Retinal Ganglion Cell Loss Precedes Retinal Nerve Fiber Thinning in Nonarteritic Anterior Ischemic Optic Neuropathy

Analysis of retinal nerve fiber layer thickness and macular ganglion cell layer loss provides a noninvasive method to assess optic chiasmal compression. These techniques may provide valuable data for patient evaluation and management when combined with findings on clinical examination and neuroimaging results.; ; Data from 20 eyes of 10 patients with pituitary tumor treated at Inha University Hospital from 2011 to 2013 were collected. This included results of ophthalmologic examination, fundus photography, spectral domain optical coherence tomography (SD-OCT), automated visual field testing, and brain magnetic resonance imaging (MRI). Abnormal color patterns on thickness and deviation maps obtained by macular ganglion cell analysis (GCA) were evaluated and compared with visual field defects.; ; Patients with pituitary tumor showed preferential ganglion cell loss in the nasal hemiretina and characteristic vertical midline-respecting perimacular ganglion cell-inner plexiform layer defects, which anatomically matched the visual field defects.; ; Macular GCA using SD-OCT can be used to complement visual field assessment and brain MRI findings during evaluation of patients with pituitary tumor.

Original Contribution Retinal Ganglion Cell Loss Precedes Retinal Nerve Fiber Thinning in Nonarteritic Anterior Ischemic Optic Neuropathy Mohammadreza Akbari, MD, Parisa Abdi, MD, Masoud Aghsaei Fard, MD, FICO, Marjan Afzali, MD, Ahmad Ameri, MD, Alireza Yazdani-Abyaneh, MD, Massod Mohammadi, MD, Sasan Moghimi, MD Background: Loss of retinal ganglion cell-inner plexiform layer (GCIPL) thickness has been shown in different optic neuropathies. In this study, we evaluated the capability of GCIPL analysis by optical coherence tomography (OCT) to detect early neuronal loss during the time course of nonarteritic anterior ischemic optic neuropathy (NAION). Methods: Twenty-four patients with unilateral NAION participated in this prospective, comparative study. Affected and unaffected eyes underwent spectral domain OCT measurement of the retinal nerve fiber layer (RNFL), total macula, and GCIPL thicknesses. These measurements were recorded in the acute phase (within 7 days) and at 1, 3, and 6 months. Results: At the initial presentation and 1, 3, and 6 months, the mean RNFL thickness in the NAION eyes was 236.5 mm ± 74.2, 157.1 mm ± 45.7, 61.4 mm ± 6.1, and 55.0 mm ± 19.5, respectively. Similar to RNFL, thinning of the mean total macular thickness in inner and outer rings started after 3 months and thicknesses decreased to 307.7 mm ± 15.3 and 273.1 mm ± 21.2 after 3 months and to 309.1 mm ± 15.0 and 273.4 mm ± 13.8 after 6 months, compared with unaffected contralateral eyes, respectively (all P , 0.0001). Thinning of the GCIPL was first evident in the affected NAION eyes at 1 month, and the mean inner and outer GCIPL thicknesses were 62.8 mm ± 14.6 and 53.9 mm ± 7.2 at 1 month in the NAION eyes compared with unaffected eyes (P , 0.001). After 3 and 6 months, the inner and outer GCIPL thicknesses were 51.1 mm ± 8.1 and 47.4 mm ± 5.31, and 50.6 mm ± 11.5 and 47.9 mm ± 5.6, respectively. Eye Research Center, Department of Neuro-Ophthalmology, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran. The authors report 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 full text and PDF versions of this article on the journal's Web site (www. jneuro-ophthalmology.com). Address correspondence to Masoud Aghsaei Fard, MD, FICO, Eye Research Center, Department of Neuro-Ophthalmology, Farabi Eye Hospital, South Kargar, Qazvin SQ, Tehran 13352, Iran; E-mail: [e-mail] Akbari et al: J Neuro-Ophthalmol 2016; 36: 141-146 Conclusions: Thinning of the GCIPL is first detectable at 1 month after NAION and persists for 3 months. GCIPL thinning occurs before RFNL thinning in NAION. Journal of Neuro-Ophthalmology 2016;36:141-146 doi: 10.1097/WNO.0000000000000345 © 2016 by North American Neuro-Ophthalmology Society N onarteritic anterior ischemic optic neuropathy (NAION) is the most common clinical presentation of acute ischemic damage to the optic nerve and is characterized by a sudden, painless decrease in vision, optic disc edema, and visual field loss (1). Optical coherence tomography (OCT) in NAION is useful to monitor the peripapillary retinal nerve fiber layer (RNFL) thickness changes. However, thickening of the peripapillary RNFL in the acute phase prevents the assessment of axonal loss (2-5). Retinal ganglion cell elements exist in 3 layers in the retina: the RNFL (ganglion cell axons), the ganglion cell layer (ganglion cell bodies), and the inner plexiform layer (ganglion cell dendrites). For OCT analysis, the last 2 layers have been designated