Clinical and Optic Disc Characteristics of Patients Showing Visual Recovery in Leber Hereditary Optic Neuropathy

Background: The visual prognosis in Leber hereditary optic neuropathy (LHON) is generally poor. However, some individuals can have spontaneous visual recovery (VR) in one or both eyes by a mechanism that is not yet clearly understood. The purpose of this study was to determine whether certain clinical and optic disc features are associated with VR in patients with LHON. Methods: We retrospectively examined 80 eyes of 40 patients with LHON using clinical databases, fundus photographs, and high-definition spectral-domain optical coherence tomography (OCT) images. VR was defined as a gain of 3 or more lines of logarithm of the minimum angle of resolution (logMAR)-scaled visual acuity from nadir; this represents a doubling of the visual angle. Patients were divided into VR and nonrecovery (NR) groups. Using fundus photographs, we measured optic disc size and evaluated for the presence of optic disc features, including peripapillary telangiectasia, disc hyperemia, and swelling. We also measured the disc area, cup-to-disc ratio, and rim area of the optic disc using OCT. Results: Twenty-one of 80 eyes (26%) had a VR. The VR occurred within 2 years after onset in 81% of cases. The VR group showed younger age at onset (21 vs 29 years, P = 0.017) and better visual acuity at the nadir (1.39 vs 2.16 logMAR, P < 0.001) compared with the NR group. Optic disc features, particularly peripapillary telangiectasia (P = 0.027) and disc hyperemia (P = 0.006), were more prominent in the NR group. The cup-to-disc ratio was significantly smaller (0.64 vs 0.71, P = 0.004) and the rim area was significantly greater (1.17 vs 0.85 mm, P < 0.001) in the VR group compared with the NR group. Conclusions: A younger age at onset and a less severe reduction of visual acuity at the nadir were associated with a higher probability of VR. Presence of peripapillary telangiectasia and optic disc hyperemia may serve as predictive factors for poor visual prognosis in patients with LHON.

Clinical Research: Epidemiology Meets Neuro-Ophthalmology Section Editors: Heather E. Moss, MD, PhD Stacy L. Pineles, MD Clinical and Optic Disc Characteristics of Patients Showing Visual Recovery in Leber Hereditary Optic Neuropathy Yeji Moon, MD, Ungsoo S. Kim, MD, PhD, Jinu Han, MD, Hyosook Ahn, MD, PhD, Hyun Taek Lim, MD, PhD, Background: The visual prognosis in Leber hereditary optic neuropathy (LHON) is generally poor. However, some individuals can have spontaneous visual recovery (VR) in one or both eyes by a mechanism that is not yet clearly understood. The purpose of this study was to determine whether certain clinical and optic disc features are associated with VR in patients with LHON. Methods: We retrospectively examined 80 eyes of 40 patients with LHON using clinical databases, fundus photographs, and high-definition spectral-domain optical coherence tomography (OCT) images. VR was defined as a gain of 3 or more lines of logarithm of the minimum angle of resolution (logMAR)–scaled visual acuity from nadir; this represents a doubling of the visual angle. Patients were divided into VR and nonrecovery (NR) groups. Using fundus photographs, we measured optic disc size and evaluated for the presence of optic disc features, including peripapillary telangiectasia, disc hyperemia, and swelling. We also measured the disc area, cup-to-disc ratio, and rim area of the optic disc using OCT. Results: Twenty-one of 80 eyes (26%) had a VR. The VR occurred within 2 years after onset in 81% of cases. The VR group showed younger age at onset (21 vs 29 years, P = 0.017) and better visual acuity at the nadir (1.39 vs 2.16 logMAR, P , 0.001) compared with the NR group. Optic disc features, particularly peripapillary telangiectasia (P = 0.027) and disc hyperemia (P = 0.006), were more prominent in the NR group. The cup-to-disc ratio was significantly smaller (0.64 vs 0.71, P = 0.004) and the rim area was significantly greater (1.17 vs 0.85 mm2, P , 0.001) in the VR group compared with the NR group. Department of Ophthalmology (YM, HA, HTL), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; Department of Ophthalmology (USK), Kim’s Eye Hospital, Seoul, Korea; Department of Ophthalmology (USK), Konyang University College of Medicine, Daejeon, Korea; and Department of Ophthalmology (JH), Institute of Vision Research, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. The authors report no conflicts of interest. Address correspondence to Hyun Taek Lim, MD, PhD, Department of Ophthalmology, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-2-dong, Songpa-gu, Seoul, Korea 05505; E-mail: [e-mail] Moon et al: J Neuro-Ophthalmol 2020; 40: 15-21 Conclusions: A younger age at onset and a less severe reduction of visual acuity at the nadir were associated with a higher probability of VR. Presence of peripapillary telangiectasia and optic