Correlation of Visual Quality of Life With Clinical and Visual Status in Friedreich Ataxia

Original Contribution Correlation of Visual Quality of Life With Clinical and Visual Status in Friedreich Ataxia Parisa Afsharian, Rachel Nolan-Kenney, BS, Abigail E. Lynch, Laura J. Balcer, MD, MSCE, David R. Lynch, MD, PhD Background: The primary objective was to determine the association of patient-reported vision-specific quality of life to disease status and visual function in patients with Friedreich's ataxia (FRDA). Methods: Patients with FRDA were assessed with the 25Item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) along with measures of disease status (ataxia stage) and visual function (low- and high-contrast letter acuity scores). The relations of NEI-VFQ-25 scores to those for disease status and visual function were examined. Results: Scores for the NEI-VFQ-25 were lower in patients with FRDA (n = 99) compared with published disease-free controls, particularly reduced in a subgroup of FRDA patients with features of early onset, older age, and abnormal visual function. Conclusions: The NEI-VFQ-25 captures the subjective component of visual function in patients with FRDA. Journal of Neuro-Ophthalmology 2020;40:213-217 doi: 10.1097/WNO.0000000000000878 © 2020 by North American Neuro-Ophthalmology Society F riedreich ataxia (FRDA) is a rare autosomal recessive ataxia caused by mutations in the gene located on chromosome 9q13-q21 (1-3). Most (96%) of affected individuals carry a guanine-adenine-adenine (GAA) triplet expansion in the first intron of both alleles, with 4% having a single expanded allele and a point mutation or deletion of the other allele (1-3). Expansions, point mutations, and deletions all lead to functional frataxin deficiency, which impairs the construction of iron sulfur Division of Neurology (PA, AL, DRL), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; and Departments of Neurology (RN-K, LJB), Population Health and Ophthalmology, NYU School of Medicine, Sackler Institute of Graduate Biomedical Sciences, New York, New York. The authors report no conflicts of interest. Address correspondence to David R. Lynch, MD, PhD, Division of Neurology, Children's Hospital of Philadelphia, 502 Abramson Research Center, 3615 Civic Center Blvd, Philadelphia, PA 191044318; E-mail: [e-mail] Afsharian et al: J Neuro-Ophthalmol 2020; 40: 213-217 clusters, mitochondrial function, and energy production. Such dysfunction leads to the clinical features of FRDA including progressive ataxia, fatigue, scoliosis, cardiomyopathy, and, in some individuals, diabetes (1-3). Vision loss is an under-recognized clinical feature of FRDA, becoming more prominent as the disease progresses (4-12). In FRDA, reduced scores for lowcontrast letter acuity, the perception of gray letters on a white or retroilluminated background (4-6), are associated with stronger predictors of disease severity and progression such as longer GAA repeat length, younger age of onset, and worsening clinical status as measured by exam scores. Anatomically, visual impairment in FRDA largely reflects optic neuropathy, which may be chronic or subacute. Anterior visual pathway involvement in patients with FRDA has been confirmed by imaging of the retina with optical coherence tomography (OCT) (6,10-12). To a lesser degree, abnormalities may appear in the central visual pathways based on imaging approaches (12). TABLE 1. Demographic and disease-related features of the FRDA cohort (n = 99) Variable Mean ± SD FARS Vision score Age ADL FDS Age of onset Duration Shorter GAA 57.3 113 23.9 13.2 3.5 11.2 12.7 648 ± ± ± ± ± ± ± ± Median (IQR) 20.9 53 (42.3-70.2) 27 121 (97-136) 11.5 21 (16-29) 6.6 14 (8-18.5) 1.6 4 (2-5) 6.6 10 (7-13) 8.6 10 (7-18) 217 699 (510-787) Skewness 0.49 21.2 1.3 0.1 20.2 2.2 1.2 20.42 Demographic features of this FRDA cohort reveal it to be a very early onset group, with relatively short duration. Skewness values were calculated by STATA. ADL, activities of daily living; FARS, Friedreich Ataxia Rating Scale; FDS, functional disability score; FRDA, Friedreich's ataxia; GAA, guanine-adenine-adenine; IQR, interquartile range. 