Partial Recovery of Amblyopia After Fellow Eye Ischemic Optic Neuropathy

Recovery from amblyopia in adulthood after fellow eye (FE) vision loss is a well-known phenomenon. Incidence of recovery varies widely following different FE pathologies, and the rate of recovery after FE ischemic optic neuropathy (ION) has not been examined. We aimed to determine the frequency and degree of improvement in amblyopic eye (AE) visual function after ION in the FE.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Partial Recovery of Amblyopia After Fellow Eye Ischemic Optic Neuropathy Hannah H. Resnick, MD, Mark F. Bear, PhD, Eric D. Gaier, MD, PhD Background: Recovery from amblyopia in adulthood after fellow eye (FE) vision loss is a well-known phenomenon. Incidence of recovery varies widely following different FE pathologies, and the rate of recovery after FE ischemic optic neuropathy (ION) has not been examined. We aimed to determine the frequency and degree of improvement in amblyopic eye (AE) visual function after ION in the FE. Methods: We performed a retrospective chart review of patients between 2007 and 2021 confirmed to have amblyopia and ischemic optic neuropathy in different eyes. Patients with unstable ocular pathology potentially limiting vision were excluded. We compared the best-corrected visual acuity (VA) in each eye before and after FE ION over time. For patients with available data, we examined change in perimetric performance over time. Results: Among the 12 patients who met the inclusion criteria (mean age 67 ± 8 years), 9 (75%) improved $1 line and 2 (17%) improved $3 lines. The median time from ION symptom onset to maximal improvement was 6 months (range: 2–101 months). Reliable perimetric data were available for 6 patients. Mean sensitivity improved in the AE for all patients, with mean improvement of 1.9 ± 1.1 dB. There was no correspondence between foci of ION-related field loss and gains in field sensitivity in the AE. Department of Ophthalmology (HHR, EDG), Harvard Medical School, Boston, Massachusetts; Department of Ophthalmology (HHR, EDG), Massachusetts Eye and Ear Infirmary, Boston, Massachusetts; Picower Institute for Learning and Memory (MFB, EDG), Massachusetts Institute of Technology, Cambridge, Massachusetts; and Department of Ophthalmology (EDG), Boston Children’s Hospital, Boston, Massachusetts. M. F. Bear: NIH R01 EY029245, RPB #42894. E. D. Gaier: NIH K08 EY030164, Children’s Hospital Ophthalmology Foundation. M. F. Bear: Luminopia, Inc. (scientific advisor and equity). E. D. Gaier: Luminopia, Inc. (scientific advisor, equity, and patent) and Stoke Therapeutics Inc. (consultant). H. H. Resnick: No conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www. jneuro-ophthalmology.com). This article was posted to medRxiv: https://doi.org/10.1101/2021.12. 16.21267939. Address correspondence to Eric D. Gaier, MD, PhD, Department of Ophthalmology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115; E-mail: [e-mail] 76 Conclusions: A high proportion of patients with amblyopia and contralateral ION experience improvement in AEVA. Modest gains in perimetric sensitivity in the AE may accompany FE ION. These findings support the view that residual plasticity in the adult visual cortex can be tapped to support functional improvement in amblyopia. Journal of Neuro-Ophthalmology 2023;43:76–81 doi: 10.1097/WNO.0000000000001646 © 2022 by North American Neuro-Ophthalmology Society A mblyopia results from abnormal visual experience during early childhood and is a common cause of visual impairment among children and adults (1). Treatment for amblyopia has long consisted of occluding the fellow, unaffected eye (FE) before 7 years of age, after which treatment responses are limited (2). Even when treated within this window, amblyopia often persists into adulthood, with an estimated global prevalence of 3.29% among those older than 20 (1). The presence of residual amblyopia increases the lifetime risk of significant visual impairment (3). Clinically significant improvement in amblyopic eye (AE) visual acuity (VA) has been widely reported to occur in adulthood in the setting of FE pathology, including ischemia, trauma, and other causes of vision loss (4–8). Younger age, depth of amblyopia, extent of FE vision loss, and AE fixation pattern have all been reported to be associated with greater gains in AEVA, although inconsistently (4–6), and reports of the incidence of this phenomenon vary from 19% to 90% (4–7). Anterior ischemic optic neuropathy (ION) is the most common cause of acute optic nerve–related visual loss in adults (9,10). To date, only 3 cases of AEVA improvement after FE ION have been reported (8), and the frequency of amblyopia recovery after FE ION is unknown. Given the relatively high prevalence of both amblyopia and ION, a better understanding of this