disc hyperemia may serve as predictive factors for poor visual prognosis in patients with LHON. Journal of Neuro-Ophthalmology 2020;40:15–21 doi: 10.1097/WNO.0000000000000830 © 2019 by North American Neuro-Ophthalmology Society L eber hereditary optic neuropathy (LHON) is the most common inherited optic neuropathy. It is caused by mitochondrial DNA (mtDNA) mutations. The majority of LHON patients carry one of 3 mtDNA point mutations— m.11778 G.A, m.3460 G.A, or m.14484T.C—which affect NADH dehydrogenase subunits of Complex I in the mitochondrial respiratory chain. The disrupted mitochondrial oxidative phosphorylation results in defective cellular energy metabolism (1–4). The clinical features of LHON are associated with degeneration of retinal ganglion cells (RGCs) (1,5). LHON typically presents as subacute, painless visual loss and central scotoma in one eye, which worsens with progression to a large and dense cecocentral scotoma over 4–6 weeks after onset. Similar visual loss in the fellow eye occurs usually within several weeks to months. Optic disc changes during the acute stage include peripapillary telangiectasia, hyperemia, and swelling. As the disease progresses, the optic disc pallor becomes apparent and cupping can develop with loss of RGC axons (1,6). Visual prognosis of LHON is generally poor. Treatment options are very limited, and there is no definite therapy. Although most LHON patients experience permanent visual loss, spontaneous visual recovery (VR) can occur in one or both eyes, by a mechanism that remains unclear (7– 10). A few studies have explored prognostic factors associated with VR. Younger age at onset, better visual acuity at 1 15 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology year after onset, m.14484T.C mutation, and a larger optic disc size have been reportedly associated with VR and better visual outcome (1,11–21). However, very little attention has been paid to optic disc characteristics, especially peripapillary telangiectasia, optic disc hyperemia, and swelling concerning their possible associations with VR in LHON patients. In this study, we investigated clinical features and optic disc characteristics of LHON patients who had a significant VR. The main purpose of our study was to determine whether certain optic disc features are associated with a spontaneous VR and good visual prognosis. METHODS We included all patients who were diagnosed with LHON at the neuro-ophthalmology clinic of 3 hospitals in Seoul, Korea (Asan Medical Center, Kim’s Eye Hospital, and Severance Hospital), from January 2000 to March 2017. Exclusion criteria were the following: (1) asymptomatic carrier, (2) first visit later than 6 months after symptom onset, (3) follow-up duration shorter than 6 months, (4) last visit within 1 year from symptom onset, and (5) systemic or other ophthalmological diseases that might affect visual acuity or visual field test results. We reviewed patient medical records for medical history and results of a comprehensive ophthalmological examination, including best-corrected visual acuity (logarithm of the minimum angle of resolution [logMAR]), refraction, slit-lamp biomicroscopy, standard fundus photography (TRC-50DX; Topcon Medical System, Tokyo, Japan), visual field test using a Humphrey-automated perimeter (Swedish Interactive Threshold Algorithm 30-2 alg30-2; Carl Zeiss Meditec, Dublin, CA), and optical coherence tomography (OCT) using a Cirrus HD-OCT device (Carl Zeiss Meditec, Inc). This study adhered to the tenets of the Declaration of Helsinki, and the protocol was approved by the Institutional Review Board of Asan Medical Center. We defined VR as a gain of 3 or more lines of logMAR visual acuity from nadir, rather than conventional 2 or more lines difference, because our initial intention was to identify patients having a truly significant vision improvement. An increase in 3 lines of logMAR acuity represents a doubling of the visual angle and is considered a truly significant change. Visual acuity values were converted to the logMAR. Count fingers and hand motion vision were converted to 2.0 and 3.0 logMAR, respectively. Considering this semiquantitative scale in very low vision range, patients were classified as the “VR group” only when their final visual acuity was 1.0 logMAR or better and, at the same time, when their visual gain was 0.3 logMAR or more (22,23). We compared clinical and optic disc characteristics between the VR group and those classified as the “nonrecovery (NR) group” composed of patients with LHON who did not meet the above criteria for VR. 16 We assessed optic disc characteristics using standard fundus photographs and OCT scans. First, we measured the optic disc size from fundus photographs using ImageJ software (version 1.51; National Institutes of Health, Rockville, MD). Because the fundus photographs at the acute stage of the disease might not be appropriate for the measurement of the optic