between worse scores and greater brain MRI lesion burden
Ophthalmologic studies of HCVA support use of a one-line within the optic tracts, optic radiations, and occipital white
(five-letter) cut-off (Rosser et al., 2003; Beck et al., 2007). matter (Wu et al., 2007). Through its ability to discern
Examination of inter-rater and test-retest reliability of retinal anatomy at high resolution (Fig. 2), OCT showed
LCLA demonstrated that seven letters corresponds to two in vivo that LCLA scores reflect the axonal and neuronal
standard deviations of difference (Balcer et al., 2000). losses in the anterior visual pathways that characterize
 16

Table 1 Visual outcomes reported from Phase 2 and 3 trials of approved agents for multiple sclerosis
Agent Trial Visual outcome Results Reference
measures
Alemtuzumab CAMMS223: Phase 2 trial of alemtuzumab (two doses) or Visual contrast sensitivity Statistically significant difference favouring treatment with alemtuzumab in Graves et al.,
subcutaneous interferon beta-1a in relapsing-remitting mul- measured using Pelli- proportion of eyes with sustained improvement in contrast sensitivity at 2013
tiple sclerosis, to assess relapse rate, 6 month confirmed Robson charts 3 and 6 months
EDSS disability progression and mean EDSS change
CARE-MS I and II: Phase 3 2-year studies of alemtuzumab or Low contrast letter acuity (i) Statistically significant outcome favouring alemtuzumab in Balcer et al.,
subcutaneous IB1A in relapsing-remitting multiple sclerosis measured using Sloan 1.25% and 2.5% contrast Sloan chart visual acuity assessment 2013
patients, to assess relapse rate and time to 6-month con- charts; visual acuity plus (ii) Statistically significant outcome favouring alemtuzumab on pro-
firmed accumulation of disability MSFC outcomes portion of subjects with improved visual acuity outcomes on
| BRAIN 2015: 138; 11–27

2.5% contrast Sloan chart at Month 12

(iii) Statistically significant outcome favouring alemtuzumab in
mean changes of scores for 1.25% and 2.5% contrast Sloan
charts at 12 and 18 months
(iv) Statistically significant changes in MSFC plus Sloan scores fa-
vouring alemtuzumab in 1.25% and 2.5% contrast Sloan charts
over 24 months
4-Aminopyridine 10-week randomized placebo-controlled double blind cross- VEPs, visual acuity, OCT While treated, patients had: Horton et al.,
over trial of 4 aminopyridine in multiple sclerosis patients measures of RNFL (i) Faster P100 waves on VEP assessment 2013
with optic neuropathy thickness (ii) Improvement in visual acuity in a subset of patients
(iii) Best responses in patients with RNFL measures between 60
and 80 mm

Fingolimod FREEDOMS: Phase 3 study of fingolimod (two doses) or Visual acuity, central foveal (i) Mean visual acuity and central foveal thickness remained stable Cohen et al.,
placebo; thickness at 24 months within the treatment groups and did not differ 2010; Kappos
TRANSFORMS: Phase 3 study of fingolimod (two doses) between the groups et al., 2010
or intramuscular IB1A; Both studies in relapsing-remit- (ii) Increased risk of macular oedema with fingolimod treatment
ting multiple sclerosis, to assess annualized relapse rate, at 0.5 mg daily dose
new or enlarging lesions on MRI and 3-month con-
firmed disability progression
Interferon beta- BENEFIT: placebo controlled and open label follow-up trial in EDSS Visual Function Small, insignificant change in Visual Functional System Score of the EDSS Kappos et al.,
1b clinically isolated syndrome patients with two or more clin- System score over 5 years 2009
ically silent brain MRI lesions, to assess time to clinically
definite multiple sclerosis and to confirm EDSS progression

Natalizumab AFFIRM: placebo controlled study in relapsing multiple scler- Visual acuity measured (i) Statistically significant difference in mean change from baseline Balcer et al.,
osis to assess relapse rate after 1 year and time to onset of with Sloan charts; 20% in 2.5% contrast Sloan chart visual Z score (number of stand- 2007
sustained disability progression over 2 years measured by change in visual acuity ard deviations from baseline mean) favoring natalizumab
EDSS (ii) Statistically significant difference in probability of worsening
low-contrast acuity scores on 2.5% contrast Sloan chart favor-
ing natalizumab
(iii) Statistically significant difference in proportion of subjects with
improvement of low-contrast visual acuity scores from
baseline
(iv) Addition of confirmed 20% worsening on low-contrast visual
acuity as a fourth component of the MSFC improved sensitiv-
ity to detect a difference between placebo- and natalizumab
treated patients in cumulative probability of confirmed disabil-
ity worsening
L. J. Balcer et al.