213 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 2. VFQ scores in the FRDA cohort (n = 99) Variable Mean ± SD NEI-VFQ-25 composite (overall) score 86.4 ± 19.2 (P = 0.0019) 77.7 ± 19.4 (P , 0.0001) 83.9 ± 18.8 58.0 80.0 90.4 84.8 81.8 92.2 86.0 88.4 89.3 77.1 94.2 82.6 10-Item Neuro-Ophthalmic Supplement to the NEI-VFQ-25 NEI-VFQ-25 + 10-Item Supplement NEI-VFQ-25 subscale scores General health General vision Ocular pain Near activities Distance activities Vision-related social functioning Vision-related mental health Vision-related role dysfunction Vision-related dependency Driving Central vision Peripheral vision ± ± ± ± ± ± ± ± ± ± ± ± 24.0 21.4 14.6 24.7 24.3 20.3 23.3 23.5 23.9 32.9 19.6 26.6 Median (IQR) Skewness 94.2 (84.4-97.4) 22.4 80.0 (71.1-94.1) 21.2 90.3 (81.1-95.1) 22.2 50.0 80.0 100 91.7 91.7 100 100 100 100 100 100 100 20.11 21.4 21.6 22.2 21.9 23.2 22.1 22.5 22.4 21.6 23.9 21.7 (50-75) (80-100) (87.5-100) (83.3-100) (75-100) (100-100) (81.2-100) (87.5-100) (91.6-100) (83.3-100) (100-100) (75-100) Mean values are compared with a published control group (15). FRDA, Friedreich's ataxia. Quantitative assessment of visual dysfunction in FRDA has been defined using a variety of methods including lowcontrast letter acuity charts, OCT, and visual field testing. However, patient-reported outcome measures of visionspecific quality of life in FRDA have not yet been examined. The 25-Item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) is a self- or intervieweradministered survey designed by researchers to measure vision-specific quality of life in persons affected with eye diseases (13,14). The NEI-VFQ-25 includes a series of 25 primary questions followed by 2 supplemental sections, thus providing quantifiable data on a person's vision- specific quality of life. The NEI-VFQ-25 generates a series of vision-targeted subscales using both the core 25-item questionnaire and the supplementary questions; sub-scales include a general vision rating, near-vision activities, distance vision activities, limitations in social functioning due to vision, role limitations due to vision, dependency on others due to vision, mental health symptoms due to vision, driving difficulties, limitations with peripheral and color vision, and ocular pain (13). In this study, we used the NEI-VFQ-25 to assess a self-reported vision-specific quality of life in FRDA and to determine the association of scores with markers of disease status and visual impairment. Scores FIG. 1. VFQ composite score. 214 Afsharian et al: J Neuro-Ophthalmol 2020; 40: 213-217 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 3. Rank correlations of NEI-VFQ-25 scores with neurological and visual status in FRDA Outcome NEI-VFQ-25 score NEI-VFQ-25 +10-Item Supplement FARS FARSa FARSb FARSc FARSd FARSe Low-Contrast Acuity Score ADL FDS 20.39* 20.39† 20.44* 20.45* 20.32‡ 20.30‡ 20.37† 20.38† 20.37† 20.35† 20.37† 20.35† 20.52* 0.46* 0.35‡ 0.31‡ 0.40* 0.40* *Spearman rank correlations: P , 0.0001. † Spearman rank correlations: P # 0.001. ‡ Spearman rank correlations: P , 0.01. ADL, activities of daily living; FDS, functional disability score; FARS, Friedreich Ataxia Rating Scale; FARSa, bulbar subscale of FARS; FARSb, upper-extremity subscore; FARSc, lower-extremity subscore; FARSd, peripheral subscore; FARSe, upright stability subscore; FRDA, Friedreich's ataxia. from the 10-Item Supplement to the NEI-VFQ-25, designed to capture neuro-ophthalmologic symptoms (15), were also examined for associations with visual and disease markers. METHODS This study was approved by the IRB at the Children's Hospital of