disc, mainly due to the presence of disc margin blurring, we obtained fundus photographs taken at least 6 months after symptom onset to assess the size of the optic disc. We measured the longest diameter and its perpendicular short diameter of the optic disc. The disc size was calculated as an average of the 2 measured diameters of the optic disc. Having considered various photographic factors that could influence the accuracy of quantitative measurements of the optic disc size, we used the parameter of the disc-to-macula distance to disc size (DM/DS) ratio for our quantitative analysis. The parameters were averaged from repeated measurements performed twice independently by a single examiner (Y.M.). The intraclass coefficient value of the parameters was 0.978. Next, we measured the disc area, cup-to-disc (C/D) ratio, and rim area of the optic nerve head using OCT at the last visit. The OCT scan protocol was the Cirrus Optic Disc Cube 200 · 200 (dimensions, 6 · 6 mm), in which the disc parameters were calculated automatically by the Cirrus built-in algorithm (software version 6.0). Only wellfocused, well-centered images without eye movement and signal strength $7 were used. Finally, using standard fundus photographs, we evaluated optic disc characteristics, such as the degree of peripapillary telangiectasia, disc hyperemia, and swelling. Optic disc features were classified as the “absence group” and “presence group” depending on each of the disc characteristics (Fig. 1). To evaluate the optic disc features, we analyzed color fundus photographs taken within 2 months after symptom onset (24). Each classification was performed independently by 2 of the authors (Y.M. and H.T.L.) in a randomized and blinded manner. Any disagreement was resolved through discussion with a senior author (H.A.). Demographic factors, mitochondrial genotype profile, clinical data, and optic disc features were analyzed using the Mann–Whitney U test, Fisher exact test, and linear by linear analysis. All statistical analyses were performed using SPSS version 21.0 (SPSS, Inc, Chicago, IL). RESULTS A total of 80 eyes from 40 patients were included in our final analysis. According to the aforementioned visual improvement criteria, 21 eyes (26.25%) from 11 patients were classified as the VR group and 59 eyes (73.75%) from 30 patients as the NR group. Visual prognoses were split between the 2 eyes in 1 patient, with 1 eye entered into the VR and the fellow eye into the NR group. Moon et al: J Neuro-Ophthalmol 2020; 40: 15-21 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology FIG. 1. Grading of optic disc appearance based on (A) peripapillary telangiectasia, (B) disc hyperemia, and (C) disc swelling. The VR group had a significantly earlier age at onset than the NR group (mean age, 21 and 29 years, respectively, P = 0.017). Regarding the results of mtDNA sequencing, m.11778 G.A was the most commonly detected mutation among both groups. There was no significant difference in the frequency of mutations between the 2 groups (Table 1). Visual acuity at the nadir (defined as the worst-documented visual acuity during follow-up period) was significantly higher in the VR group than in the NR group (logMAR 1.39 and 2.16, respectively, P # 0.001) (Table 1). Table 2 presents data on the distribution of the worst-documented visual acuity during the course of disease in the VR and NR groups. Concerning the extent of VR, the best-documented visual acuity during our study period was widely variable from 0.8 to 0.0 logMAR in the VR group (Fig. 2). In the total of 21 eyes with VR, the recovery occurred mostly within 24 months after symptom onset, as was the case for 17 of 21 eyes (81%) in our study. The longest time interval from the onset of symptoms to the occurrence of VR was 77 months (Fig. 3). Thirteen eyes (61.9%) in the VR group and 38 eyes (64.4%) in the NR group had fundus photographs taken within 2 months after symptom onset. Twenty-eight (74%) of 38 eyes in the NR group comprised the presence group in telangiectasia evaluation and 26 eyes (68%) in hyperemia evaluation. In the VR group, only 5 eyes (31%) and 3 eyes (23%) comprised the presence group in telangiectasia and hyperemia evaluation, respectively. This difference was statistically significant (P = 0.027 and 0.006, respectively). Eighteen (47%) eyes in the NR group had mild to severe disc swelling in the acute phase, whereas only 3 (23%) eyes had disc swelling in the VR group. The distribution difference for optic disc swelling was not statistically significant between the 2 groups (Table 3). DM/DS ratio measurements were performed in 20 eyes (95.2%) from the VR group and 36 eyes (94.7%) from the NR group using fundus photographs. The average DM/DS ratio of the VR and NR group was 2.72 and 2.92, respectively. This difference had borderline significance (P = 0.049). OCT analysis was performed in 17 eyes (81%) in the VR group and 33 eyes (87%) in the NR group to