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Show Retinal Ganglion Cell Layer Analysis by Optical Coherence Tomography in Toxic and Nutritional Optic Neuropathy Luisa Margarida Cabral Vieira, MD, Nuno Filipe Aguiar Silva, MD, Arnaldo Miguel Dias dos Santos, MD, Rita Serrano dos Anjos, MD, Luis Alexandre Pereira Abegão Pinto, MD, PhD, André Rodrigues Vicente, MD, Bárbara Isabel Correia Coelho Jardim Borges, MD, Joana Patrícia Tavares Ferreira, MD, Duarte Moreira Amado, MD, João Paulo Pedrosa Branco da Cunha, MD Objective: To analyze the retinal ganglion cell layer (RGL) by optical coherence tomography (OCT) in toxic and nutritional optic neuropathy and to correlate its thickness and volume with functional damage. Methods: We conducted an observational cross-sectional study in healthy subjects and in patients with toxic optic neuropathy observed in the Neuro-Ophthalmology Depart-ment of Central Lisbon Hospital Center. Complete ophthal-mologic examination, OCT (Heidelberg Spectralis), and automated static perimetry were performed. Thickness and macular volume of RGL layer and inner plexiform layer were measured after manual segmentation. Results: The study included 16 eyes of 12 healthy subjects and 16 eyes of 8 patients with toxic and nutritional optic neuropathy. Age and gender did not differ between the 2 groups. Ethambutol was the cause of toxic optic neurop-athy in 4 patients and nutritional factors (tobacco-alcohol) in 4 patients. A statistically significant decrease in thickness and volume of RGL, in all quadrants at 2 and 3 mm, was detected in individuals with optic neuropathy compared with controls (P , 0.01). A positive correlation between RGL thickness and mean deviation (MD) and between RGL volume and MD was detected (P , 0.05). There was a neg-ative correlation between MD and time of disease (r = 0.846 P = 0.001) and a positive correlation between MD and visual acuity in logMAR (r = 0.739 P = 0.006). A majority of the structural parameters also correlated negatively with time of disease (P , 0.05). Conclusions: Decreased RGL thickness and volume detected in this study support a mechanism of RGL toxicity. RGL analysis may contribute to the diagnosis and management of toxic and nutritional optic neuropathies. Journal of Neuro-Ophthalmology 2015;35:242-245 doi: 10.1097/WNO.0000000000000229 © 2015 by North American Neuro-Ophthalmology Society Toxic and nutritional optic neuropathies (TNON) are characterized by bilateral, progressive, and painless vision loss (1). Ganglion cell toxicity has been proposed as a pathophysiologic mechanism in these optic neuropa-thies, although the precise mechanism remains poorly understood (2-5). Typical patients with TNON develop central or ceco-central scotomas, and color vision and contrast sensitivity are impaired (1, 2, 4, 6). Early in the clinical course, the optic discs appear normal, and additional testing may be required to establish the correct diagnosis. In TNON, ret-inal nerve fiber layer (RNFL) thinning measured by optical coherence tomography (OCT) can be helpful in detecting disease before fundus changes appear. Thinning of the RNFL begins in the inferotemporal sector of papillomacular bundle and involves all quadrants in later stages (2, 7-9) but not before vision loss (10-12). Retinal ganglion cell layer (RGL) analysis by spectral domain OCT (SD-OCT) has been described in a variety of optic neuropathies, including Department of Ophthalmology (LMCV, NFAS, AMDdS, RSdA, LAPAP, ARV, BICCJB, JPTF, DMA, JPPBdC), Central Lisbon Hospital Center, Lisbon, Portugal; Faculty of Medicine (LAPAP), Institute of Pharma-cology and Neurosciences, University of Lisbon, Lisbon, Portugal; and Faculty of Medical Sciences (JPPBdC), New University of Lisbon, Lisbon, Portugal. Presented as a poster at ARVO 2014, Association for Research in Vision and Ophthalmology. 