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Assessing vision in multiple sclerosis BRAIN 2015: 138; 11–27 | 17

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Figure 2 Single frame of spectral-domain OCT images through the fovea and macular region of the left eye with retinal layers
labelled. (A) A 41-year-old female with relapsing-remitting multiple sclerosis. (B) Research study volunteer with no history of ocular or
neurological disease. Note visible relative thinning of the macular GCL in the patient with multiple sclerosis (total macular volume = 7.52 mm3)
compared to the disease-free control (total macular volume = 8.67 mm3). Similarly, the peripapillary RNFL was thinner in the patient with
multiple sclerosis (85 mm) compared to the disease-free control (98 mm). Images are courtesy of Rachel Nolan and Lisena Hasanaj, Neurology
Vision Research Laboratory, New York University School of Medicine.

multiple sclerosis (Frohman et al., 2008b; Burkholder et al., (both with and without a history of acute optic neuritis) is
2009; Saidha et al., 2011, 2013). the correlation between RNFL thickness and visual func-
Trip and colleagues (2005) found a 33% reduction in tion, both cross-sectionally (Costello et al., 2006; Fisher
RNFL thickness using time-domain (second generation et al., 2006; Henderson et al., 2008; Zaveri et al., 2008)
technology) OCT in multiple sclerosis eyes with incomplete and longitudinally over time (Henderson et al., 2010;
recovery from optic neuritis compared to eyes of matched Talman et al., 2010). These findings suggest the possibility
controls. Costello and colleagues (2006) reported that up to of screening potential neuroprotective or repair-promoting
75% of patients with multiple sclerosis and acute optic strategies in multiple sclerosis by their ability to prevent
neuritis develop 10–40 mm of RNFL loss within 3–6 axonal loss measured by OCT RNFL thickness in acute
months, a striking finding given that the RNFL is 110– optic neuritis. The trajectory and time course of RNFL
120 mm thick by age 15 and most individuals without a axonal loss seen with OCT following an episode of acute
history of glaucoma or macular degeneration lose only optic neuritis is important for determining the ‘window of
0.27% per year in retinal thickness (10–20 mm over opportunity’ within which a neuroprotective or repair
60 years) (Kanamori et al., 2003; Harwerth et al., 2008). agent might be administered in a clinical trial setting.
Costello et al. (2006) also provided compelling evidence for Neuronal loss—observed directly (Cifelli et al., 2002) or
an injury threshold within the RNFL of 75 mm by time- inferred through detection of grey matter atrophy on MRI
domain OCT; thinning of the RNFL below this level was (Fisher et al., 2008; Fisniku et al., 2008)—is increasingly
associated with impaired visual function measured by auto- recognized as an important cause of worsening disability in
mated visual field testing. One of the most important find- multiple sclerosis. Spectral-domain OCT permits measure-
ings from OCT in studies of patients with multiple sclerosis ment of the GCL + IPL and other nucleus-containing
18 | BRAIN 2015: 138; 11–27 L. J. Balcer et al.

