Dyschromatopsia in Multiple Sclerosis Patients: A Marker of Subclinical Involvement?

To investigate corneal biomechanical properties among individuals with unilateral nonarteritic anterior ischemic optic neuropathy (NAION) compared to healthy gender- and age-matched subjects.; ; The study subjects were separated into 2 groups: 66 eyes of 33 patients with unilateral NAION (study group) and 33 eyes of 33 healthy individuals (control group). Reichert ocular response analyzer (Reichert Ophthalmic Instruments) was used to assess corneal hysteresis (CH), corneal resistance factor (CRF), corneal-compensated intraocular pressure (IOPcc), and Goldmann-correlated intraocular pressure values. Also, central corneal thickness was measured using Scheimpflug camera combined with a Placido disc corneal topographer (Sirius; Costruzioni Strumenti Oftalmici).; ; Mean CH and median CRF values were significantly lower in the affected eyes (8.8 ± 1.8 mm Hg, 9.4 mm Hg, respectively) and contralateral unaffected eyes (9.1 ± 1.6 mm Hg, 9.8 mm Hg, respectively) of NAION patients than those in the control group (9.9 ± 1.3 mm Hg, 10.4 mm Hg, respectively; all P < 0.017). Mean IOPcc was significantly higher in the affected eyes of NAION patients (19.2 ± 3.5 mm Hg) than in the eyes of control group (17.1 ± 3.6 mm Hg; P = 0.002).; ; CH and CRF are significantly reduced in patients with NAION, possibly indirectly reflecting structural weakness in the lamina cribrosa.

Original Contribution Dyschromatopsia in Multiple Sclerosis Patients: A Marker of Subclinical Involvement? Helena Felgueiras, MD, Joana Parra, MD, Simão Cruz, MD, Pedro Pereira, MD, Ana F. Santos, MD, Adriana Rua, MD, Dália Meira, MD, Pedro Fonseca, MD, Catarina Pedrosa, MD, João N. Cardoso, MD, Cristina Almeida, MD, Maria Araújo, MD, Ernestina Santos, MD Background: In multiple sclerosis (MS), even in the absence of a clinical episode of optic neuritis (ON), the optic nerve and retinal nerve fiber layer (RNFL) may be damaged leading to dyschromatopsia. Subclinical dyschromatopsia has been described in MS associated with lower motor and cognitive performances. Objectives: To set the prevalence of dyschromatopsia in eyes of MS patients without a history of ON, to compare its prevalence in patients with and without ON history, and to explore the association between dyschromatopsia and disease duration, average peripapillary RNFL thickness, macular volume, and cognitive and motor performances. Neurology Department (HF), Centro Hospitalar de Vila Nova de Gaia/ Espinho, Vila Nova de Gaia, Portugal; Neurology Department (JP), Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; Neurology Department (SC), Hospital Fernando Fonseca, Lisboa, Portugal; Neurology Department (PP), Hospital Garcia de Orta, Almada, Portugal; Neurology Department (AFS), Hospital de Braga, Braga, Portugal; Neurology Department (AR), Centro Hospitalar do Porto, Porto, Portugal; Ophthalmology Department (DM), Centro Hospitalar de Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal; Ophthalmology Department (PF), Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; Ophthalmology Department (CP), Hospital Fernando Fonseca, Lisboa, Portugal; Ophthalmology Department (JNC), Hospital Garcia de Orta, Almada, Portugal; Ophthalmology Department (CA), Hospital de Braga, Braga, Portugal; Ophthalmology Department (MA), Centro Hospitalar do Porto, Porto, Portugal; Instituto de Ciências Biomédicas de Abel Salazar da Universidade do Porto (ES), Porto, Portugal. Partially funded with a grant from Biogen Idec. H. Felgueiras declared receipt of honoraria from Biogen Idec. E. Santos received Biogen Idec funding from advisory board sessions. The authors declare that Biogen Idec funded this project meeting sessions and the acquisition of the Hardy-Rand-Rittler plates used in this study and provided statistical analyzes assistance. The supporting source had no involvement in the study design; collection, analysis, and interpretation of data; writing of the report or in the decision to submit the report for publication. All authors had access to the study data. Address correspondence to Helena Felgueiras, MD, Neurology Department, Centro Hospitalar de Vila Nova de Gaia/Espinho, Rua Conceição Fernandes, 4434-502 Vila Nova de Gaia, Portugal, 227830209; E-mail: [e-mail] Felgueiras et al: J Neuro-Ophthalmol 2016; 36: 275-279 Methods: An observational cross-sectional study was conducted at multiple medical centers. Data were collected after single