phenomenon could inform clinical decision-making, especially as experimental therapies intended to promote visual recovery in the IONafflicted FE are considered. Resnick et al: J Neuro-Ophthalmol 2023; 43: 76-81 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution To address these knowledge gaps, we conducted a retrospective chart review of patients with amblyopia and FE ION with the primary goal of quantifying AEVA improvement. We examined relationships between clinical factors associated with AE recovery in other contexts and analyzed previously unexplored relationships in perimetric performance. We hypothesized that FE ION would lead to improvement in the AEVA and visual field sensitivity and that perimetric improvement would reflect the location and depth of FE visual field loss. METHODS after FE ION served as the baseline. Refractive correction worn at each visit was recorded as documented. When refractive correction was not documented, but correction was used in the VA measurement, the worn refractive correction was inferred based on (1) the most proximally measured worn refraction or (2) the most recently provided manifest refraction. The use of pinhole during VA measurement was noted and used as the best-corrected measurement. Snellen values were converted to logMAR (11) with additional letters scored as ±0.2 from each line. Counting fingers, hand motion, light perception, and no light perception were designated as 2.1, 2.4, 2.7, and 3.0 logMAR, respectively (11). Visual Fields Patients This study was approved by the Mass General Brigham Institutional Review Board and adhered to the tenets of the Declaration of Helsinki. We examined medical records for patients $18 years of age who were diagnosed with both amblyopia and ION. Cases were collected through medical record billing queries (diagnostic codes H53.0, including all subcodes, and H47.01) for patients registered in the Massachusetts Eye and Ear Infirmary electronic medical record system with diagnosis codes entered between 2007 and 2021. Cases were supplemented with provider (E.D.G.) patient lists. Charts were reviewed manually to determine inclusion. To be included, patients had to have notes confirming diagnoses of amblyopia and ION in opposite eyes and VA measurements within 1 month of FE ION onset. Patients were excluded if the onset of FE ION to the month and year could not be determined. Exclusion criteria also included (1) VA of $20/20 in the non-ION eye at the time of diagnosis or at the preceding visit and (2) a history of bilateral amblyopia. Longitudinal automated visual field (HVF; 24-2 and/or 302 SITA) performance reports were available for a subset of patients at and/or following presentation for FE ION. Given that fixation instability is a defining feature of amblyopia (12), reliability thresholds for exclusion were set as (1) absence of the physiologic blind spot on the grayscale and (2) false positives or negatives $20%. To assess for changes in perimetric sensitivity patterns in the AE over time, raw sensitivity values between the first and last available HVFs were compared at each point. The 2 most nasal points on 24-2 HVFs were excluded to allow for homonymous retinotopic comparisons with the FE. Outermost points on 30-2 HVFs were excluded to allow for comparisons with 24-2 fields over time and blind spots (second-most temporal points above and below the horizontal meridian in 24-2 fields) were excluded. Unweighted Chart Review Patient charts, including scanned outside ophthalmology notes, were manually reviewed for demographic data (age and sex) and ocular history, including history or presence of strabismus and other ocular conditions at the time of FE ION. Laterality of amblyopia was determined as documented in visit notes (Case 6 had inconsistent documentation of AE laterality that was isolated to one provider’s notes with multiple other providers in agreement, so the commonly documented laterality was used). The follow-up length was determined by the last visit with recorded VA measurements or by the onset of a new, vision-limiting FE disorder. Timeframes were recorded to the nearest month if within a few days or as ranges between 2 months otherwise. Graphing and timeframe calculations were performed by rounding the month up if a range was recorded. If VA measurements before FE ION onset were available, AEVA baseline was determined using the best AEVA in the 5 years preceding ION onset. Otherwise AEVA at the first visit Resnick et al: J Neuro-Ophthalmol 2023; 43: 76-81 FIG. 1. Flowchart depicting patient selection. FE, fellow eye; ION, ischemic optic neuropathy; VA, visual acuity. 