assess the disc area, C/D ratio, and rim area of the optic disc. The mean optic disc area measured by OCT was 2.00 mm2 in the VR group and 1.91 mm2 in the NR group (P = 0.101). The disc TABLE 1. Demographics and visual acuity of the participants Age at onset, years Sex (M:F) Follow-up period after symptom onset (range, mo) Mutation m.11778 G.A m.14484T.C m.3460 G.A Others Idebenone treatment (yes:no) Worst visual acuity (range, logMAR) VR Group (n = 21 Eyes) NR Group (n = 59 Eyes) 20.9 ± 14.4 (5–48) 16:5 45.9 ± 58.4 (12–206) 28.9 ± 13.4 (14–63) 47:12 41.8 ± 36.5 (12–140) 13 (61.9%) 4 (19.0%) 0 4 (19.0%) 11:10 (52.4%) 1.39 ± 0.57 (0.4–2.0) 43 (72.9%) 10 (16.9%) 0 6 (10.2%) 21:38 (64.4%) 2.16 ± 0.70 (0.4–3.0) P value 0.017 0.479 0.347 0.454 0.138 ,0.001 logMAR, logarithm of the minimum angle of resolution; NR, nonrecovery; VR, visual recovery. Bold text indicates a statistically significant difference with a P value less than 0.05. Moon et al: J Neuro-Ophthalmol 2020; 40: 15-21 17 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology TABLE 2. Distribution of worst visual acuity in the follow-up period in both groups Worst visual acuity . CF Worst visual acuity # CF VR Group (n = 21 Eyes) NR Group (n = 59 Eyes) P value 13 (61.9%) 8 (38.1%) 10 (16.9%) 49 (83.1%) ,0.001 CF, counting fingers; NR, nonrecovery; VR, visual recovery. Bold text indicates a statistically significant difference with a P value less than 0.05. area measured by OCT and the DM/DS ratio measured in fundus photographs were highly correlated with each other (Spearman rank correlation coefficient = 20.68, P , 0.001). The C/D ratio was smaller (0.64 vs 0.71) and the rim area was larger (1.17 vs 0.85 mm2) in the VR group than in the NR group. The differences were statistically significant (P = 0.004 and P , 0.001, respectively) (Table 4). DISCUSSION In this study, a younger age at onset and less severe reduction of visual acuity at the nadir were associated with a higher probability of VR, consistent with previous studies (2,17,21). Approximately, 25% of the eyes with LHON experienced VR. It is widely accepted that the likelihood of VR is greatest with the mtDNA mutation 14,484 and least with the mutation 11,778 (3,11–14,18–20). We were unable to demonstrate this association. This inconsistency may be attributable to the fact that in our study, a majority of patients had mutation 11,778, whereas only a small proportion of patients had mutation 14,484, and no patients had mutation 3,460. In our patients with mutation 11,778, 13 of 56 eyes (23.3%, 7 of 28 patients) had VR. Among them, 6 eyes (10.7%, 3 patients) achieved visual acuities of 20/40 or better. Compared with previous studies, a relatively higher proportion of patients experienced VR in this study. Stone et al (7) reported 5 (4%) of 136 patients spontaneously recovered 20/40 or better visual acuity in at least 1 eye. In a clinical study conducted in a Japanese population, 15 (17.0%) of 88 patients with 11,778 mutation or 22 of 176 eyes (12.5%) were reported to have a recovery of vision $20/100 (25). This difference in the rate of VR in LHON with same mutation could be attributed, at least partly, to the difference in ethnicity and the criteria for VR. Idebenone has been considered to have beneficial effects in preventing further vision impairment and promoting vision recovery in patients with LHON relative to the natural course of the disease based on multiple experimental and clinical studies (26–30). We have also recommended oral idebenone treatment in patients with disease duration of less than 1 year since 2014. Presently, we simply reviewed the number of patients who received oral idebenone in the VR and NR group. There were no significant differences in the frequency of idebenone treatments between the VR and NR group. However, it should be noted that our study could not control the dose and duration of the idebenone treatment due to the retrospective nature of the study. More detailed analysis on the effect of idebenone on VR is beyond the scope of this study. Further studies on this topic are therefore recommended. Several studies have reported VR in LHON patients mostly occurs in the first year after disease onset (2,3,19,31). Most cases of VR occurred within 2 years after the onset in the current study, although only 8 eyes (38.1%) experienced VR within the first year after the onset. What is interesting is that some cases of VR occurred many years, a maximum of 6.5 years, after symptom onset in our study. This finding underscores the importance of FIG. 2. Distribution of the best visual acuity after visual recovery in the visual recovery group. 