the ganglion cell-inner plexiform layer (GCIPL) (6-8). When compared to the RNFL, the GCIPL thickness is less likely to be affected by optic disc edema in the acute phase of NAION and could potentially be useful for tracking axonal loss over time with OCT (7). The retinal ganglion cell layer is 2 or more cell layers thick at the macula (cell density up to 4-6 cell bodies). Loss of retinal ganglion cells in NAION is, therefore, reflected by a reduction in the macular and central retinal thicknesses. In addition, macular thinning in chronic NAION is a good clinical indicator of visual dysfunction (8-14). Rebolleda et al (15) have demonstrated thinning of the inner retina in chronic NAION using the Spectralis OCT software. Excellent repeatability and reproducibility of each 141 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution retinal layer thickness measurements using this software (version 6.0) also have been reported (16). However, assessment of the macular and ganglion cell thickness in acute NAION remains largely unexplored. In addition, the pattern of the RGC thickness changes in NAION over time is not clear. The purpose of our study was to investigate the changes observed in the total macular thickness, macular GCIPL, and peripapillary RNFL thicknesses over time after an acute episode of NAION. METHODS Between January 2012 and January 2014, patients at the Fabari Eye Hospital with unilateral NAION were considered for this prospective, comparative study. The study was performed after the approval of the research ethics committee was received. Written informed consent was obtained from all patients, and the study was conducted in accordance with the Declaration of Helsinki. Inclusion criteria were: 1) acute onset of the visual acuity and/or visual field loss of less than 1-week duration, 2) a relative afferent pupillary defect on the affected side, 3) optic disc swelling with or without hemorrhages that resolved in the 3-month follow-up period, 4) a visual field defect consistent with NAION, and 5) the patient's cooperation for imaging studies. The exclusion criteria were: 1) visual loss of more than 1-week duration, 2) any clinical suspicion of optic neuritis, 3) clinical and laboratory findings suggestive of arteritic AION. Contralateral unaffected eyes served as control eyes. Patients with any history or clinical evidence of retinal disease including diabetic retinopathy, neurologic disease, glaucoma, intraocular pressure of more than 21 mm Hg, intraocular surgery or laser therapy, and a refractive error beyond ±4.00 diopters in both affected and control eyes also were excluded. Patients with unilateral NAION completed all clinical and ancillary testing within 7 days of visual dysfunction and at 1, 3, and 6 months later in both affected and unaffected eyes. Ophthalmic examination included measurement of bestcorrected visual acuity, applanation tonometry, slit-lamp biomicroscopy, automated perimetry, and funduscopy. Best-corrected visual acuity was measured using a Snellen chart at 6 m and converted into the logarithm of the minimum angle of resolution (LogMAR) for statistical analysis. Perimetry was performed with the Standard Swedish Interactive Thresholding Algorithm (SITA) using the 24-2 pattern on the Humphrey Field Analyzer (Carl Zeiss Meditec, Dublin, CA), and the mean deviation (MD) of perimetry was used for data analysis. All OCT measurements were performed with spectral domain OCT (Heidelberg Spectralis SD OCT; Heidelberg Engineering, Heidelberg, Germany) by the same operator (M.K.). All OCT images were saved during the study and the Spectralis software version 6 was used for retinal layer segmentation during the data collection. The quality scores 142 for scans are expressed as the signal-to-noise ratio in decibels (dB). The quality of the scans above 20 dB was considered acceptable. For macular OCT with automatic real time of 100 frames, 3 circular lines representing 1-, 3-, and 6-mm scan diameters were obtained. The data of the innermost circle that defined the fovea were not used. The outer total macular thickness (outer nasal, outer temporal, outer superior, and outer inferior) was delineated by the 2 outer circles, whereas the inner total macular thickness was delineated by the area between the inner circle and the fovea (inner nasal, inner temporal, inner superior, and inner inferior). Because the total points and the area measured by the inner and outer sectors were different (inner and outer macular sectors contain 38 and 74 data points, respectively), we averaged the inner sections (as 9 inner + superior + inner inferior + inner nasal + inner temporal/4). The peripapillary RNFL thickness was measured using a 360° peripapillary circle scan around the optic nerve head with a diameter of 