retinal layers and has increased our understanding of dis- 2012) will help refine MRI’s role and feasibility for use in
ease mechanisms in multiple sclerosis (Ishikawa et al., multicentre optic neuritis and multiple sclerosis trials.
2005; Tan et al., 2008, 2009; Walter et al., 2012). These Improvements continue to be made with regard to acquisi-
studies demonstrated that GCL + IPL thinning, suggesting tion times and standardization across centres to make optic
ganglion cell loss, was significantly associated with reduced nerve diffusion tensor imaging and magnetization transfer
visual function and vision-specific quality of life. imaging accessible for trials and clinical practice.
GCL + IPL thinning has been demonstrated 3 and 6 Evidence is conflicting regarding the prevalence of poster-
months following acute optic neuritis (Syc et al., 2012) ior visual pathway (i.e. optic radiation) axonal degener-
by quantitative segmentation (Davies et al., 2011). ation in the setting of anterior visual pathway
Importantly, baseline GCL + IPL thickness did not demon- demyelination in optic neuritis. Recent studies combining
strate swelling as seen in the RNFL. GCL + IPL thickness OCT and MRI provide evidence of trans-synaptic degener-
correlates with cortical grey matter and caudate atrophy ation, both in the anterior and posterior visual pathways
(Saidha et al., 2013). Thus, GCL + IPL thickness has rap- (Sriram et al., 2012; Gabilondo et al., 2014), which may
idly emerged as a useful structural marker in multiple scler- appear months to years after optic neuritis. The link be-
osis, paralleling findings of MRI studies that associate grey tween functional recovery from optic neuritis and posterior
matter disease (and by implication neuronal loss) with cog- visual pathway integrity and neuroplasticity also has been
nitive and neurologic disability. the topic of several functional MRI investigations (Werring
et al., 2000; Toosy et al., 2005; Korsholm et al., 2007;
Structural assessment: MRI Jenkins et al., 2010a, b; Raz et al., 2011, 2013; Costello,
2013). Some of these studies demonstrated that dynamic
OCT and MRI provide complementary information about changes in functional connectivity are observed following
visual pathway integrity. MRI-detected anterior and poster- acute optic neuritis, suggesting the potential for compensa-
ior visual pathway lesion volumes correlate with binocular tory neuroplasticity in both lower and higher order visual
LCLA (Wu et al., 2007). MRI is able to assess brain areas of the brain.

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structural integrity more globally. Five groups have
shown RNFL thinning correlates with brain atrophy
(Gordon-Lipkin et al., 2007; Sepulcre et al., 2007; Visual evoked potentials and
Grazioli et al., 2008; Siger et al., 2008; Dorr et al., 2011). electroretinography
MRI of the optic nerve has been a challenge, although a
high signal lesion is visible in almost all cases of acute optic Electrophysiological measures of visual pathway integrity
neuritis when using a fat-suppressed T2-weighted sequence have had increasing roles in the investigation of vision in
that is focused on the optic nerves (Fig. 3). There is also optic neuritis and multiple sclerosis clinical trials.
evidence that diffusion tensor imaging may be valuable in Demyelination results in both conduction delay and
quantifying tissue integrity of this structure. Optic nerves of block. The former probably accounts for the characteristic
eyes with remote optic neuritis history had abnormal dif- finding in optic neuritis and multiple sclerosis of a main
fusion tensor imaging, either increased radial diffusivity or (P100) VEP wave form that is well-formed but of pro-
decreased fractional anisotropy, which was associated with longed latency. Reduced VEP amplitude may reflect con-
greater degrees of RNFL thinning by OCT and worse duction block due to demyelination or damage to and/or
visual function (Naismith et al., 2010; Smith et al., loss of axons. A serial study of acute optic neuritis showed
2011). In a recent study of acute optic neuritis, axial dif- that early prolongation of VEP latency predicted subse-
fusivity measured by diffusion tensor imaging of the optic quent retinal axonal loss measured by OCT (Henderson
nerve correlated with 6-month outcomes of contrast sensi- et al., 2011), suggesting that demyelinated axons are pre-
tivity, HCVA, RNFL thickness by OCT, and VEP ampli- disposed to degenerate in the setting of acute inflammation.
tude and latency (Naismith et al., 2012). Optic nerve However, one limitation of pattern VEP as an outcome
diffusion tensor imaging may have the potential to enrich measure for clinical trials is that the VEP may be undetect-
or stratify enrolment into optic neuritis clinical trials or able early in the course of optic neuritis, so demonstrating
guide allocation of new therapies for those patients who changes in VEP latency from baseline may be challenging.
have the most dysfunctional axons and, therefore, might Use of multifocal VEP, which captures a significantly larger
benefit most from treatment. area of the visual field than pattern VEP and can provide
Magnetization transfer imaging to measure the magnet- topographic assessment of amplitude and latency, may pro-
ization transfer ratio may correlate with myelin content in vide a useful adjunct or alternative in the setting of acute
multiple sclerosis (Schmierer et al., 2004). A significant as- optic neuritis (Klistorner et al., 2008, 2009). Multifocal
sociation between optic nerve magnetization transfer ratio VEP may complement OCT measures in examining re-
and time-linked VEP latency following optic neuritis sug- gional integrity of optic nerve axons and visual pathway
gests a role for the former in detecting remyelination structures.
(Hickman et al., 2004). Further studies of diffusion tensor The potential role for pattern electroretinography versus
imaging and magnetization transfer imaging (Wang et al., VEP latency in distinguishing macular disease from acute
Assessing vision in multiple sclerosis BRAIN 2015: 138; 11–27 | 19

