Utilization of Visual Acuity Retroilluminated Charts for the Assessment of Afferent Visual System Dysfunction in a Pediatric Neuroimmunology Population

Background: Visual acuity has been a significant outcome measure in clinical trials for patients suffering from neuro-ophthalmological diseases and multiple sclerosis; however, there are limited data on the comparison of various testing strategies in pediatric patients with these disorders. Clinical trials using vision as an outcome could include a variety of tools to assess the acuity, including 2-m and 4-m standardized retroilluminated charts.

Clinical Research: Epidemiology Meets Neuro-Ophthalmology Section Editors: Heather E. Moss, MD, PhD Stacy L. Pineles, MD Utilization of Visual Acuity Retroilluminated Charts for the Assessment of Afferent Visual System Dysfunction in a Pediatric Neuroimmunology Population Downloaded from http://journals.lww.com/jneuro-ophthalmology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 05/04/2022 Peter V. Sguigna, MD, Morgan C. McCreary, PhD, Darrel L. Conger, CRA, Jennifer S. Graves, MD, PhD, Leslie A. Benson, MD, Amy T. Waldman, MD, Benjamin M. Greenberg, MD, MHS, on behalf of the PERCEPTION Collaboration Background: Visual acuity has been a significant outcome measure in clinical trials for patients suffering from neuroophthalmological diseases and multiple sclerosis; however, there are limited data on the comparison of various testing strategies in pediatric patients with these disorders. Clinical trials using vision as an outcome could include a variety of tools to assess the acuity, including 2-m and 4-m standardized retroilluminated charts. Methods: We investigated the difference in Early Treatment Diabetic Retinopathy Study (ETDRS) scores obtained using 2-m and 4-m charts, as well as the impact of optic neuritis, use of vision correction, age, and gender on visual acuity data from 71 patients with pediatric neuroimmunological conditions in a cross-sectional study. Results: We determine that the ETDRS letter scores obtained using 4-m charts are on average 3.43 points Multiple Sclerosis Division (PVS, MM, DC, BMG), Department of Neurology and Neurotherapeutics, University of Texas Southwestern, Dallas, Texas; Department of Neurology (JG), University of California San Diego, San Diego, California; Department of Neurology and Pediatrics (LB), Boston Children’s Hospital, Boston, Massachusetts; Division of Neurology (ATW), Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; and Departments of Neurology and Pediatrics (ATW), Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. This work was supported in part by the National Multiple Sclerosis Society (NMSS). P. V. Sguigna has received grant support from the NMSS and PSTP. Morgan McCreary has nothing to declare. A. T. Waldman has received grant support from the NIH (K23NS069806), NMSS, and the United Leukodystrophy Foundation. She has received additional support for investigator-initiated research from Biogen Idec and Ionis Pharmaceuticals. She has received honoraria from UpToDate and consulting fees from Optum Inc. B. M. Greenberg has received grant support from the NIH, NMSS, Transverse Myelitis Association, PCORI, Guthy-Jackson Charitable Foundation, Chugai, MedImmune, MedDay, and Genentech. He has received consulting fees from Alexion, Novartis, EMD Serono, and Celgene. He is an unpaid board member of the Transverse Myelitis Association. The remaining authors report no conflicts of interest. Address correspondence to Benjamin M. Greenberg, MD, Department of Neurology and Neurotherapeutics, University of Texas Southwestern, 5323 Harry Hines Boulevard, Dallas, TX 75390; E-mail: [e-mail] Sguigna et al: J Neuro-Ophthalmol 2021; 41: 19-23 less (P = 0.0034) when testing monocular ETDRS letter scores and on average 4.14 points less (P = 0.0008) when testing binocular ETDRS letter scores, relative to that obtained using the 2-m charts. However, we find that when performing monocular testing, optic neuritis in the eye being tested did not result in a statistically significant difference between 2-m and 4-m ETDRS letter scores. Conclusions: Although visual acuity charts are formatted by the distance, there are significant differences in the number of letters correctly identified between 2-m and 4-m charts. Although the differences may not impact the clinical acuity, research protocols should consider these differences before collapsing data across disparate studies. Journal