Philadelphia, and participants provided written informed consent through the Friedreich Ataxia Clinical Outcome Measures Study (FACOMS) before testing. All subjects were participants in FACOMS; the only inclusion criterion is the presence of genetically confirmed FRDA. No subjects had coexistent ophthalmologic disease beyond refractive error. All were recruited between July 9, 2018, and December 12, 2018. Subjects also completed the 10Item Supplement to the NEI-VFQ-25 (15), designed to capture additional visual signs and symptoms of patients with neurologic disorders. The NEI-VFQ-25 and 10-Item Supplement were self-administered (with help of coordinator as needed) by each patient either at the time of their usual FACOMS appointment or at home after the visit. Responses were manually entered into a secure data processing system and then scored using a program predesigned based on the scoring guidelines for the NEI-VFQ-25. In addition, data from the FACOMS database were obtained for association with the NEI-VFQ-25 results (16-20). The FACOMS measures included age, sex, duration of FRDA, Friedreich Ataxia Rating Scale (FARS) score (a quantified neurological exam), and low-contrast letter acuity score. Participant characteristics were summarized using descriptive statistics of mean/median or proportions as appropriate for each variable. Spearman rank-correlation coefficients were calculated in a pairwise fashion to determine associations of NEI-VFQ-25 scores with disease status and visual function; non-parametric tests were used where possible as the data were generally skewed with tails at the worse end of the quality of life, disease status, and lowcontrast acuity scales. T-tests were used for comparison with outside control data bases (15,16). RESULTS The present cohort of FRDA patients (n = 99) was younger than most natural history cohorts but had a GAA repeat length longer than most natural history cohorts and an earlier age of onset (median = 11.2 years) (17-22). All participants of the FA-COMS study at Children's Hospital of Philadelphia starting July 5 were included in the study. Disease duration was relatively short (median = 10 years); none of the participants had diabetes, and 43% (n = 43) had self-reported cardiomyopathy. The median functional disability score was 3.5, consistent with a person using a cane with significant difficulty walking (Table 1). In patients with FRDA, scores from the NEI-VFQ-25 were generally skewed with median values higher that mean values (Table 2). This skewness was apparent graphically as well (Fig. 1), with FRDA subjects' overall scoring worse than a published control group (Table 2) (15,16). Certain subscores were most affected in FRDA, including the TABLE 4. Relation of Disease Features in FRDA to NEI-VFQ-25 scores Vision-Specific Quality of Life Outcome NEI-VFQ-25 NEI-VFQ-25 + 10-Item Supplement Age GAA Minimum Repeat 20.21 (P = 0.047) 20.28 (P = 0.0089) 20.17 (P = 0.13) 20.16 (P = 0.15) Age of Onset Sex (0 = male, 1 = female) Duration of FRDA 0.26 (P = 0.015) 0.19 (P = 0.07) 0.013 (P = 0.91) 20.018 (P = 0.87) 20.40 (P = 0.0001) 20.43 (P = 0.0001) FRDA, Friedreich's ataxia; GAA, guanine-adenine-adenine. Afsharian et al: J Neuro-Ophthalmol 2020; 40: 213-217 215 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 5. Comparison of features of FRDA participants by category of NEI-VFQ-25 score Outcome/Demographic Factor Vision score Age ADL FDS FARS Age of onset GAA Duration Mean + SD, VFQ ,80 (n = 17) 73 ± 43 27.9 ± 10.5 15.8 ± 6.9 4.5 ± 1.5 72 ± 25 8.6 ± 4.1 718 ± 211 19.3 ± 9.6 Mean + SD, VFQ .80 (n = 65) 121 ± 25 22.9 ± 11.6 12.9 ± 6.5 3.2 ± 1.5 53 ± 18 12.0 ± 7.0 630 ± 216 10.9 ± 7.4 (P (P (P (P (P (P (P (P , 0.0001) = 0.11) = 0.11) = 0.0021) = 0.0006) = 0.059) = 0.14) = 0.0002) ADL, activities of daily living; FDS, functional disability score; FARS, Friedreich Ataxia Rating Scale; FRDA, Friedreich's