18 Moon et al: J Neuro-Ophthalmol 2020; 40: 15-21 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology FIG. 3. Time interval from symptom onset to visual recovery. providing long-term follow-up care and guidance about potential late improvement of vision to patients with LHON. We also found out that eyes with more prominent peripapillary telangiectasia and disc hyperemia during the acute phase of the disease were unlikely to experience VR. In other words, the presence and severity of peripapillary telangiectasia and hyperemia were inversely associated with VR. To the best of our knowledge, this is the first report to document that the peripapillary telangiectasia is an optic disc feature associated with VR in patients with LHON. The reason for this association is not clear, but it might be related to the neuropathology of this disease. LHON involves a neurodegenerative process in RGCs and their axons, which occurs due to a mitochondrial dysfunction. There is considerable evidence that RGCs have the highest demand for mitochondrial energy and have the highest susceptibility to mitochondrial respiratory chain dysfunction (19). Thus, a significant mitochondrial dysfunction may induce respiratory chain defect that compromises axoplasmic transport and results in axonal swelling and compression of the capillaries of the optic disc and the retinal nerve fiber (32). Considering this pathologic background, it seems reasonable to assume that the peripapillary telangiec- tasia in LHON patients is a consequence of the axonal swelling and compression of the capillaries in the optic nerve head and may represent a surrogate marker of significant mitochondrial dysfunction. Hence, it can be hypothesized that more severe mitochondrial dysfunction is linked with more prominent peripapillary telangiectasia and lower probability of VR in LHON patients. Although the specific mechanism of VR is not clear, it has been suggested that some inactive but viable RGCs may remain for prolonged periods and then may regain function over time as axonal transport is re-established (9). Thus, patients with severe peripapillary telangiectasia may tend to have fewer viable RGCs and a lower probability of VR. Concerning the optic disc parameters, the C/D ratio and rim area differed between the VR and NR groups. In the fundus photograph analysis, disc size was larger in the VR group with borderline significance. However, there was no significant difference in the disc area between the VR and NR groups in OCT. A large optic disc may be a good prognostic factor for VR in LHON patients and may be a powerful protective factor for disease conversion in LHON carriers (16). This discrepancy may be due in part to the difference in the methods of measurement and TABLE 3. Disc appearance analysis using standard fundus photographs VR Group (n = 13 Eyes) NR Group (n = 38 Eyes) 8 (61.5%) 5 (30.8%) 10 (26.3%) 28 (73.7%) 10 (76.9%) 3 (23.1%) 12 (31.6%) 26 (68.4%) 10 (76.9%) 3 (23.1%) 20 (52.6%) 18 (47.4%) Peripapillary telangiectasia Absence Presence Disc hyperemia Absence Presence Disc swelling Absence Presence P value 0.027 0.006 0.112 NR, nonrecovery; VR, visual recovery. Bold text indicates a statistically significant difference with a P value less than 0.05. Moon et al: J Neuro-Ophthalmol 2020; 40: 15-21 19 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology TABLE 4. Disc area, cup-to-disc ratio, and rim area measured using optical coherence tomography in both groups Disc area Cup-to-disc ratio Rim area VR Group (n = 20 Eyes) NR Group (n = 33 Eyes) P value 2.00 ± 0.25 0.64 ± 0.09 1.17 ± 0.28 1.31 ± 0.55 0.71 ± 0.09 0.85 ± 0.22 0.101 0.004 ,0.001 NR, nonrecovery; VR, visual recovery. Bold text indicates a statistically significant difference with a P value less than 0.05. the study populations. The latter study used Stratus OCT (time domain) for image analysis and was performed in Brazilian and Italian populations. By contrast, our study used fundus photographs and Cirrus HD-OCT (spectral domain) in a Korean population. Given these results from the optic disc parameters, the VR group seemed more likely to have larger neural tissue volume compared with the NR group. However, this does not necessarily indicate that the RGCs of the VR group have more axons. Further studies are needed to clarify the relationship between the optic disc parameters and the likelihood of VR. This study has several limitations. First, this study involved a small number of subjects and fundus photographs, and OCT images could not be obtained in all subjects. Second, the length of follow-up periods was not long enough. Given the time interval from symptom onset to VR, some patients in the NR group may have a chance of VR if they had been followed for a longer time. Third, optic disc features were assessed by a semiquantitative approach, which involved a subjective assessment system. Furthermore, old analog fundus photographs of low image quality were included, although only a few. Finally, we included both eyes independently in the analysis. Although LHON is a genetic disease involving both eyes, the disc characteristics and clinical course between the 2 eyes can differ in some patients. 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