neurological and ophthalmological evaluations. Dyschromatopsia was defined by the presence of at least 1 error using Hardy-Rand-Rittler plates. Results: In our population of 125 patients, 79 patients (63.2%) never had ON and 35 (28.8%) had unilateral ON. The prevalence of dyschromatopsia in eyes of patients without ON was 25.7%. Patients with dyschromatopsia had a statistically significant lower RNFL thickness (P = 0.004 and P = 0.040, right and left eyes, respectively) and worse performance in symbol digit modalities test (P = 0.012). No differences were found in macular volume or motor function tasks. Conclusions: Dyschromatopsia occurs frequently in MS patients. It may be associated with a worse disease status and possibly serve as a marker for the detection of subclinical disease progression since it was detected even in the absence of ON. It correlated with thinner peripapillary RNFL thickness and inferior cognitive performance. Journal of Neuro-Ophthalmology 2016;36:275-279 doi: 10.1097/WNO.0000000000000401 © 2016 by North American Neuro-Ophthalmology Society M ultiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Recent evidence suggests that persistent subclinical disease activity is present in most patients, being responsible, at least in part, for diffuse cerebral atrophy and cognitive deterioration (1-3). The visual pathway is usually affected in MS patients (4- 7). Visual dysfunction may occur in up to 80% of cases during disease progression (4,8). While any portion of the visual pathways may be affected in MS, the most frequent sites of involvement are the optic nerves, optic tracts, and optic radiations (9-11). The prevalence of congenital dyschromatopsia among the general population is approximately 8.0%-8.7% in men and approximately 1% in women (5,6,12,13). Dyschromatopsia appears to be much more prevalent in MS patients, mainly in 275 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution those who have experienced episodes of acute ON (at least 93.8%) and also in the nonaffected eyes (5,6,12-14). There are a few studies dealing with color vision changes in MS patients and its occurrence in the absence of clinical ON. This acquired dyschromatopsia appears unrelated to inflammatory activity but rather due to a neurodegenerative process. Color vision deterioration may be a marker of diffuse axonal loss and subclinical disease activity, and it may be a predictor of motor and cognitive disability, as proposed by Martínez-Lapiscina et al (15). In our study, we determined the prevalence of dyschromatopsia in Portuguese MS patients without a history of ON as our primary objective. Our secondary objective was to compare the prevalence of dyschromatopsia between MS patients with and without the history of ON. Our exploratory objectives were to assess whether there is an association between the presence of dyschromatopsia in asymptomatic eyes of patients with MS and: 1; decreased peripapillary retinal nerve fiber layer (RNFL) thickness and/ or macular volume (MV), 2; physical disability, 3; cognitive impairment, and 4; disease duration. MATERIALS AND METHODS Data Collection We conducted an observational, cross-sectional, multicenter, hospital-based study involving 6 Portuguese hospitals: Centro Hospitalar de Vila Nova de Gaia/Espinho, Centro Hospitalar do Porto, Hospital de Braga, Centro Hospitalar e Universitário de Coimbra, Hospital Garcia de Orta, and Hospital Fernando Fonseca. Patients were recruited consecutively from neurology and neuro-ophthalmology clinics between 05/01/2014 and 09/30/2014. The study was approved by Portuguese Data Protection Authority and Ethics Committee of all hospitals involved. All patients signed an informed consent. Eligible subjects met the following inclusion criteria: definitive diagnosis of relapsing remitting MS (RRMS) according to the 2010 revised McDonald criteria (16); age between 18 and 55 years; less than 15 years of MS duration; an expanded disability status scale (EDSS) score (17) lower than 6; and being able to understand and to sign informed consent. All subjects with eye diseases that might interfere with the interpretation of results (e.g., glaucoma, macular disease, amblyopia, congenital dyschromatopsia, history of ocular surgery, visual acuity worse than 20/40, and ON occurring within the previous 6 months) were excluded. Data were collected after a single neurological and ophthalmological evaluation. During neurological assessment, the following data were