Figure 3 Magnetic resonance optic nerve images acquired in a 30-year-old female with a 5-day history of acute right optic
neuritis. (A) Axial post-contrast T1-weighted image shows swelling and enhancement of the intraorbital and intracanalicular parts of the
right optic nerve. (B) Coronal T2-weighted image shows swollen hyperintense right optic nerve through posterior orbit. (C) Coronal post-
contrast T1-weighted image shows gadolinium-enhancement of right optic nerve in posterior orbit. Images are courtesy of Dr Ahmed Toosy,
UCL Institute of Neurology, London, UK.

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optic neuritis has been emphasized (Holder, 2004). Optic neuritis and multiple sclerosis
The optic nerve head component of the multifocal
electroretinography may provide an electrophysiological in children
marker of axonal disruption in eyes of patients with mul- Over the past decade, research in paediatric optic neuritis
tiple sclerosis (Schnurman et al., 2014). This novel ap- and multiple sclerosis has identified similarities and differ-
proach examines the waveform of the multifocal ences in the clinical manifestations and prognosis related to
electroretinogram signal as it travels from the unmyelinated age. While the cardinal features of optic neuritis (blurred
retinal ganglion cell axon to the post-lamina cribosa vision, pain with eye movements, dyschromatopsia, and
myelinated segment of the optic nerve, and findings are visual field defects) are the same across the age spectrum,
highly correlated with both functional (LCLA) and struc- severe vision loss, bilateral involvement, and disc swelling
tural (OCT-assessed RNFL thickness) measures of the are more common in paediatric optic neuritis (Waldman
visual pathway. Future studies are needed to investigate et al., 2011). In two paediatric cohorts, 70% of children
the ability of the optic nerve head component of the had visual acuity of 20/200 or worse, and no light percep-
multifocal electroretinography to monitor visual func- tion was relatively common (Wilejto et al., 2006;
tion and predict outcome in optic neuritis and multiple Bonhomme et al., 2009). However, visual recovery tends
sclerosis. to be better than in adults. Younger children (510 years of
age) are more likely to have bilateral optic neuritis com-
pared to adolescents, in whom unilateral optic neuritis is
Fluid-based biomarkers and visual more common. The presence of unilateral or bilateral in-
volvement does not predict the risk of multiple sclerosis in
impairment in multiple sclerosis children, but multiple sclerosis risk does increase with age
Blood neurofilament heavy chain levels are elevated in pa- (Bonhomme et al., 2009; Waldman et al., 2011).
tients with acute optic neuritis and other inflammatory A few studies have assessed LCLA and OCT in paediatric
optic neuropathies and correlate with visual outcome and demyelinating diseases (Yeh et al., 2009; Yilmaz et al.,
treatment response (Petzold, 2005; Petzold and Plant, 2012; Waldman et al., 2014). Similar to adults, following
2012). Neurofilament heavy and light chain levels and optic neuritis in children, there is decreased LCLA and
other validated biomarkers, such as anti-aquaporin 4 auto- RNFL thinning compared to healthy control eyes. The
antibodies, need to be explored in longitudinal studies to data are conflicting on whether LCLA and RNFL thickness
determine their relation to structural measures of the visual are decreased in the eyes of children with multiple sclerosis
pathways and prognostic value for neurodegeneration- without a history of optic neuritis. Further studies are
related visual impairment in patients with optic neuritis required, specifically, longitudinal studies of relation be-
and multiple sclerosis. tween visual function, OCT and MRI that account for
20 | BRAIN 2015: 138; 11–27 L. J. Balcer et al.