ataxia; GAA, guanine-adenine-adenine. general health, general vision, distance vision, and peripheral vision scores. This is consistent with the visual phenotype of FRDA, in which peripheral vision is typically affected earlier and central visual loss occurs later in life. We then sought to identify the features of FRDA patients with lower NEI-VFQ-25 scores (Table 3). Using rank correlations, NEI-VFQ25 scores (with and without addition of the 10-Item Neuro-Ophthalmic Supplement to the NEI-VFQ-25) were lower (worse quality of life) among patients with greater impairment of clinical status in FRDA. This was true for both FRDA-based and visual function scores. In addition, NEI-VFQ-25 scores were worse among patients of older age, greater disease duration, and among those with higher GAA repeat length (genetic severity); these rank correlations were moderate and significant in magnitude (Table 4). We also examined the features of patients with lower NEI-VFQ-25 scores (,80) (Table 5). FRDA patients with lower scores were older, had longer GAA repeat lengths (although this did not reach significance), and demonstrated greater severity of visual and neurological dysfunction. DISCUSSION This study identifies the NEI-VFQ-25 and 10-Item NeuroOphthalmic Supplement as appropriate patient-reported measures of vision-specific quality of life in patients with FRDA. Scores from these tests were significantly lower than a published control group as well as a series of other control groups from studies of neurological and ophthalmological disorders, not explicitly age-matched but similarly composed of young adults (16,23-25). Worse quality of life scores are associated with greater clinical and visual dysfunction. NEI-VFQ-25 and 10-Item Supplement scores were less reflective of genetic severity in our cohort, emphasizing their utility as more direct measures of clinical status. In addition, modest correlations of worse quality of life with increasing age and significant correlations with longer disease duration suggest that NEI-VFQ-25 scores decrease (worsen) as FRDA progresses and the visual dysfunction becomes more severe. 216 Although the cohort size is large for a rare disease, the conclusions are limited by its moderate size and thus the inability to separate closely related variables such as age and duration of disease. Still, in addition to OCT, Humphrey visual field, and visual low contrast acuity testing, NEIVFQ-25 scores can be a useful supplement to evaluate visual function in FRDA. In particular, subscores with the greatest reductions compared with published population norms include peripheral vision, a selective feature of the optic neuropathy associated with FRDA not captured by visual acuity alone. Thus, the NEI-VFQ-25 and complimentary 10-Item Supplement are strong candidates for potential use in therapeutic trials in FRDA. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: P. Afsharian, L. J. Balcer, and D. R. Lynch; b. Acquisition of data: P. Afsharian, R. Nolan-Kenney, A. E. Lynch, and D. R. Lynch; c. Analysis and interpretation of data: P. Afsharian, R. Nolan-Kenney, A. E. Lynch, L. J. Balcer, and D. R. Lynch. Category 2: a. Drafting the manuscript: P. Afsharian, R. Nolan-Kenney, A. E. Lynch, L. J. Balcer, and D. R. Lynch; b. Revising it for intellectual content: P. Afsharian, R. Nolan-Kenney, A. E. Lynch, L. J. Balcer, and D. R. Lynch; Category 3: a. Final approval of the completed manuscript: P. Afsharian, R. NolanKenney, A. E. Lynch, L. J. Balcer, and D. R. Lynch. REFERENCES 1. Strawser C, Schadt K, Hauser L, McCormick A, Wells M, Larkindale J, Lin H, Lynch DR. Pharmacological therapeutics in Friedreich ataxia: the present state. Expert Rev Neurother. 2017;17:895-907. 2. Babady NE, Carelle N, Wells RD, Rouault TA, Hirano M, Lynch DR, Delatycki MB, Wilson RB, Isaya G, Puccio H. 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