collected: demographic information, clinical diagnosis, age at first symptoms, age at diagnosis, concurrent illnesses, medications, and history of episodes compatible with acute optic neuropathy. The following scales and tests were administered: EDSS score, 276 9-hole peg test (9-HPT), timed 25-foot walk test (T25FWT), symbol digit modalities test (SDMT) (oral version), and Hardy-Rand-Rittler (HRR) pseudoisochromatic plates (18- 21). Ophthalmologic evaluation included best-corrected visual acuity increased with the Early Treatment Diabetic Retinopathy Study chart, biomicroscopy of anterior segment, intraocular pressure measured by Goldmann applanation tonometry, funduscopy, and determination of peripapillary RNFL thickness and MV using Sprectralis spectral domain-optical coherence tomography (Heidelberg Engineering; Franklin, MA) (performed in 4 hospitals). In our study, dyschromatopsia was defined by at least 1 error using HRR plates, considering that this cutoff has been shown to have good screening sensitivity (18). The presence of prior ON was determined based on the definition stated in the International Headache Society Criteria (22). Physical disability was assessed by EDSS score, as well as by the performance with the 9-HPT and the T25FWT. Cognitive status was evaluated by the SDMT. Statistical Analysis To answer our primary objective, we selected those patients without a history of ON and determined the prevalence of dyschromatopsia per patient in this subgroup. Furthermore, in order to evaluate this issue per eye among the total sample of eyes, we selected only those without prior ON, and then, we calculated the frequency of dyschromatopsia. Using x2 test, we also searched for any difference concerning the frequency of dyschromatopsia between eyes of patients without ON in either eye and those with prior ON in one eye. For the purpose of comparing the prevalence of dyschromatopsia between patients with and without the history of ON (secondary objective), we selected 1 eye per patient. In patients with unilateral ON, the affected eyes were chosen; among patients without prior ON in either eye or among those with bilateral ON, we randomly selected 1 eye. Then, x2 test was used. Concerning the exploratory objectives, linear regression models were studied for the following variables: EDSS, 9HPT, T25FWT, SDMT, right and left eye's average peripapillary RNFL thickness, and right and left eye's average MV. For independent variables, age, gender, and MS disease duration were considered. Dyschromatopsia and history of optic neuritis (ON), both referring to each eye individually, were also independent variables in this analysis. ON was codified as categorical variable, as "present" or "absent." Dyschromatopsia was codified as categorical variable as "absent," "present in both eyes," and "present in one eye" (since dyschromatopsia was present only in 1 eye in 15 cases). 9HPT, T25FWT, SDMT, RNFL, and MV were codified as continuous variables. Although EDSS is not a continuous variable, for statistical analysis it was considered as such. For statistical analysis in this study, SPSS Statistics for Windows, Version 21.0 (IBM Corp, Armonk, NY) was used, and a confidence interval of 95% was set. Felgueiras et al: J Neuro-Ophthalmol 2016; 36: 275-279 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution RESULTS Our study included 125 RRMS patients. Sixty-eight percent of these patients were female; mean age at inclusion was 38.45 ± 8.60 years (range, 18-55 years) and mean age at the onset of symptoms was 31.53 ± 8.63 years (range, 16-55 years). Elementary grade school level was found in 0.56%, 34.4% completed high school education, and 47.2% had an academic degree. Mean duration of disease was 7.02 ± 4.57 years (range, 0-15 years). EDSS score ranged between 0 and 5.5. TABLE 1. Relationship between dyschromatopsia and either average peripapillary RNFL thickness or average MV Study Variables Average RNFL thickness (mm): right eye Prevalence of Dyschromatopsia in MS Patients Out of the 125 patients, 10 (8.0%) had bilateral ON and 36 (28.8%) had unilateral ON. Among the 79 patients without prior ON, dyschromatopsia was found in 23 (29.1%), bilaterally in 17, and unilaterally in 6. For the purpose of an eye-based analysis, a total of 250 eyes were considered: 194 eyes (77.6%) never had prior ON. Within this group, dyschromatopsia was found in 50 eyes (25.7%). Among the 56 eyes with prior ON, dyschromatopsia was observed in 29 (51.8%). Furthermore, when comparing the proportion of dyschromatopsia in unaffected eyes of patients without prior ON and in those with ON in the fellow eye, a nonsignificant (P = 0.299) difference was found (26.6% vs 36.1%, respectively). No statistically differences in terms of gender, age, or visual acuity were found between the groups of patients with and without dyschromatopsia. Comparison of Dyschromatopsia Between Patients With and Without Prior Optic Neuritis When comparing patients with prior ON and those without ON regarding the proportion of subjects with dyschromatopsia, the former group had a significantly higher value (52.8% vs 31.6%; P = 0.031; u = 0.202). Dyschromatopsia, RNFL Thickness, and MV in Eyes Without ON A significantly lower average peripapillary RNFL thickness was found in eyes with dyschromatopsia when compared with those with normal color vision. Disease duration had a significant contribution to this result (Table 1). There were no statistically significant differences when this comparison was made by quadrants. However, in patients with dyschromatopsia, the temporal RNFL quadrants had a significantly higher thickness than the equivalent nasal ones (P , 0.001). No statistically significant differences were found between these groups regarding the average MV. Dyschromatopsia and Physical Disability (EDSS, 9-HPT, T25FWT), Cognitive Status, and Disease Duration in Patients Without ON The results of the comparison between patients with and without dyschromatopsia regarding disease duration, Felgueiras et al: J Neuro-Ophthalmol 2016; 36: 275-279 Average RNFL thickness (mm): left eye Average MV (mm3): right eye Average MV (mm3): left eye Independent Variables Adjusted R2 P Dyschromatopsia 0.228 0.004* 0.266 0.077 0.341 0.094 0.004* 0.040* 0.144 0.054 0.465 0.091 0.003* 0.054 0.146 0.007* 0.521 0.206 0.272 0.096 Optic neuritis Age Gender Disease duration Dyschromatopsia Optic neuritis Age Gender Disease duration Dyschromatopsia Optic neuritis Age Gender Disease duration Dyschromatopsia Optic neuritis Age Gender Disease duration 0.004* 0.137 0.409 0.424 *Statistically different. MV, macular volume; RNFL, retinal nerve fiber layer. cognitive status, EDSS score, and physical disability tests are shown in Table 2. A significantly higher EDSS score was found among patients with dyschromatopsia. Additionally, these patients presented a significantly lower number of correct associations on SDMT, and age had a significant effect on this relationship. No statistically significant differences were found for the remaining variables. DISCUSSION This study aimed to explore the association between color vision impairment and subclinical progression in MS. To better understand this question, we determined the frequency of subclinical dyschromatopsia and whether dyschromatopsia is a marker of worse motor and cognitive performances. Some studies have shown that subclinical decline in MS is a continuum, and the presence of color vision impairment may have an important role in the understanding of the disease and its severity (11,15). 277 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 2. Relationship between dyschromatopsia and either cognitive status, EDSS score, or physical disability Study Variables EDSS (total score) Independent Variables Adjusted R2 P Dyschromatopsia 0.073 0.032* Optic neuritis Age Gender Disease duration 9-HPT (seconds) Dyschromatopsia Optic neuritis Age Gender Disease duration T25FWT Dyschromatopsia (seconds) Optic neuritis Age Gender Disease duration SDMT (number Dyschromatopsia of correct associations) Optic neuritis Age Gender Disease duration 0.099 0.254 0.070 0.391 0.715 0.611 0.530 0.070 0.008* 0.064 0.718 0.177 0.229 0.002* 0.236 0.871 0.012* 0.082 0.484 ,0.0001* 0.677 0.580 *Statistically different. 9-HPT, 9-hole peg test; EDSS, expanded disability status scale; SDMT, symbol digit modalities test; T25FWT, timed 25-foot walk test. Our results showed that changes in color vision are more frequent in patients without a history of ON (29.1%) when compared with the results found in other studies of the general population (15). The prevalence of dyschromatopsia was 51.8% for eyes with previous ON. This is significantly lower than that reported in the Optic Neuritis Treatment Trial (14). The difference may be that in the ONTT, color vision was assessed during an acute episode of ON, while patients in our study were examined during the recovery phase, as color vision tends to improve (23). Dyschromatopsia