3.4-mm, with 16 averaged consecutive circular B-scans. The RNFL Spectralis protocol generated a map showing the average thickness, and maps with 6 sector thicknesses (superonasal, nasal, inferonasal, inferotemporal, temporal, and superotemporal). The Spectralis software was used for retinal layer segmentation. The reflectivity of the ganglion cell layer and inner plexiform layer was very similar, which made these layers almost indistinguishable from one another. Therefore, we calculated the sum of the ganglion cell layer and the inner plexiform layer as the GCIPL. The data were grouped in 9 macular sectors within 3 concentric circles similar to the total macular thickness. The minimum thickness on the map of the ganglion cell and inner plexiform layer defined the location of the center of the fovea. This location defined the center of the concentric circles. The data of the innermost circle with the very thin layer of the GCIPL layer were not used. The outer GCIPL (outer nasal, outer temporal, outer superior, and outer inferior) and the inner GCIPL (inner nasal, inner temporal, inner superior, inner inferior) thicknesses were used for data analysis. Similar to the total macular thickness map, we averaged the inner sectors of the GCIPL and the outer sectors of the GCIPL. Statistical analysis was performed using SPSS software version 17 (SPSS Inc, Chicago, IL). The Shapiro-Wilk test was used to determine the normal distribution of the data. A 2-sided t test was used to determine the difference in OCT measures as well as the visual acuity and visual field MD between the affected NAION eye and the contralateral unaffected eye, as the examined variables followed a normal distribution. One-way repeated-measures analysis of variance (ANOVA) was used to compare the GCIPL thickness of the affected eye at different time intervals. Pairwise multiple comparison was performed using Bonferroni correction. ANOVA test was not used for macular and peripapillary nerve fiber layers because of early thickening and late thinning. The associations between the baseline Akbari et al: J Neuro-Ophthalmol 2016; 36: 141-146 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution LogMAR visual acuity and the inner and outer total macular and GCIPL thicknesses were analyzed using the Pearson correlation coefficient test. Differences were significant if P was less than 0.05. RESULTS Thirty-two patients with NAION were initially enrolled in this study. Four patients were lost to follow-up and were excluded from the study. Three patients with subretinal fluid in the acute phase of NAION (17) and one patient with poor retinal layer segmentation were also excluded. Therefore, 24 patients (mean age: 52.7 ± 7.8 years [range, 38-66], 14 male) were included in this prospective study. The mean time from the onset of NAION to the initial examination was 3.9 ± 1.6 days. Eighteen (75%) of NAION patients had at least 1 vasculopathic risk factor and 3 patients had 2 risk factors. Fourteen patients had systemic hypertension, 4 had diabetes mellitus (without diabetic retinopathy), and 3 had hypercholesterolemia. Four were current smokers or ex-smokers. Six patients had sleep apnea symptoms with loud snoring. All patients were followed for 6 months. The mean baseline LogMAR visual acuity of the NAION eyes was 0.73 ± 0.62 (Snellen equivalent of 20/100). The visual acuity worsened by more than 2 Snellen lines between the initial and last follow-up visits in 25% of the patients, improved by more than 2 lines in 20.8% of the patients, and remained stable in 54.2%. The mean change in LogMAR visual acuity between the initial and the last visit was 20.04 ± 0.2. The mean baseline visual field MD in the NAION eyes and the unaffected fellow eyes was 217.2 dB ± 8.7 and 21.9 dB ± 3.3, respectively. The MD was 217.9 dB ± 8.4, 219.1 dB ± 9.7, and 218.7 dB ± 10.2 at 1, 3, and 6 month follow-up periods in the NAION eyes, respectively. The summary of the longitudinal NAION OCT segmentation analysis at each visit in the affected and fellow eyes is shown in Supplemental Digital Content 1, Table E1, http://links.lww.com/WNO/A192. At initial presentation, the mean RNFL thickness in the NAION eyes was thicker than unaffected eyes. At 1, 3, and 6 months, the average RNFL in the NAION eyes gradually decreased and the average RNFL was thinner at 3 and 6 months when compared to the contralateral unaffected eyes (all P , 0.001). In the acute phase, the mean inner and outer total macular ring thicknesses were 352.2 mm ± 28.5 and 316.1 mm ± 22.0 in the NAION eyes and 343.3 mm ± 21.9 and 301.1 mm ± 15.0 in the unaffected fellow eyes, respectively (P = 0.23, P = 0.01, respectively). Similar to the baseline measurement, the outer macular thickness was thicker in the affected eyes vs the unaffected eyes (P = 0.03). There was no significant difference in the inner total macular thickness between the NAION and unaffected eyes at 1 month (P = 0.98). The thinning of the mean inner and outer total macula started after 3 months. Significant Akbari et al: J Neuro-Ophthalmol 2016; 36: 141-146 differences were found between the affected and unaffected eyes at 3 and 6 months (P values were less than 0.001). At the initial presentation, the mean inner and outer ring GCIPL thicknesses in the NAION eyes were not different from unaffected eyes (P = 0.9, P = 0.8, respectively). The mean inner and outer GCIPL thickness was 62.8 ± 14.6 and 53.9 mm ± 7.2 at 1 month in the NAION eyes. There was a significant difference in the GCIPL thickness between the NAION and the unaffected eyes at 1 month (P , 0.001). We observed 28.7 mm loss of thickness in the inner GCIPL and 12.1 mm loss in the outer GCIPL at 1 month. After 3 and 6 months, the inner and outer GCIPL was also statistically thinner than unaffected eyes (all P , 0.001). A repeated-measures ANOVA with a Greenhouse-Geisser correction showed that the average of each GCIPL sector in the NAION eyes (superior inner, superior outer, inferior inner, inferior outer, nasal inner, nasal outer, temporal inner, and temporal outer) differed significantly among time points (all P , 0.001). Post hoc tests using the Bonferroni correction revealed that each sector GCIPL thickness decreased at 1, 3, and 6 months compared with baseline with a statistically significant difference (all P , 0.001). There were significant differences in the thickness of most sectors between 1 and 3 months (superior inner sector, P = 0.02; superior outer sector, P = 0.07; inferior inner, P , 0.001; inferior outer, P , 0.001; nasal inner sector, P = 0.1; nasal outer, P = 0.001; temporal inner, P = 0.01; temporal outer, P = 0.009). The thickness differences between 3 and 6 months were not statistically significant (superior inner sector, P = 0.7; superior outer sector, P = 1; inferior inner sector, P = 1; inferior outer, P = 0.22; nasal inner sector, P = 1; nasal outer, P = 1; temporal inner, P = 1; temporal outer sector, P = 1). The NAION eyes were analyzed for any association between the baseline visual acuity and the inner and outer GCIPL and total macular thickness at different times. The baseline visual acuity was associated with the inner and outer GCIPL thickness at 1 (r = 20.52, P = 0.009 and r = 20.47, P = 0.01, respectively), 3 (r = 20.54, P = 0.006 and r = 20.65, P = 0.001, respectively), and 6 months (r = 20.64, P = 0.001 and r = 20.41, P = 0.04, respectively). The baseline inner and outer GCIPL thickness was not highly correlated with the baseline visual acuity (r = 20.04, r = 0.1). No strong correlation was observed between the baseline visual acuity and the inner and outer total macular thickness at baseline (r = 20.2, P = 0.1 and r = 20.01, P = 0.9), 1 month (both r = 20.1, P = 0.4), and 3 months (r = 20.1, P = 0.3 and r = 20.06, P = 0.7). A strong association was only detected between baseline visual acuity and the inner total macular thickness at 6 months (P = 0.01, r = 0.57). DISCUSSION In our study, we performed longitudinal measurements of the peripapillary RNFL thickness, total macular thickness, 143 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Optical coherence tomographic images show retinal ganglion cell and inner plexiform layer (A), total macula (B), and peripapillary retinal nerve fiber layer maps (C) of a patient with nonarteritic anterior ischemic optic neuropathy at 4 follow-up periods. A. Figures depict thinning of superior retinal ganglion cell and inner plexiform layer at 1 month. B and C show that thinning of superior macula and nerve fiber layer was detected at 3 months. 144 Akbari et al: J Neuro-Ophthalmol 2016; 36: 141-146 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution and GCIPL thickness at baseline and 1, 3, and 6 months after NAION and compared the results to the unaffected fellow eyes. We found that in the acute phase of NAION, there were no differences in the inner ring total macular thickness and all sector GCIPL thickness between the affected and unaffected eyes, whereas the average RNFL thickness and outer ring total macular thickness were significantly greater in the affected NAION eyes. This was due to peripapillary nerve fiber layer edema (18), which extended to the macular area. The increased thickness of RNFL and outer ring total macular persisted at 1 month and then began to resolve. Thinning of the GCIPL was evident in the affected NAION eyes at 1 month in comparison with both ipsilateral baseline GCIPL and the contralateral eyes and continued at 3 months but this stabilized at 6 months (Fig. 1). Interestingly, the thinning of the inner ring total macular