of Neuro-Ophthalmology 2021;41:19–23 doi: 10.1097/WNO.0000000000001001 © 2020 by North American Neuro-Ophthalmology Society V isual acuity is increasingly used as an outcome measure in multiple sclerosis (MS) studies. As the second largest contributor to functional disability as measured by the Expanded Disability Status Scale, the high-contrast visual acuity has significant correlations with both traditional and innovative retinal structural metrics (1). The structure– function relationship between the retina, optic nerve, and visual acuity make measurements of vision an attractive focus of neuroprotection and remyelination studies (2–4). Visual acuity is also an attractive outcome because it has been correlated with patient-centered outcomes regarding the quality of life (5,6). There are numerous ways to measure the visual acuity, although historically the visual acuity has often been measured using Early Treatment Diabetic Retinopathy Study (ETDRS) charts (7,8), most notably in the Optic Neuritis (ON) Treatment Trial (9,10). This allows for both monocular and binocular visual assessment, which has important correlates for imaging studies and the development of higher-order vision such as stereoacuity 19 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology (11,12). In the realm of pediatric MS, there is a dearth of data for visual assessment in a population with increased neurological and ophthalmological comorbidities (13). A standard testing protocol using retroilluminated ETDRS charts in neurologic trials typically suggests that the subject attempts the 4-m chart. If the subject is unable to read the 20/ 200 line, the 4-m chart is moved closer to the patient, and the acuity is tested at 2 m. The scoring accounts for testing among patients with good and poor acuity. In this protocol, the 4-m chart is used at both distances; however, there is also an ETDRS chart formatted for testing at 2 m. The 2-m chart has been favored in clinical practice because the distance is more suitable to smaller examination rooms and allows for less time in research protocols. It also allows testing of patients with generally intermediate visual acuities and has good interrater reliability (14). Although, in general, the FDA advocates for testing at 4 m for trial purposes, they also support the validation of tools that use letters of varying sizes and repeats threshold testing to determine the smallest letters correctly. The ETDRS charts are formatted at 2 m and 4 m based on the visual angle and distance; thus, the letter sizes between the charts are not equivalent. Although the scores are similar in patients with good vision and unlikely to influence clinical practice, the scores are divergent in adults with ophthalmologic pathology such as age-related macular degeneration, diabetic retinopathy, and cataracts (15). These conditions are rare in pediatrics, and it is unknown whether the acuity scores of youth with ON and MS differ between 2-m and 4-m charts. The PEdiatric Research Collaboration ExPloring Tests In Ocular Neuroimmunology (PERCEPTION) study was developed to address the gaps in knowledge regarding outcome metrics and their interpretation in pediatric neuroinflammatory diseases. Children with central nervous system neuroinflammatory disease are enrolled at 4 academic centers: Boston Children’s Hospital, Children’s Hospital of Philadelphia, University of Texas Southwestern/Children’s Hospital Dallas, and the University of California San Diego (previously recruited from the University of California, San Francisco). As part of the process of creating a uniform data collection protocol, various assessments were analyzed to determine data reliability. Although there are standard operating procedures for testing vision using retroilluminated cabinets with standard 2- or 4-m ETDRS charts, to the best of authors’ knowledge, there are no data to determine whether the vision measured with each chart is interchangeable in pediatrics. If the data are not interchangeable, then a multicenter study would have to ensure that every site used the same ETDRS charts. This study was designed to determine whether data using 2-m and 4-m charts are comparable in children. METHODS Children seen at the Children’s Medical Center Dallas Demyelinating Clinic underwent routine visual acuity test20 ing with ETDRS retroilluminated charts. Children were tested with 2-m and 4-m charts per standardized protocols on the same day, and their relative