was detected in 25.7% of eyes without previous ON. Similarly, Martínez-Lapiscina et al (15), using HRR plates, found dyschromatopsia in 27% of MS patients (16 of 59) with no history of ON. We found that average peripapillary RNFL thickness, a marker of axonal damage, was significantly lower in eyes with dyschromatopsia, as previously reported (11,15). These changes also may be partially explained by a longer disease duration. In our cohort, average MV, which seems to correlate with axonal loss (4,24), was not affected by the presence of dyschromatopsia. In our patients, this could be explained by the preservation of the temporal quadrants of 278 the RNFL, when compared to the nasal quadrants of the same eye. In our study, we found that patients with dyschromatopsia had a significantly lower performance in SDMT, reflecting worse cognitive performance. Furthermore, older patients had worse results in this test. To the best of our knowledge, SDMT previously has not been used to compare cognitive status in similar studies. Patients with dyschromatopsia also had significantly higher EDSS scores and, consequently, more severe disease. There were no differences in motor performances between groups with and without dyschromatopsia, as determined by the results in T25FWT and 9-HPT. Martínez-Lapiscina et al (15) found that dyschromatopsia in non-ON eyes appeared to be associated with greater disability on motor and cognitive tasks, as patients had lower MS Composite scores. Contrary to our study, their patients with color vision impairment had longer disease duration. Although HRR plates were used to evaluate color vision in our and in other cited studies, the definition of dyschromatopsia differed in each one and therefore, direct comparisons cannot be made (11,18). An attempt to correlate the number of errors in HRR plates with disease duration or disability indicators was not pursued because HRR plates were not designed for the quantitative assessment of dyschromatopsia. Considering the variability of color saturation among different plates, one can infer that a higher number of errors might not necessarily mean more severe dyschromatopsia. We acknowledge the limitations of our study. First, the relatively small sample size of the study population may have limited the detection of significant differences in some parameters of our analyses. A long-term evaluation of these patients would allow the study of the progression of color vision impairment over time. It would be interesting to analyze the progression of dyschromatopsia in parallel to the progression of EDSS and cognitive decline. HRR plates are used for the qualitative assessment of color dysfunction, and for that reason, the severity of dyschromatopsia could not be determined. For the same reason, a possible association between the severity of dyschromatopsia and cognitive and motor performance could not be assessed. Finally, we did not evaluate contrast sensitivity, visual fields, visual evoked potentials, and brain magnetic resonance imaging. Dyschromatopsia appears to be a marker for the detection of subclinical progression of MS, as it can be detected in eyes without previous ON. There is a growing interest in the degenerative component of MS and how it may affect response to treatment and provide clues for the development of new drugs. Longitudinal studies designed to assess color vision impairment over time may prove to be a helpful adjunct in the assessment of progressive axonal degeneration in patients with MS. Felgueiras et al: J Neuro-Ophthalmol 2016; 36: 275-279 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: H. Felgueiras, J. Parra, S. Cruz, P. Pereira, A. F. Santos, A. Rua, D. Meira, E. Santos; b. Acquisition of data: H. Felgueiras, J. Parra, S. Cruz, P. Pereira, A. F. Santos, A. Rua, D. Meira, P. Fonseca, C. Pedrosa, J. N. Cardoso, C. Almeida, M. Araújo, E. Santos; c. Analysis and interpretation of data: H. Felgueiras, J. Parra, S. Cruz, P. Pereira, D. Meira, E. Santos; Category 2: a. Drafting the manuscript: H. Felgueiras, J. Parra, S. Cruz, P. Pereira, A. F. Santos, A. Rua, D. Meira, P. Fonseca, C. Pedrosa, J. N. Cardoso, C. Almeida, M. Araújo, E. Santos; b. Revising it for intellectual content: H. Felgueiras, J. Parra, S. Cruz, P. Pereira, A. F. Santos, A. Rua, D. Meira, P. Fonseca, C. Pedrosa, J. N. Cardoso, C. Almeida, M. Araújo, E. Santos; Category 3: a. Final approval of the completed manuscript: H. Felgueiras, J. Parra, S. Cruz, P. Pereira, A. F. Santos, A. Rua, D. Meira, P. Fonseca, C. Pedrosa, J. N. Cardoso, C. Almeida, M. Araújo, E. Santos. 