ABSTRACT
Purpose: To investigate the efficacy and safety of selective intra-ophthalmic arterial combined nimodipine and alteplase infusion in patients with central retinal artery occlusion (CRAO). Design: Non-randomized, prospective interventional study. Methods: All patients with CRAO who presented at our institute within 24 hours from CRAO onset from August 2020 to July 2022 were included. Intra-arterial nimodipine and alteplase were given selectively into the ophthalmic artery. Visual acuity was recorded during and after the procedure. Change in best corrected visual acuity (BCVA) 1 month post-treatment, relative to baseline, was set as the primary outcome measure. Significant improvement in vision and adverse events are reported as secondary outcomes. Patients: Nine patients with non-arteritic CRAO were enrolled. Results: A total of nine patients with CRAO underwent selective intra-ophthalmic arterial nimodipine and alteplase injection. Overall, BCVA had statistically significantly improved by 0.78 logarithm of the minimum angle of resolution (logMAR) at 1 month compared with baseline (95% confidence interval: (-1.24, -0.31), p-value = 0.001). Seven (77.8%) patients had significant visual improvement (≥0.3 logMAR) at 1-month post-treatment. There were minor adverse events during administration of the nimodipine, including chemosis and headache, which resolved after the discontinuation of nimodipine. There were also asymptomatic thromboembolic events in 2 patients (22.2%) after the intervention procedure, without any morbidity or mortality. Conclusion: The use of selective intra-ophthalmic arterial combined nimodipine and alteplase was efficacious in improving BCVA at 1 month for patients with non-arteritic CRAO presenting between 24 hours from onset, with minor adverse events but no serious adverse events.
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PURPOSE: Recent evidence suggests that diabetic retinopathy (DR) is associated with abnormal melatonin regulation, possibly related to dysfunction of the melanopsin-expressing intrinsically photosensitive retinal ganglion cells. This study explored melatonin regulation in type 2 diabetes (T2D) patients with DR and its relation to sleep and circadian functioning. METHODS: Thirty-five participants (10 non-diabetic controls, 10 T2D without DR, and 15 T2D with DR) were recruited. Overnight urine 6-sulfatoxymelatonin (aMT6s) and objective sleep and wrist activity (7-day actigraphy) were obtained. RESULTS: After adjusting for covariates, having T2D with DR was significantly associated with lower urinary aMT6s (ß = - 1.369, p = 0.004) compared with controls, while having T2D without DR was not (p = 0.418). T2D patients with DR reported poorer sleep quality (p = 0.014) and had greater variability of sleep duration (p = 0.017) than others, while no differences were found in sleep duration, efficiency, and rest-activity rhythm. After adjusting for covariates, lower nocturnal aMT6s was significantly associated with greater sleep variability. CONCLUSION: T2D patients with DR exhibited low overnight production of aMT6s which likely contributed to sleep irregularities possibly due to weak circadian signaling. Whether or not melatonin supplementation could improve health in T2D patients with DR remains to be explored.