increasing disease duration. Multiple sclerosis is rare in neuroprotective or reparative agents designed to improve
children, and thus, paediatric studies currently are limited visual recovery following acute optic neuritis (Table 2). A
by small sample sizes, emphasizing the importance of multi- variation on this design is to enrol patients with multiple
centre collaborations. sclerosis and a prior history of afferent visual system in-
volvement to determine whether there is evidence of repair
manifested as improvement in functional or structural
Visual outcomes in optic measures. Two recent exploratory trials of autologous mes-
enchymal stem cell infusion used this approach (Connick
neuritis and multiple et al., 2012; Cohen, 2013).
sclerosis clinical trials
Recommendations for assessment of
Secondary and exploratory outcomes vision in clinical trials and practice
in Phase 3 multiple sclerosis clinical Tools to measure visual function, vision-related quality of
trials and post-marketing studies life, structure of the visual pathways, electrophysiology,
Several Phase 3 clinical trials and post-marketing studies in and body fluid biomarkers in optic neuritis and multiple
multiple sclerosis included visual outcomes as secondary or sclerosis are in various stages of development. Defining nor-
exploratory outcomes (Table 1). Many of these trials mative values for these tests in disease-free volunteers and
showed that measures such as LCLA and contrast sensitiv- patients with multiple sclerosis with and without a history
ity were able to detect treatment benefits with sensitivity of acute optic neuritis has been challenging (Petzold et al.,
similar to that of more traditional efficacy measures (clin- 2010), but values for average LCLA and HCVA testing
ical relapse rate and confirmed disability worsening). scores for monocular and binocular vision are now avail-
Addition of LCLA to the MSFC may increase sensitivity able for adult (Sakai et al., 2011) and paediatric (Waldman

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to changes in disability that are not detected by the original et al., 2014) multiple sclerosis.
three-component MSFC (Balcer et al., 2003). Published stu- Visual outcomes can be added to other clinical and ima-
dies to date have focused on clinically isolated syndromes ging outcomes as secondary or exploratory outcomes in
or relapsing multiple sclerosis. More comprehensive studies standard Phase 2 or 3 trial designs (Table 1). LCLA,
of visual dysfunction as secondary outcomes in Phase 3 either alone or as a component of the MSFC, could provide
trials, particularly for progressive multiple sclerosis, are additional assessment of neurologic impairment. Similarly,
needed. OCT could be used to supplement MRI to provide an add-
itional assessment of CNS tissue integrity, both loss and
Visual outcomes in trials of acute recovery.
Assessment of visual outcomes in acute optic neuritis
optic neuritis shows promise as a model system for Phase 2 trials to
Early trials aimed at improving visual outcome following screen putative neuroprotective or repair-promoting treat-
acute optic neuritis used HCVA as the primary outcome ment strategies (Table 2). Acute optic neuritis lesions are
measure. The Optic Neuritis Treatment Trial (Beck et al., representative of acute inflammatory demyelination else-
1992; Beck and Gal, 2008) was important in establishing where in the CNS and, thus, can serve as a more global
the role for other outcome measures. First, the Optic model for neuroprotection and repair. The optic nerve is
Neuritis Treatment Trial demonstrated that visual recovery one of the few CNS locations where clinical function can
following acute optic neuritis often is incomplete when be assessed in parallel with direct and non-invasive in vivo
assessed by measures of low-contrast vision, with Pelli- measures of structure and electrophysiology. Moreover,
Robson contrast sensitivity demonstrating the greatest fre- measures of visual function are more reliable, sensitive,
quency of persistent abnormalities (Optic Neuritis Study and quantitative relative to functional measures of other
Group, 2008b). Reduction in contrast sensitivity was asso- anatomic sites in the CNS. While there is not yet consensus
ciated with reduced vision-related quality of life (Cole et al., on the preferred primary outcome measure in optic neuritis
2000) and provided the rationale for considering assess- trials, Phase 2 proof-of-concept trials will likely use a struc-
ment of low-contrast vision as a sensitive visual outcome tural marker such as RNFL or GCL + IPL thickness,
in multiple sclerosis clinical trials. Another key outcome whereas Phase 3 trials will need to demonstrate clinically
measure in the Optic Neuritis Treatment Trial was auto- relevant benefit on vision as well as structural preservation.
mated (Humphrey) visual field testing (Keltner et al., 1994, It is imperative that trials focusing on acute optic neuritis
2010). This quantitative method remains an important have sufficiently stringent eligibility criteria to insure accur-
aspect of visual assessment of optic neuritis and other ate diagnosis and to avoid enrolling participants with other
neuro-ophthalmological disorders affecting the optic nerve. forms of optic neuropathy or causes of visual loss.
More recently, visual outcomes have been used as the Similarly, it will be important to avoid participants with
primary measure in Phase 2 clinical trials of putative comorbidities that might affect clinician-assessed or
Table 2 Acute optic neuritis trials recently completed or in progress