9. 10. 11. 12. 13. 14. ACKNOWLEDGMENTS The authors thank all the colleagues in the hospitals participating in this study. They also thank Maria José Sá, MD, PhD, and José Vale, MD, for organizing and making this project possible and Pedro Oliveira, MD, PhD, for statistical analysis support. 15. 16. REFERENCES 1. Garcia-Martin E, Pueyo V, Almarcegui C, Martin J, Ara JR, Sancho E, Pablo LE, Dolz I, Fernandez J. Risk factors for progressive axonal degeneration of the retinal nerve fibre layer in multiple sclerosis patients. Br J Ophthalmol. 2011;95:1577-1582. 2. Gordon-Lipkin E, Chodkowski B, Reich DS, Smith SA, Pulicken M, Balcer LJ, Frohman EM, Cutter G, Calabresi PA. Retinal nerve fiber layer is associated with brain atrophy in multiple sclerosis. Neurology. 2007;69:1603-1609. 3. Sepulcre J, Murie-Fernandez M, Salinas-Alaman A, GarcíaLayana A, Bejarano B, Villoslada P. Diagnostic accuracy of retinal abnormalities in predicting disease activity in MS. Neurology. 2007;68:1488-1494. 4. Frohman EM, Frohman TC, Zee DS, McColl R, Galetta S. The neuro-ophthalmology of multiple sclerosis. Lancet Neurol. 2005;4:111-121. 5. Shah A, Hussain R, Fareed M, Afzal M. Prevalence of red-green color vision defects among muslim males and females of Manipuri, India. Iranian J Publ Health. 2013;42:16-24. 6. Norn M. Prevalence of congenital colour blindness among inuit in East Greenland. Acta Ophthalmol Scand. 1997;75:206-209. 7. Mowry E, Balcer L, Galetta S. Multiple sclerosis and the ophthalmologist. Compr Ophthalmol Update. 2007;8:39-49. 8. Sorensen TL, Frederiksen JL, Bronnum-Hansen H, Petersen HC. Optic neuritis as onset manifestation of multiple Felgueiras et al: J Neuro-Ophthalmol 2016; 36: 275-279 17. 18. 19. 20. 21. 22. 23. 24. sclerosis: a nationwide, long-term survey. Neurology. 1999;53:473-478. Hornabrook RSL, Miller DH, Newton MR, MacManus DG, du Boulay GH, Halliday AM, McDonald WI. Frequent involvement of the optic radiations in patients with acute isolated optic neuritis. Neurology. 1992;42:77-79. Plant GT, Kermode AG, Turano G, Moseley IF, Miller DH, MacManus DG, Halliday AM, McDonald WI. Symptomatic retrochiasmal lesions in multiple sclerosis: clinical features, visual evoked potentials, and magnetic resonance imaging. Neurology. 1992;42:68-76. Villoslada P, Cuneo A, Gelfand J, Hauser SL, Green A. Color vision is strongly associated with retinal thinning in Multiple Sclerosis. Mult Scler. 2012;18:991-999. Al-Aqtum MT, Al-Qawasmeh MH. Prevalence of colour blindness in young Jordanians. Ophthalmologica. 2001;215:39-42. Modarres M, Mirsamadi M, Peyman GA. Prevalence of congenital color deficiencies in secondary-school students in Tehran. Inter Ophthalmol. 1996;20:221-222. Optic Neuritis Study Group. The clinical profile of optic neuritis. Experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol. 1991;109:1673-1678. Martínez-Lapiscina E, Ortiz-Pérez S, Fraga-Pumar E, MartínezHeras E, Gabilondo I, Llufriu S, Bullich S, Figueras M, Saiz A, Sánchez-Dalmau B, Villoslada P. Colour vision impairment is associated with disease severity in multiple sclerosis. Mult Scler. 2014;20:1207-1216. Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Montalban X, O'Connor P, Sandberg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS. Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria. Ann Neurol. 2011;69:292-302. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33:1444-1452. Birch J. Clinical use of the American optical company (Hardy, Rand and Rittler) pseudoisochromatic plates for red-green colour deficiency. Ophthalmic Physiol Opt. 1997;17:248-254. Rudick RA, Cutter G, Reingold S. The multiple sclerosis functional composite: a new clinical outcome measure for multiple sclerosis trials. Mult Scler. 2002;8:359-365. Smith A. Symbol Digit Modalities Test Manual. Los Angeles, CA: Western Psychological Services, 1982. Rao SM; Cognitive Function Study Group, NMSS. A Manual for the Brief, Repeatable Battery of Neuropsychological Tests in Multiple Sclerosis. New York, NY: National Multiple Sclerosis Society, 1991. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013;33:629-808. Compston A. Mechanisms of axon-glial injury of the optic nerve. Eye. 2004;18:1182-1187. Costello F. Evaluating the use of optical coherence tomography in optic neuritis. Mult Scler Int. 2011;2011:148394. 279 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.