thickness was not observed at 1 month. Thinning of the RNFL and inner and out rings total macular thickness was first evident at 3 months as compared to the contralateral unaffected eyes. GCILP thickness in the affected eyes 6 months after the acute event remained reduced as compared with the affected eyes at baseline and contralateral eyes at 6 months (Fig. 2). According to our data, serial GCIPL thinning occurs for 1-3 months and is likely a reflection of permanent neuronal loss within the ganglion cell layer and damage to ganglion cell layer dendrites within the inner plexiform layer. The GCIPL becomes thinner with the death of ganglion cells. The present results regarding early ganglion cell damage are in accordance with histological measurements of early retinal ganglion cell loss with progressive thinning over the first few weeks in the rodent model of NAION. Bernstein et al (19) showed bimodal (by 8 hours and by 3 days) induction of retinal stress-associated genes (cfos) in the rodent model of NAION. Brn3b (a retinal ganglion cell-specific transcription factor) gene expression declines approximately 50% by 1 day and remains low after 1 week. Immunostaining for Brn3a showed retinal ganglion cell loss by apoptosis, beginning at 7 days and mostly occurring by 21 days after ischemia. Similarly, Fard et al (20) showed 42% loss of retinal ganglion cells with Brn3a staining starting 8 days after ischemic optic neuropathy in the rodent, which continued for 2 weeks. However, in this study, the total macular thickness and peripapillary RNFL thinning showed a delay after GCIPL thinning. The first explanation for this time delay is axonal swelling, which masks the detection of RNFL loss until 3 months after NAION (7). Similar to the peripapillary nerve fiber layer, the total macular thickness might also be prone to edema in the acute phase. Macular thinning might be masked by macular nerve fiber layer edema at initial presentation and at 1 month. Second, neurodegenerative changes in the RNFL thickness measured by the OCT initially lag behind in vivo ganglion cell soma counts (21,22). Previous studies have explored reductions in the ganglion cell layer and total macular thickness after an episode of NAION. The results of 2 such studies using the ganglion cell complex map of spectral domain OCT (RTvue-100; Optovue, Inc, Fremont, CA) demonstrated that the ganglion cell complex thickness decreased for at least FIG. 2. Mean ± SD of average retinal nerve fiber layer, retinal ganglion cell and inner plexiform layer (GCIPL), and total macular thicknesses in inner and outer rings of nonarteritic anterior ischemic optic neuropathy at each stage of follow-up (*significant thinning with P , 0.05 compared with unaffected eyes). RNFL, retinal nerve fiber layer. Akbari et al: J Neuro-Ophthalmol 2016; 36: 141-146 145 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution 6 months after injury (12,13). Rebolleda et al (15) compared the Cirrus and Spectralis OCT software in detection of ganglion cell thinning in patients who had experienced NAION at least 6 months previously. They found a significant correlation between the visual acuity and the total macular thickness (outer nasal sector) and GCIPL using Cirrus OCT. In addition, the highest correlation was found for the central sector of the inner plexiform layer using the Spectralis instrument. Larrea et al (14) hypothesized that the ganglion cell loss could be used to detect early axonal damage in the acute phase of NAION that cannot be detected by measuring the RNFL. Our study had several limitations. Although our sample size was small, it was in line with previous studies, and given our statistically significant findings, the overall results of the study could be generalized. Second, our study was one of very few that used Spectralis software for retinal layer segmentation in NAION. Although we have yet to establish a normative database of the thickness of different retinal layers, excellent repeatability and reproducibility of each of 8 individual retinal layer thickness measurements have been demonstrated with Spectralis software (version 6.0) (16). Third, our study patients were approximately 10 years younger than those of other studies (12,14,15). However, in our 2 previous studies, the average age of NAION patients also was 54 years. This age differential might be related to geographic or ethnic differences. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: P. Abdi, M. A. Fard, M. Akbari, M. Afzali, and S. Moghimi; b. acquisition of data: P. Abdi, M. A. Fard, M. Akbari, M. Afzali, A. Yazdani-Abyaneh, and S. Moghimi; c. analysis and interpretation of data: P. Abdi, M. Akbari, M. Afzali, A. Ameri, A. Yazdani-Abyaneh, and S. Moghimi. 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