Agent Trial design Visual outcome measures Results Reference

Simvastatin Placebo-controlled trial to assess whether Contrast sensitivity (primary), visual acuity, In simvastatin-treated subjects: trend for Tsakiri et al., 2012
simvastatin 80/day for 6 months improves colour vision, VEPs, visual analogue scale improved contrast sensitivity (P = 0.06);
visual outcome at 6 months following an improved VEP (latency shortened and
episode of acute optic neuritis (n = 64) amplitude increased) improved visual ana-
logue scale (P = 0.04)
Erythropoietin Placebo-controlled trial to assess whether OCT-measured change in RNFL thickness In erythropoietin-treated subjects: smaller Suhs et al., 2012
Assessing vision in multiple sclerosis

erythropoietin 33 000 IU/day for 3 days between baseline and 16 weeks (pri- decrease in RNFL thickness and optic
prevents retinal axonal loss at 16 weeks mary); visual acuity, visual fields, VEPs, nerve diameter; shorter VEP latency at
following an episode of acute optic neur- optic nerve atrophy on MRI 16 weeks
itis (n = 40)
Memantine Placebo-controlled trial to assess whether OCT-measured RNFL thickness (primary); In memantine-treated subjects: higher Esfahani et al., 2012
memantine 5 mg/day for 1 week then visual acuity; visual fields, contrast sensi- RNFL thickness (mean 91.3 versus
10 mg/day for 2 weeks prevents retinal tivity; VEPs 78.9 mm, P = 0.01); no difference in visual
axonal loss at 3 months following an epi- function measures
sode of acute optic neuritis (n = 60)
Phenytoin Placebo-controlled trial to assess whether OCT-measured RNFL thickness after 6 Trial in progress Neuroprotection with
phenytoin prevents retinal axonal loss fol- months (primary); visual acuity; low-con- phenytoin in optic
lowing acute optic neuritis trast acuity; colour vision; VEPs; optic neuritis
nerve area, lesion size, magnetization
transfer ratio on MRI
Amiloride Placebo-controlled trial to assess whether Scanning laser polarimetry-measured RNFL Trial in progress Amiloride clinical trial in
amiloride prevents retinal axonal loss at thickness after 6 months (primary); OCT- optic neuritis (ACTION)
6 months following an episode of acute measured RNFL thickness; diffusion MRI
optic neuritis of posterior visual pathways; MR spec-
troscopy of visual cortex; low-contrast
acuity; visual acuity; colour vision; VEPs,
QOL
Anti-LINGO Placebo-controlled trial to assess whether Whole field VEP latency after 6 months Trial in progress 215ON201 BIIB033 in
antibody anti-lingo antibody shortens visual (primary); OCT-measured RNFL thick- acute optic neuritis
evoked potential P100 latency at 24 ness; OCT-measured retinal ganglion (RENEW)
weeks following an episode of acute cell/inner plexiform layer thickness; low-
optic neuritis contrast acuity
Erythropoietin Placebo-controlled trial to assess whether Low-contrast letter acuity (co-primary); Trial in progress Treatment of optic neuritis
erythropoietin improves visual function RNFL thickness (co-primary); macular with erythropoietin
at 6 months after an episode of acute volume; papillomacular bundle; contrast
optic neuritis vision, visual field; VEPs, NEI-VFQ-25
Adrenocorticotrop- Trial comparing the ability of adrenocorti- Mean RNFL thickness in adrenocortico- Trial in progress A Phase IV trial of neuro-
hic hormone cotrophic hormone versus IV methylpred- trophic-hormone-treated subjects after 6 protection with ACTH in
nisolone to reduce RNFL loss at 6 months (primary); comparison of adreno- acute optic neuritis
months following an episode of acute corticotrophic hormone and IV methyl-
optic neuritis prednisolone for RNFL thickness at 1, 3
and 6 months; multifocal VEPs; pupillary
diameter
BRAIN 2015: 138; 11–27