77 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Resnick et al: J Neuro-Ophthalmol 2023; 43: 76-81 Case # Age Range (yr) Gender 1 70–79 Female 2 70–79 Male 3 60–69 Male 4 60–69 Male 5 60–69 Male 6† 7 8 9 60–69 60–69 60–69 40–49 Female Male Male Male 10 60–69 Female 11 70–79 12 60–69 Notable Ocular Conditions and Changes over the Course of Follow-up* 1. MDF dystrophy, OU, diagnosed after FE ION 1. Pseudophakia, OU, before FE ION 2. ION, AE, 21 days after FE ION onset 1. Congenital cataracts, OU, not visually significant 2. s/p LASIK with monovision (AE near, FE far) 3. ERM, AE, mild 4. ION, AE, w4 years before FE ION 1. Peripheral retinoschisis, FE, before ION 1. Pseudophakia, OU, before FE ION 2. Posterior capsular opacities, OU, mild 3. ERM, OU, mild with lamellar macular hole AE 1. Pseudophakia, OU, before FE ION None 1. Pseudophakia, OU, before FE ION None Strabismus Ever Systemic Steroids Baseline AEVA Yes Yes 20/600 Yes No Yes Best AEVA AEVA Improvement (Lines) Time From ION to Best AEVA Worst FEVA Follow-up Time 1.8 4 mo 20/20 4 mo 20/150 1/20 (20/400) NI 0.0 NA 20/600 12–13 mo No 20/40 20/25-1 1.8 2 mo 20/50-1 2–3 mo (3 d after best) No No 20/50 20/40-1 0.8 4 mo 20/250-1 11–12 mo Yes Yes 20/40 20/25-2 1.6 1 yr, 8–9 mo LP sc 2 yr, 8–9 mo Yes No No No No No No No 20/30-2 20/25-1 20/40 20/400 20/2520/20 NI 20/200 1.0 1.2 0.0 3.0 8 yr, 5 mo 2 mo NA 2–3 mo HM 20/25-3 CF 20/50 10 yr, 8–9 mo 2 yr, 1–2 mo 2 mo 2–3 mo (same as best) 1 yr, 11–12 mo Yes No 20/40 20/30-1 + 2‡ 1.4 8 mo 20/200 Male 1. ION, AE, timing unknown with pale ON at FE ION onset 2. NPDR, OU 3. s/p LASIK, OU 4. ERM, FE, 4–5 mo after FE ION onset (visually insignificant) 1. Ptosis, AE Yes Yes 20/100 20/60-2 1.8 NLP Male None§ No No 20/50 20/20-2 3.6 2 yr, 7–8 mo 9 mo 20/40 2 yr, 7–8 mo (same as best) 4 yr, 5–6 mo *Presence of mild and/or overall stable cataracts not included. † Inconsistencies in documented laterality of amblyopia. ‡ HOTV linear. § ION with subretinal peripapillary hemorrhage; infectious serologic work-up including Lyme and Bartonella negative. AE, amblyopic eye; CF, counts finger; ERM, epiretinal membrane; FE, fellow eye; HM, hand motion; ION, ischemic optic neuropathy; LASIK, laser-assisted in situ keratomileusis; LP, light perception; MDF, map-dot-fingerprint; NI, no improvement; NLP, no light perception; NPDR, nonproliferative diabetic retinopathy. Original Contribution 78 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 1. Characteristics and visual acuities of cases of amblyopia with contralateral ischemic optic neuropathy Original Contribution mean sensitivity at each timepoint was also calculated using raw sensitivities at each included location. Statistical Analysis Statistical analyses were conducted using SPSS (IBM, Armonk, NY). Given the lack of normality among baseline logMAR values (P = 0.003, Kolmogorov–Smirnov test), comparisons of eye-specific VAs between baseline and follow-up visits were assessed using a 2-tailed Wilcoxon signed-rank test. Distribution of time to best AEVA and follow-up time were also non-normal (P = 0.004 and 0.019, respectively; Kolmogorov–Smirnov test), so median and range is reported; otherwise mean (SD) is provided. Associations between the magnitude of change in AEVA and dichotomous factors were assessed using 2-tailed t tests. Spearman correlation testing was used to quantify associations between VA change and continuous factors. In all cases, P , 0.05 was considered statistically significant. RESULTS Case Characteristics Of 34 potential cases, 18 cases were excluded because of ION and amblyopia in the same eye, lack of clearly documented ION and/or amblyopia in notes (presumed billing error), or lack of available VA data fitting inclusion criteria. After initial chart review of the remaining 16 cases, 2 were excluded due to uncertainty regarding the etiology of FE optic neuropathy and 2 were excluded due to significant potential confounders (FE trauma before ION in one case and optic disc edema in the AE at the initial evaluation in the other) (Fig. 1). Twelve cases were included in the final analysis (Table 1). Of these, 2 (Cases 3 and 10) had a history of stable ION in the AE (onsets 4 years and within 8 months prior, respectively) and 2 were women (2/12; 17%). The mean (SD) age was 67 ± 8.0. The history of occlusion therapy in childhood was noted in 6/12 cases (50%), and 7/12 (58.3%) had current or prior strabismus. ION was treated in 3/12 (25%) patients with systemic corticosteroids. The median length of follow-up was 13.5 months (range: 2–129 months). Change in AEVA The median baseline AEVA was 0.35 logMAR (Snellen 20/ 40-20/50), range: 0.12–1.48 (20/25-1 to 20/600) (Table 1). The baseline AEVA measurements preceded ION onset in 6 cases, of whom 4 had ,1 line of difference between the AEVA before and at the initial evaluation for FE ION. The baseline AEVA before FE ION onset was 2 and 4.9 logMAR lines greater than that measured at FE ION presentation for Cases 3 and 7, respectively, with Case 7 using only PH rather than prescribed refractive