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 Luisa Margarida Cabral Vieira, MD, Rua Julieta Ferrão Edifício Gémeos, Bloco RS n°145, 1600-131 Lisboa, Portugal; E-mail: luisa5vieira@gmail.com 242 Vieira et al: J Neuro-Ophthalmol 2015; 35: 242-245 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. glaucoma (13-18), optic neuritis (19, 20), nonarteritic ischemic optic neuropathy (21, 22), papilledema due to idiopathic intracranial hypertension (23), and Leber hered-itary optic neuropathy (24). The purpose of our study was to analyze RGL layer by SD-OCT in patients with TNON and correlate its thickness and volume with functional damage. METHODS Participant Selection A prospective, observational cross-sectional study was per-formed on all patients with TNON in our Neuro- Ophthalmology Department from August 1, 2012 to July 31, 2013. Age- and sex-matched healthy controls were selected from the General Ophthalmology Department of the Central Lisbon Hospital Center. The diagnosis of TNON was established by a neuro-ophthalmologist after obtaining a careful history and excluding other causes of optic neuropathy including Leber hereditary optic neuropathy (negativity for the 3 major mitochondrial DNA mutations: 11778 G.A, 3460 G.A, and 14484T.C), autosomal dominant optic atrophy, inflammatory optic neuropathy, ischemic optic neuropathy, compressive optic neuropathy, and glaucoma. Patients were excluded with concomitant ocu-lar or neurological disease and with refractive error ± 4 diop-ters. Based on self-reporting and analysis of medical records, we documented the time and onset of TNON. Causative factors of the optic neuropathy were etham-butol (4 patients) and poor nutrition (alcohol-tobacco) (4 patients). Ethambutol was prescribed for pulmonary (3 patients) and renal (1 patient) tuberculosis. The regimen of 2 patients was 2 months of isoniazid, rifampicin, pyrazi-namide, and ethambutol followed by 4 months of isoniazid and ethambutol (2HRZE/6HE), 1 patient 3 times weekly and 1 daily. The regimen of the other 2 patients with iso-niazid resistance was 6 months of rifampicin, pyrazinamide, and ethambutol (daily) (6RZE). Ethambutol dosage was 20 mg/kg on daily regimen and 35 mg/kg on 3 times weekly regimen. The first 2 patients were diagnosed during the continuation phase of treatment (fifth and seventh months) and the other 2 after the end of the treatment (1 and 2 months after completion). Patients with nutri-tional optic neuropathy had a long history of heavy tobacco use (30, 58, 44, and 75 pack-years) and alcohol consump-tion (252, 174, 286, 56 g daily for 13, 16, 14, and 30 years, respectively). One patient had low levels of vitamin B12 and folate, and the others had normal values. Two patients had high serum lactate levels. Controls were healthy individuals based on the criteria of 20/20 visual acuity (VA) and no history of ocular, neurologic, or systemic disease. Procedures All participants underwent full ophthalmologic examination, SD-OCT (Heidelberg Engineering, Heidelberg, Germany), and automated static perimetry (ASP) using Octopus 900 (Haag-Streit, Switzerland). VA was calculated in logMAR. RGL segmentation was performed manually by transferring the points of the 2 boarding lines of the retina obtained automatically to RGL borders. Three to 9 points were needed to define the borders, depending on the boundary curvature. This segmentation, centered on the fovea, was performed in 25 horizontal scans with 6.1-mm length separated by 250 mm. The macular thickness (in micro-meters) and volume (in cubic micrometers) of RGL (RGL and inner plexiform layer) were then obtained automatically, in a circular area centered on the fovea with 2 and 3 mm diameters, in superior (S), temporal (T), inferior (I), and nasal (N) quadrants (Fig. 1). ASP was acquired with Octopus strategy G2 and analyzed as mean deviation (MD in decibel). Two patients with TNON did not have reliable ASP results and were excluded from the analysis. SD-OCT and ASP were evaluated offline by 1 masked observer. Macular thickness and volume of RGL of the TNON group were compared with those of the control group. In the TNON group, macular thickness and volume of RGL, MD, VA, and time of disease were correlated. Statistics Statistical analysis was conducted using SPSS Statistics version 20.0. Mean and SD were calculated. Groups were compared using Mann-Whitney or x2 tests. Spearman