Subject(s)
Diabetes Mellitus, Type 2/physiopathology , Diabetic Retinopathy/physiopathology , Melatonin/analogs & derivatives , Sleep/physiology , Adult , Case-Control Studies , Diabetes Mellitus, Type 2/epidemiology , Diabetic Retinopathy/epidemiology , Female , Humans , Male , Melatonin/urine , Middle AgedABSTRACT
PURPOSE: To study the safety and efficacy of intra-arterial chemotherapy (IAC) as a treatment for intraocular retinoblastoma in Thailand. DESIGN: Retrospective, interventional case series. METHODS: In this study, IAC was performed as primary or secondary treatment for patients with intraocular retinoblastoma using melphalan with or without additional topotecan or carboplatin. Survival rate, globe salvage rate, and treatment complications were recorded and analyzed. RESULTS: Of 27 eyes of 26 patients with retinoblastoma, 7 (26%) had IAC as primary treatment and 20 (74%) had IAC as secondary treatment. The eyes were classified by International Classification of Retinoblastoma (ICRB) as group B (n = 3, 11%), group C (n = 1, 4%), group D (n = 12, 44%), and group E (n = 11, 41%). Catheterization was successful in 75 (94%) of 80 sessions. The median number of IAC sessions was 3 (range, 1-7). At a mean follow-up of 32 months (range, 3-95 months), the overall globe salvage rate was 52%, with 100% in groups B and C, 75% in group D, and 9% in group E. Complications of IAC included occlusive vasculopathy (n = 4, 15%), vitreous hemorrhage (n = 3, 11%), retinal artery precipitation (n = 2, 7%), strabismus (n = 2, 7%), and transient ischemic attack (n = 1, 4%). The overall survival rate was 96% (n = 25). CONCLUSIONS: Our experience suggests that IAC is a safe and effective treatment for patients with ICRB group B, C, D, and some group E retinoblastoma. Careful patient selection and experienced surgeons are critical for achieving the best treatment outcome.
Subject(s)
Carboplatin/administration & dosage , Melphalan/administration & dosage , Retina/diagnostic imaging , Retinal Neoplasms/drug therapy , Retinoblastoma/drug therapy , Tertiary Care Centers , Topotecan/administration & dosage , Adolescent , Adult , Catheterization, Peripheral , Child , Child, Preschool , Dose-Response Relationship, Drug , Drug Therapy, Combination , Female , Fluorescein Angiography , Follow-Up Studies , Fundus Oculi , Humans , Incidence , Infusions, Intra-Arterial , Male , Middle Aged , Ophthalmoscopy , Retinal Neoplasms/diagnosis , Retinal Neoplasms/epidemiology , Retinoblastoma/diagnosis , Retinoblastoma/epidemiology , Retrospective Studies , Survival Rate/trends , Thailand/epidemiology , Time Factors , Ultrasonography , Young AdultABSTRACT
PURPOSE: There is no established therapy for exudative-hemorrhagic complications in primary retinal arteriolar macroaneurysm (RAM). METHODS: Retrospective multicenter interventional study of anti-vascular endothelial growth factor in symptomatic RAMs. Central macular thickness in µm and best-corrected visual acuity in logMar were correlated with the RAM size and distance to the macula. Statistical analyses were performed using paired comparisons and Pearson correlation. RESULTS: Thirty-two eyes (32 patients) were treated with a mean of 2.7 injections over a mean follow-up of 16.6 months. Initial best-corrected visual acuity correlated with the RAM size and distance to the macula (P = 0.02). Central macular thickness decreased by 131,180, and 211 µm at 1, 2, and 3 months after the first injection (P < 0.001). Best-corrected visual acuity improved by 0.47 and 0.38 Early Treatment Diabetic Retinopathy Study lines at 2 and 3 months (P = 0.005). Anti-vascular endothelial growth factor response correlated with the RAM size (P = 0.04) and the distance to the macula (P = 0.009). CONCLUSION: Symptomatic RAMs can be treated successfully with anti-vascular endothelial growth factor injections, leading to a decrease in macular edema.