NEI-VFQ-25 = National Eye Institute Visual Function Questionnaire; QOL = quality of life.
| 21

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22 | BRAIN 2015: 138; 11–27 L. J. Balcer et al.

patient-reported visual outcomes, or at least to collect suf- (and relapsing multiple sclerosis) relate to the more grad-
ficient information so that these factors can be accounted ual, presumably neurodegenerative processes that underlie
for in the statistical analyses. An appropriate primary end- progressive multiple sclerosis (Lublin et al., 2014).
point of a Phase 2 trial in acute optic neuritis would be a Longitudinal studies of OCT underscore the value of a
between-group comparison of peripapillary RNFL thick- central OCT reading centre for clinical trials (Keltner et al.,
ness at 6 months (or as early as 4 months), when most 2011). Analogous to a central MRI reading centre, which
of the acute thinning has occurred (Costello et al., 2006, has become the standard approach in multiple sclerosis
2008; Henderson et al., 2010). Henderson and colleagues trials, a central OCT reading centre would be responsible
(2010) estimated that, using time-domain OCT technology, for training sites in standardized image acquisition proced-
a between-group difference of 40% reduction in the overall ures, developing case report forms, and deploying compu-
loss of RNFL thickness of the affected eye could be de- terized retinal segmentation software. Such multicentre
tected with 80% power with 90 eyes of participants with studies will require transparent and validated quality con-
unilateral optic neuritis (Henderson et al., 2010). This trol procedures (Schippling et al., 2014).
sample size seems to be quite manageable for a multicentre Clinical trials recently have been launched in paediatric
clinical trial. Additional endpoints could include other OCT multiple sclerosis. In comparison to adults, paediatric mul-
measures (GCL + IPL thickness and macular volume), tiple sclerosis is rare, which creates many challenges for
LCLA, patient-reported outcomes, MRI measures (volume trial design. More importantly, investigators, pharmaceut-
or length of optic nerve hyperintensity, optic nerve diffu- ical companies, and regulators must appreciate the differ-
sion tensor imaging and magnetization transfer imaging, ences between adult and paediatric multiple sclerosis when
and possibly functional MRI), and electrophysiological interpreting results. For example, the EDSS does not cap-
measures (standard or multifocal VEP). It must be recog- ture treatment effects in paediatric multiple sclerosis owing
nized that MRI studies of the optic nerve are limited tech- to the very low likelihood of accrual of physical disability
nically by its small size and mobility in the orbit. within the first 10 years from disease onset in the paediatric
There are several caveats to this study design. As the population. The MSFC has not been validated in children.

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window of therapeutic opportunity for neuronal recovery Specifically, there are no normative data for the component
or protection is likely to be short, it is important to recruit tests. With respect to vision, testing binocular acuity in
potential study participants as soon as possible after the paediatric trials may not detect subtle deficits or treatment
onset of acute optic neuritis. Body fluid biomarker levels effects due to the greater capacity for binocular summation
at onset may provide diagnostic and prognostic informa- in children compared to adults. Nevertheless, addition of
tion and help inform statistical analyses of outcome meas- LCLA and OCT assessments to paediatric trials would ad-
ures. Specimens should be collected and banked to permit vance vision research in paediatric multiple sclerosis.
future validation studies. For recruitment to be feasible,
trial centres need to have an efficient referral process to
identify potential participants and schedule evaluations ex-
Future directions
peditiously. This design also depends on having a thera- The unique accessibility and structure-function correlations
peutic agent that can be initiated quickly and has a rapid provided by the afferent visual system in multiple sclerosis,
onset of action. Optic nerve swelling and resultant increase combined with additional understanding provided by elec-
in peripapillary RNFL thickness is often observed acutely in trophysiology, make vision a useful model system to test
optic neuritis (Kupersmith et al., 2012) and precludes ac- new multiple sclerosis therapies. Research over the past
curate measure of baseline RNFL thickness, which must be decade has expanded our understanding of vision in mul-
taken into consideration in the statistical analysis plan. One tiple sclerosis substantially; ongoing and future studies will
suggested approach is to use RNFL thickness in the clinic- take advantage of the growing and now well-organized
ally unaffected fellow eye as a baseline measure, which re- network of investigators in this area. However, much
duces sample size by around one-third (Henderson et al., work remains to be done in a number of areas, including
2010). However, this approach assumes the fellow eye is practical aspects of implementing clinical outcome meas-
normal, which usually is the case in patients with acute ures in multicentre studies, further validation of fluid-
optic neuritis as a clinically isolated syndrome but often based biomarkers, development and application of new
is not the case in optic neuritis in the setting of multiple electrophysiological and imaging techniques, and assessing
sclerosis (Fisher et al., 2006). Therefore, recent analyses to the inter-relationships among these measures both cross-
calculate potential sample sizes have used a variety of meth- sectionally and longitudinally. In particular, studies
ods, including accounting for the fellow eye versus con- addressing how clinical measures of visual impairment cor-
sidering the affected eye only (Henderson et al., 2010). relate over time with or predict more general measures of
Analysing thinning of the GCL + IPL layer, which is not neurologic disability are needed. It will be important to
affected by this issue, is a potential alternative approach confirm the clinical meaningfulness of objective visual out-
(Syc et al., 2012; Kupersmith, 2014). Finally, further stu- comes using patient-reported outcomes for them to be ac-
dies are needed to assess how the neuroprotective or repair cepted by regulatory agencies for drug development and
effects demonstrated in an acute lesion in optic neuritis approval. In addition, development of normative values
Assessing vision in multiple sclerosis BRAIN 2015: 138; 11–27 | 23

