Balcer 2015 Vision and Vision Related Outcome
Balcer 2015 Vision and Vision Related Outcome
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,
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
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),
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
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,
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
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.
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.
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.
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
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
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.
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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