visual acuities were assessed (16). Testing was performed in an area free from distraction testing the right eye first, the left eye second, and both eyes last. Children were tested with the best-corrected visual acuity with a recent refraction, and separate charts were used at 2 m and 4 m to eliminate memory of the chart as a confounder. Children were seated across from charts at a fixed distance with direct supervision during testing. Statistical analysis was performed using SAS software, Version 9.4. Copyright, SAS Institute Inc. SAS, and all other SAS Institute Inc. product or service names are registered trademarks of SAS Institute Inc, Cary, NC. To assess the difference between 2-m and 4-m chart ETDRS letter scores corresponding to the monocular and binocular examinations while controlling for measurements from the same patient, a marginal model was fit to the difference between the 2 scores (4 m 2 2-m) with the identity link function, and the intrasubject correlation was captured using the generalized estimating equations (GEE) approach assuming an unstructured correlation matrix. We determined the difference between 2-m and 4-m ETDRS letter scores and the impact of age, gender, use of vision correction, and history of ON on the difference, and these variables were included as covariates in the marginal model. The appropriateness of the specified identity link function was examined using the cumulative residual plot. The significance level was defined to be 5%. RESULTS ETDRS measurements using the 2-m and 4-m charts for the left eye, right eye, and both eyes were available for n = 71 patients (n = 142 eyes) diagnosed with pediatric-onset MS. Of the 71 patients, 16 patients had a history of bilateral ON and 6 patients had a history of unilateral ON, 3 in the left eye and 3 in the right eye. Approximately 86% of patients were on disease-modifying therapy at the time of testing. Table 1 displays demographic information for the patients in the study. For the entire cohort, the mean ETDRS scores using the 2-m charts including binocular scores was 57.61 (SD = 7.02) compared with 54.61 (SD = 7.31) on the 4-m charts, which represents a mean difference of 23.00 letters (SD = 22.59), further categorized in Table 2. Figure 1 displays the differences between 2-m and 4-m ETDRS scores for tests performed on both eyes, the left eye, and the right eye. The difference between 2-m and 4-m ETDRS scores for monocular testing was estimated to be 3.43 letters (95% CI: 1.14–5.72, P = 0.0034), and the difference between 2- and 4-m ETDRS scores for binocular testing was estimated to be 4.14 letters (95% CI: 1.72–6.57, P = 0.0008). Incorporating the data into the marginal model did not suggest a significant impact of gender (P = 0.69), the use of vision Sguigna et al: J Neuro-Ophthalmol 2021; 41: 19-23 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Sguigna et al: J Neuro-Ophthalmol 2021; 41: 19-23 56.99 (6.04) 58 (35–69) 56.55 (6.32) 58 (35–69) 57.95 (5.38) 58.5 (50–67) 53.46 (8.11) 56 (24–69) 52.12 (8.49) 56 (24–69) ETDRS, Early Treatment Diabetic Retinopathy Study; ON, optic neuritis. 54.42 (7.11) 55 (32–63) 53.69 (6.89) 55 (28–68) 52.53 (7.95) 54 (33–63) 53.38 (7.15) 55 (28–68) 60.06 (6.14) 61 (42–70) 60.36 (5.37) 62 (51–70) 56.28 (7.92) 59 (29–70) 56.06 (8.05) 58.5 (29–70) 56.89 (7.72) 59 (35–68) 56.39 (6.50) 56 (35–70) 56.31 (6.51) 56 (35–70) 56.63 (6.63) 56 (40–67) No ON 52 ON 19 Right TABLE 2. ETDRS scores for the cohort Total 71 CONCLUSIONS We demonstrated a number of statistically significant differences in the 2-m and 4-m ETDRS chart scores in a pediatric neuroimmunology population. The difference in the ETDRS letter scores obtained using the 2-m and 4-m ETDRS charts persisted in the GEE model even after controlling for ON, vision correction, gender, and age. Although the difference between scores is evident when testing both eyes simultaneously or each eye individually, the difference between the charts is greater during binocular testing relative to monocular testing. These results suggest that studies collecting visual acuity data using the ETDRS charts in the pediatric population will need to strongly consider either a 4-m or 2-m ETDRS chart because these results are not commensurate. Patients had statistically significant better vision scores on the 2-m ETDRS chart relative to the 4-m ETDRS chart, despite letters being scaled down on the 2-m chart by design. Although the literature has described a roughly 