correction at the time of FE ION presentation. Resnick et al: J Neuro-Ophthalmol 2023; 43: 76-81 From baseline through the follow-up period, best AEVA improved significantly by a mean (SD) of 0.15 ± 0.11 logMAR (1.5 lines, 95% CI: 0.83–2.17 lines, P = 0.004) (Fig. 2). Of the 12 cases analyzed, 9 (75%) experienced $1 line of AEVA improvement and 2 (16.7%, Cases 9 and 12) exhibited $3 lines of improvement. The median time from onset of ION symptoms to best AEVA was 6 months (range: 2–101 months), with 6/9 (66.7%) improved cases reaching their best AEVA within 1 year. We next evaluated clinical factors that may contribute to AEVA improvement in the setting of FE ION. Among the 9 patients whose AEVA improved $1 line, 8 had available data on their refractive correction at baseline and follow-up time points. Different refractive correction for the AE, with or without pinhole, was used by 7 patients between baseline and when the best AEVA was recorded.; spherical equivalent changed by .1.0 D in 2 cases (1 and 11) (See Supplemental Digital Content, Table S1, http://links.lww. com/WNO/A612). The mean (SD) FEVA nadir was 1.3 ± 1.1 logMAR. There was neither association between baseline AEVA and lines of AEVA improvement (P . 0.3) nor between FEVA nadir and lines of AEVA improvement (P . 0.2) (See Supplemental Digital Content, Figure S1, http://links.lww.com/WNO/A610; Supplemental Figures Legend). Of those with strabismus, 6/7 (85.7%) improved $1 line in AEVA. There was no difference in the magnitude of AEVA improvement between those with strabismus and those without (P . 0.6). The 3 cases treated with systemic corticosteroids experienced AEVA improvement of 0.16–0.18 logMAR (1.6–1.8 lines), similar to that seen among those not treated (P . 0.6). AE Visual Fields Reliable HVFs were available for 6/12 patients (Cases 3, 5, 7, 10, 11, and 12). Cases 3 and 10 had AE field defects in the setting of prior ION. The mean (SD) unweighted mean sensitivity (MS) at baseline was 24.8 ± 2.9 dB and improved in 6/6 patients by a mean (SD) of 1.9 ± 1.1 dB (Fig. 3). There was no significant association between the change in MS and AEVA lines of improvement (P . 0.9). Cases 3 and 11, who exhibited the greatest improvement in MS (+2.24 and +4.04 dB, respectively), both improved 1.8 lines in AEVA. There was no appreciable relationship between the pattern of change in AE HVF sensitivity over time and the acquired visual field deficit in the FE (See Supplemental Digital Content, Figure S2, http://links.lww.com/ WNO/A611; Supplemental Figures Legend). CONCLUSIONS The report of patients with amblyopia and FE ION is limited to one published series of 3 cases, all of whom experienced AEVA improvement (8). Analyzing 12 cases of amblyopia and FE ION, we show that partial, but clinically significant, AEVA recovery is common. To the best of our 79 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution knowledge, this is the first report of peripheral amblyopic visual recovery after FE injury, thereby expanding the clinical phenotype of amblyopia recovery in adulthood. We found that 75% of patients experience $1 line of AEVA improvement, with 17% experiencing improvement of $3 lines. Prior reported incidences of AE improvement after FE injury have varied widely. A 1984 European study found an incidence of improvement of 28.5% (4). In a 2002 United Kingdom study including patients with FE vision loss from multiple causes, Rahi et al (5) reported only 48/254 (19%) of cases experienced AEVA improvement with 10% improving $2 lines. By contrast, studies examining AEs in the setting of several specific causes of FE vision loss, rather than any cause of decreased contralateral vision, have found higher rates of recovery: 52% of those with FE uveal melanoma had $2 lines AEVA improvement (7), as did 90% of those with age-related macular degeneration (6). Wide variance in reported AEVA recovery may suggest that certain types of contralateral eye pathologies are stronger drivers of recovery than others. Closure of the critical period of visual development is defined by an increase in the threshold for the neuroplasticity necessary for recovery from amblyopia. This threshold is apparently lowered by damage to the FE. Ocular pathologies that similarly limit visual function in the FE may impart drastically different effects on retinal ganglion cell function, the visual signals transmitted to the brain (e.g., cataract vs ION), and the potential for recovery from amblyopia. Precisely how different forms of FE damage promote recovery remains to be determined, but recent animal studies have shown that temporary silencing of the retina ganglion cell activity in one or both eyes enables rapid recovery from deprivation amblyopia in adults that persists when FE activity is restored (13–16). These observations are readily explained by