correlation was used to correlate TNON group variables. P values less than 0.05 were considered statistically significant. Ethics Statement The study followed the tenets of the Declaration of Helsinki, and written informed consent was obtained from all participants. RESULTS Clinical data of patients with TNON and controls are summarized in Table 1. Statistically significant differences were detected in VA and MD of the ASP. A statistically significant decrease in the thickness and volume of RGL, in all quadrants at 2 and 3 mm, was detected in the optic neuropathy group compared with controls (P , 0.01). A greater decrease was detected in inferior thickness and volume at 2 mm and in nasal thick-ness and volume at 3 mm (see Supplemental Digital Con-tent, Table E1, http://links.lww.com/WNO/A142). A positive correlation (P , 0.05) between RGL thick-ness and MD and between RGL volume and MD was detected (see Supplemental Digital Content, Table E2, Vieira et al: J Neuro-Ophthalmol 2015; 35: 242-245 243 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. http://links.lww.com/WNO/A143, and Figs E1 and E2, http://links.lww.com/WNO/A137 and http://links.lww. com/WNO/A138). A negative correlation between MD and time of disease (r = 0.846 P = 0.0001) and a positive correlation between MD and VA in logMAR (r = 0.739 P = 0.006) was also obtained (see Supplemental Digital Content, Table E2, http://links.lww.com/WNO/A143, and Fig E3, http:// links.lww.com/WNO/A139). The majority of the structural parameters also correlated negatively with time of disease (P , 0.05) (see Supplemental Digital Content, Table E3, http://links.lww.com/WNO/A144, Figs E4 and E5, http://links.lww.com/WNO/A140 and http://links.lww.com/WNO/A141). DISCUSSION Observer-dependent RGL analysis by manual segmentation has been validated by Wang et al (13). Using this method, our study detected decreased RGL thickness and volume in patients with TNON, supporting the premise that these optic neuropathies are primarily due to injury of the RGLs (2-4). In the TNON group, MD decrease (MD values are positive with Octopus perimetry) correlated with VA increase and time of disease progression, which corroborates what has been reported in the literature (8, 12). With greater time of disease, there was a decrease in the thickness and volume of RGL, which, in conjunction to MD decrease and VA increase, raises questions about the functionality of the ganglion cells in the acute phase and at the end of toxic exposure. The greatest decrease in RGL thickness and vol-ume of RGL layer occurred in the inferonasal quadrants, supporting early papillomacular bundle impairment in its inferotemporal sector (2, 8). This is consistent with histo-pathology studies (5,7). A genetic predisposition of increased mitochondrial oxidative stress may be associated with TNON (25), and the pattern of RNFL and RGL loss seems similar to other mitochondrial optic neuropathies including Leber hereditary optic neuropathy (22, 26) and dominant optic atrophy (27, 28). Our study was limited by a small number of patients FIG. 1. RGL manual segmentation in a control patient. Thickness and volume by quadrants are shown in areas of 2 mm and 3 mm diameter. RGL, retinal ganglion cell layer. TABLE 1. Clinical features of patients with TNON and controls TNON Controls P value* N (eyes/patients) 16/8 16/12 Etiology (neutral/toxic) 4/4 Gender (F/M) 4/4 7/5 0.264 Age (yrs) 66.0 ± 21.1 58.2 ± 9.3 0.851 VA (logMAR) 0.82 ± 0.41 0.0 ± 0.0 ,0.001 MD (dB) 28.48 ± 6.88 0.47 ± 1.10 ,0.001 *Mann-Whitney/x2. F, female; M, male. 244 Vieira et al: J Neuro-Ophthalmol 2015; 35: 242-245 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. and the lack of complete genetic analysis of mitochondrial DNA, as we only tested for the major mutations of Leber hereditary optic neuropathy. Another limitation was the extrapolation of data collected from a cross-sectional study to the natural history of TNON. The course of the disease can only be evaluated properly in a long-term longitudinal follow-up study. REFERENCES 1. Kerrison JB. 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