for the assessments will be essential for their ultimate ap- Dr Miller has received honoraria through payments to
plication in clinical trials and clinical practice. Finally, al- his employer, UCL Institute of Neurology, for advisory
though much is known about the neurophysiology of eye committee and/or consultancy advice in multiple sclerosis
movements and the range of abnormalities in multiple studies from Biogen Idec, GlaxoSmithKline, Novartis,
sclerosis, substantial work is needed to develop practical Merck, Chugai, Mitsubishi Pharma Europe, and Bayer
methods to assess eye movements quantitatively in clinical Schering Pharma. He also received compensation through
trials. payments to his employer for perform central MRI analysis
The capacity for measures of visual function, quality of of multiple sclerosis trials from Biogen Idec,
life, visual pathway structure, and electrophysiology to GlaxoSmithKline, Merck, and Novartis. The Queen
show not only deterioration but also improvement will be Square MS Centre at UCL Institute of Neurology is sup-
critical in the emerging era of agents that repair and protect ported by the UK MS Society and UCL-UCLH Biomedical
the nervous system. For the moment, there will be contin- Research Centre.
ued reliance on structural outcomes of OCT and MRI to Dr Reingold has received personal consulting fees and/or
document benefit on reducing neuronal and axonal degen- travel reimbursement from the National Multiple Sclerosis
eration or improving tissue repair. Technological advances Society (NMSS), the European Committee for Treatment
in both modalities should enable greater sensitivity and spe- and Research in Multiple Sclerosis (ECTRIMS); Bayer
cificity in monitoring pathology in the anterior visual path- HealthCare, Biogen Idec, Coronado Biosciences Inc., the
way and its modification by therapy. One such example is Cleveland Clinic Foundation, Eli Lilly & Company, EMD
the development of improved techniques for quantitative Serono and Merck Serono, Genentech, F. Hoffmann-
diffusion tensor imaging of the optic nerve (Samson LaRoche, ISIS Pharmaceuticals Inc., Medimmune Inc.,
et al., 2013). Vision research in multiple sclerosis will con- Novartis Pharmaceuticals Corporation, Observatoire
tinue to require and benefit from the collaborative ap- Français de la Sclérosis en Plaques, Opexa Therapeutics,
proach that has contributed to its success over the past Sanofi-Aventis, SK Biopharmaceuticals, Synthon
decade. Pharmaceuticals Inc., TEVA Pharmaceutical Industries,

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and Fondation pour l’aide à la Recherche sur la Sclérosis
en Plaques; and reports membership on the editorial board
Acknowledgements of the Multiple Sclerosis Journal over the past 3 years.

The International Conference on Vision and Vision-Related

Outcomes in Multiple Sclerosis was organized under the
auspices of the International Advisory Committee on
Supplementary material
Clinical Trials in Multiple Sclerosis. We are grateful for Supplementary material is available at Brain online.
the active participation of the meeting attendees
(Appendix), who were given the opportunity to review a
draft of this manuscript and provide input. References
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