1letter difference in 2-m and 4-m ETDRS scores (16), the difference in our study is greater, possibly suggesting either a disease or population effect. In testing eyes with ON, this difference becomes insignificant, arguing against a precise disease effect. Conversely, the lack of age being a significant No ON 52 ON 19 Left Total 71 correction (P = 0.73), or age (P = 0.56) on the difference between 2-m and 4-m ETDRS letter scores. Although not statistically significant at the 5% significance level, the increase in the difference between 2-m and 4-m ETDRS letter scores when testing both eyes without ON relative to monocular testing approached significance (P = 0.06). There was no evidence to suggest that unilateral or bilateral ON led to a greater difference in 4-m and 2-m ETDRS letter scores (P = 0.23 and P = 0.83, respectively). Although not statistically significant, the impact of bilateral ON when testing both eyes approached significance and suggests a decrease in the difference between 2-m and 4m ETDRS scores by 1.50 letters (95% CI: 20.21 to 3.21, P = 0.08). 2m Mean (SD) Median (range) 4m Mean (SD) Median (range) ON 22 ON, optic neuritis; RNFL, Retinal Nerve Fiber Layer. No ON 49 71 14.96 (3.09) 15 (7–21) 25 (35.21%) 29 (40.85%) 22 (30.99%) 51 (72%) 93 (19) 8.6 (0.5) Both n Average age (SD) Median age (range) Female (%) Wears corrective lenses (%) Presence of ON (%) On disease-modifying therapy treatment Average RNFL (SD) Average macular volume (SD) Value n Variables Total 71 TABLE 1. Demographics for the sample of 71 patients 60.15 (5.88) 61 (42–70) Clinical Research: Epidemiology Meets Neuro-Ophthalmology 21 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology FIG. 1. ETDRS scores using 2-m and 4-m charts for 71 patients. ETDRS, Early Treatment Diabetic Retinopathy Study. covariate in the GEE argues against an age-related population effect. As binocular scores mirrored that which were found in monocular scores, this is unlikely to localize purely to the pertinent history of ON, as further evidenced by the lack of statistical significance for the history of ON on the model. Similarly, as the presence of visual correction was not statistically significant, this is unlikely a purely ophthalmological phenomenon regarding the angle of resolution achieved at the 2-m distance compared with the 4-m distance. Ultimately, although 5 letters is considered a clinically significant ETDRS change, a consistent imprecision of the distance in measuring the ETDRS could have unintended consequences in trials. Differences in 2-m and 4-m scores preclude the ability to compare trial results obtained at various distances. Our data further demonstrate that harmonization of such a simplistic detail in the testing protocol can avoid systematic bias in trial execution and interpretation for a potential longitudinal study. We acknowledge that we did not compare the results in patients with low vision using the 4-m chart at 2 m with their results at 2 m, as none of the subjects failed to read at least the 20/200 line on the 4-m chart. This study’s population did have an atypically high male prevalence, but gender is unlikely to have influenced the acuity because it did not achieve the statistical significance in the model. This was a single-center trial with a relatively small patient population, and hence, additional data are needed to validate the findings in a more diverse, multicenter study, with additional methodological manipulation concentrated for patients with a history of ON. Although the ETDRS chart has been historically favored by the FDA, The Jaeb Visual Acuity Screener has been recently developed for the pediatric population and includes ease of use with impressive sensitivity and specificity for disease for the younger pediatric population but is generally used as a screening test. Amblyopia Treatment Study HOTV and the E-ETDRS have been adapted particularly for study in this patient population but require standardized electronic equipment and a sophisticated testing algorithm. In the research setting, as the world moves toward computerized methodologies, it is possible 22 that the findings with our ETDRS methodology could be reflected in other measuring tools. P. V. Sguigna and M. McCreary contributed equally to the work. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: P. V. Sguigna, M. McCreary, D. Conger, A. T. Waldman, B. M. Greenberg, J. Graves, and L. Benson; b. Acquisition of data: P. V. Sguigna, D. Conger, and B. M. Greenberg; c. Analysis and interpretation of data: P. V. Sguigna, D. Conger, B. M. Greenberg, A. T. Waldman, J. Graves, M. McCreary, and L. Benson. Category 2: a. Drafting the manuscript: P. V. Sguigna, M. McCreary, and B. M. Greenberg; b. Revising it for intellectual content: P. V. Sguigna, D. Conger, B. M. Greenberg, A. T. Waldman, J. Graves, M. McCreary, and L. Benson. Category 3: a. Final approval of the completed manuscript: P. V. Sguigna, D. Conger, B. M. Greenberg, A. T. Waldman, J. Graves, M. McCreary, and L. Benson. REFERENCES 1. Murphy OC, Kwakyi O, Iftikhar M, Zafar S, Lambe J, Pellegrini N, Sotirchos ES, Gonzalez-Caldito N, Ogbuokiri E, Filippatou A, Risher H, Cowley N, Feldman S, Fioravante N, Frohman EM, Frohman TC, Balcer LJ, Prince JL, Channa R, Calabresi PA, Saidha S. Alterations in the retinal vasculature occur in multiple sclerosis and exhibit novel correlations with disability and visual function measures. Mult Scler. 2020;26:815–828. 2. Nguyen J, Rothman A, Fitzgerald K, Whetstone A, Syc-Mazurek S, Aquino J, Balcer LJ, Frohman EM, Frohman TC, Crainiceanu C, Beier M, Newsome SD, Calabresi PA, Saidha S. Visual pathway measures are associated with neuropsychological function in multiple sclerosis. Curr Eye Res. 2018;43:941–948. 3. Waldman AT, Liu GT, Lavery AM, Liu G, Gaetz W, Aleman TS, Banwell BL. Optical coherence tomography and visual evoked potentials in multiple sclerosis. Neurol. 2017;4:e356–e362. 4. Yeh EA, Marrie RA, Reginald YA, Buncic JR, Noguera AE, O’Mahoney J, Mah JK, Banwell B, Costello F; On Behalf of the Canadian Pediatric Demyelinating Disease Network. Functional-structural correlations in the afferent visual pathway in pediatric demyelination. Neurol. 2014;83:2147–2152. 5. Mowry E, Loguidice MJ, Daniels AB, Jacobs DA, Markowitz CE, Galetta SL, Nano-Schiavi ML, Cutter GR, Maguire MG, Balcer LJ. Vision related quality of life in multiple sclerosis: correlation with new measures of low and high contrast letter acuity. J Neurol Neurosurg Psychiatry. 2009;80:767–772. Sguigna et al: J Neuro-Ophthalmol 2021; 41: 19-23 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology 6. Chahin S, Miller D, Sakai RE, Wilson JA, Frohman T, Markowitz C, Jacobs D, Green A, Calabresi PA, Frohman EM, Galetta SL, Balcer LJ. Relation of quantitative visual and neurologic outcomes to fatigue in multiple sclerosis. Mult Scler Relat Disord. 2015;4:304–310. 7. Early Treatment Diabetic Retinopathy Study Research Group. Early treatment diabetic retinopathy study design and baseline patient characteristics: ETDRS report number 7. Ophthalmology. 1991;98:741–756. 8. Rosser DA, Laidlaw DAH, Murdoch IE. The development of a “reduced logMAR” visual acuity chart for use in routine clinical practice. Br J Ophthalmol. 2001;85:431–436. 9. Beck RW, Cleary PA, Anderson MM, Keltner JL, Shults WT, Kaufman DI, Buckley EG, Corbett JJ, Kupersmith MJ, Miller NR, Savino PJ, Guy JR, Trobe JD, McCrary JA, Smith CH, Chrousos GA, Thompson HS, Katz BJ, Brodsky MC, Goodwin JA, Atwell CW; Optic Neuritis Study Group. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med. 1992;326:581–588. 10. Optic Neuritis Study Group. The clinical profile of optic neuritis: experience of the optic neuritis treatment trial. Arch Ophthalmol. 1991;109:1673–1678. Sguigna et al: J Neuro-Ophthalmol 2021; 41: 19-23 11. Pineles SL, Birch EE, Talman LS, Sackel DJ, Frohman EM, Calabresi PA, Galetta SL, Maguire MG, Balcer LJ. One eye or two: a comparison of binocular and monocular low-contrast acuity testing in multiple sclerosis. Am J Ophthalmol. 2011;152:133–140. 12. Kattan JM, Velez FG, Demer JL, Pineles SL. Relationship between binocular summation and stereoacuity after strabismus surgery. Am J Ophthalmol. 2016;165:29–32. 13. Brady KM, Brar AS, Lee AG, Coats DK, Paysee EA, Steinkuller PG. Optic neuritis in children: clinical features and visual outcome. J AAPOS. 1999;3:98–103. 14. Klein R, Klein BEK, Moss SE, DeMets D. Inter-observer variation in refraction and visual acuity measurement using a standardized protocol. Ophthalmology. 1983;90:1357– 13259. 15. Wan MJ, Adebona O, Benson LA, Gorman MP, Heidary G. Visual outcomes in pediatric optic neuritis. Amer J Ophth. 2014;158:503–507. 16. Kaiser P. Prospective evaluation of visual acuity assessment: a comparison of Snellen versus ETDRS charts in clinical practice (an AOS thesis). Trans Am Ophthalmol Soc. 2009;107:311–324. 23 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.