the temporary lowering of the modification threshold for plasticity (17). Accordingly, FE optic neuropathy (ION) and retinal pathologies should, therefore, serve as relatively strong drivers of AE recovery, even in adulthood. Our findings also suggest that VA may not capture the full extent of AE improvement after FE injury. Although VA is typically used to characterize the severity of amblyopia and response to treatment, multiple other visual deficits define the amblyopic state (18,19), including decreased perimetric sensitivity (20). All patients with available and reliable visual field data demonstrated clinically meaningful improvement in AE perimetric sensitivity. The magnitude and consistency of improvement in AE MS argue against significant artifactual contributions from test–retest variance and/or familiarity with HVF testing. Although our analysis was limited by the sample size, there is no relationship between improvements in perimetric performance and VA, suggesting central and peripheral AE visual gains may be independent in the setting of FE ION. Unlike previous, largely isolated reports of AE improvement with FE pathology, our study design allows us to estimate the rate of AE recovery after FE ION. The rarity of this condition limited the power with which we could assess hypothesized clinical relationships, including the relationship between the extent of FE vision loss and the amount of improvement in the AE. Further studies of amblyopia recovery are needed to assess whether the magnitude of recovery in central and/or peripheral visions depends on the magnitude of FE vision loss. Despite this, unambiguous, clinically meaningful trends emerged from our analysis. The FIG. 2. Improvement in AE VA after FE ION. Change in AEVA from baseline to follow-up plotted across time since FE ION onset. Values at month 0 represent baselines VA values defined as the best AEVA in the 5 years preceding or at the time of presentation for FE ION. AE, amblyopic eye; FE, fellow eye; ION, ischemic optic neuropathy; VA, visual acuity. FIG. 3. Improvement in AE perimetric sensitivity after FE ION. Change in automated visual field (HVF) mean sensitivity in the AE from baseline to follow-up plotted across time since FE ION onset for the 6/12 cases with reliable AE HVF data. AE, amblyopic eye; FE, fellow eye; ION, ischemic optic neuropathy. 80 Resnick et al: J Neuro-Ophthalmol 2023; 43: 76-81 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution retrospective design, albeit the only feasible mode to study this phenomenon, introduces inconsistencies in visual functional measurements, follow-up intervals, and reliability and availability of clinical detail. Importantly, our study was unable to evaluate the effect of prior amblyopia treatment on recovery in adulthood because of inconsistent documentation of treatment history. Additional studies are needed to better understand the effect of incomplete childhood treatment on the potential for recovery later in life. To specifically mitigate the concern for sampling bias with multiple VA measurements, we used the best reported AEVA in the 5 years preceding contralateral ION where possible to provide conservative measures of improvement. In addition, our study examined patients receiving care at a tertiary center, so these patients may not be representative of the population at large. Another major concern was potential confounding by change in AE refractive correction. Improvement in AE function may have enabled these patients to provide more accurate responses during manifest refractions, and/or providers may have been more motivated to prescribe accurate AE correction after FE visual loss. Among studies of AE recovery after FE injury, this is one of the few to examine change in refractive correction over time (5). Nevertheless, the small magnitude of change in AE refractive correction and near universal employment of pinhole VA at both time points argue against a significant refractive contribution to the AEVA gains observed in our cohort. In conclusion, partial recovery of AE visual function is common and clinically significant in the setting of FE ION. Further study is needed to integrate these findings with prior reports of AE recovery, from which we may glean some important pathophysiologic insights into the neuroscientific bases for adult plasticity as it relates to visual recovery. STATEMENT OF AUTHORSHIP Conception and design: Eric D. Gaier; Acquisition of data: Hannah H. Resnick; Analysis and interpretation of data: Hannah H. Resnick, Eric D. Gaier. Drafting the manuscript: Hannah H. Resnick; Revising the manuscript for intellectual content: Hannah H. Resnick, Mark F. Bear, Eric D. Gaier. Final approval of the completed manuscript: Hannah H. Resnick, Mark F. Bear, Eric D. Gaier. 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