Subject(s)
Bevacizumab/administration & dosage , Macula Lutea/pathology , Ranibizumab/administration & dosage , Receptors, Vascular Endothelial Growth Factor/administration & dosage , Recombinant Fusion Proteins/administration & dosage , Retinal Arterial Macroaneurysm/drug therapy , Visual Acuity , Angiogenesis Inhibitors/administration & dosage , Drug Therapy, Combination , Exudates and Transudates , Fluorescein Angiography , Follow-Up Studies , Fundus Oculi , Humans , Intravitreal Injections , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Retinal Arterial Macroaneurysm/diagnosis , Retrospective Studies , Tomography, Optical Coherence , Treatment OutcomeABSTRACT
BACKGROUND: POEMS syndrome is a plasma cell disorder, which clinically manifests from paraneoplastic syndrome: polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes. The most common ocular manifestation is optic disc swelling, whereas other ocular manifestations; cystoid macular edema, serous macular detachment, venous sinus thrombosis, infiltrative orbitopathy, uveitis, neovascularization of the disc, peripapillary choroidal neovascularization and optic disc drusen, had also been reported. CASE PRESENTATION: A 52-year-old Thai man presented with 5-day sudden painless visual loss in the left eye. Ocular examination revealed visual acuity of 20/20 and no light perception in the right and left eye, respectively. Right fundoscopic examination was significant for hyperemic generalized optic disc swelling. Left fundoscopic examination revealed opaque and edematous entire retina giving the appearance of central retinal artery occlusion (CRAO) along with pallid "chalky white" optic disc swelling. Fluorescein angiography showed profound leakage of bilateral optic nerve heads and arteriolar filling defect in macular area along with leakage of small retinal arterioles in the left eye. Indocyanine green angiography demonstrated choroidal filling defect in the left eye only. Neuroimaging showed enhancement and luminal narrowing of left internal carotid artery, early subacute watershed infarctions in the left cerebral hemisphere and pachymeningeal enhancement. Cerebrospinal fluid analysis revealed high protein level with normal opening pressure. Intravenous methylprednisolone was initially started without any benefit. After extensive investigations, diagnosis of "POEMS syndrome" was made based on polyneuropathy, elevated lambda light chain level, elevated plasma vascular endothelial growth factor (VEGF), hepatomegaly, spinal sclerotic bone lesions, and thrombocytosis. Furthermore, sural nerve biopsy demonstrated neuropathy and positive VEGF staining. He was treated with eight cycles of bortezomib, cyclophosphamide and dexamethasone (BorCyDex). Polyneuropathy and thrombocytosis had remarkably improved after 2nd cycle, whereas, visual impairment had shown no recovery. Hepatomegaly was significantly reduced after the completion of BorCyDex. Our case eventually received autologous hematopoietic stem cell transplantation with high dose melphalan. CONCLUSIONS: To our knowledge, we illustrated the first patient given CRAO as the first presentation and ocular finding ever reported in POEMS syndrome. Both cerebral and ocular infarctions were presumably the result of VEGF-induced cranial vasculopathy as evidenced by neuroimaging.
Subject(s)
POEMS Syndrome/complications , POEMS Syndrome/pathology , Retinal Artery Occlusion/etiology , Retinal Artery Occlusion/pathology , Humans , Male , Middle AgedABSTRACT
PURPOSE: To report the visual and anatomic outcomes of albino retinal detachment (ARD) repair. METHODS: Collaborative retrospective analysis of ARD. Outcome measures were number of surgical interventions, final retinal reattachment, and best corrected visual acuity (BCVA) at last follow-up. RESULTS: Seventeen eyes of 16 patients (12 males; mean age =37.8 years) had the following complications at presentation: macula off (14), total (7) or inferior detachment (5), proliferative vitreoretinopathy (5), detectable break (16), lattice (5), horseshoe tears (9), and giant tear or dialysis (4). Mean number of interventions was 1.8 (range =1-5) and included cryopexy (15) with scleral buckle (11), and/or vitrectomy (8). Mean initial BCVA was counting finger (CF) 1 m and at last follow-up (mean 77 months) CF4m with mean improvement of 4.5 lines (early treatment diabetic retinopathy study) (P=0.05). Intraoperative choroidal hemorrhage occurred in three eyes. The retina was finally attached in 14 eyes, with residual inferior detachment in three eyes with silicone oil in situ. Silicone oil was kept in six of seven eyes because of residual inferior detachment (3) and removal of silicone oil, which led to redetachment (1) or fear of redetachment (2). CONCLUSION: Repair of ARD may require several interventions, with the need to keep silicone oil in several cases due to nystagmus and reduced melanin pigment.
ABSTRACT
Purpose: Retinoblastoma (RB) is a retinal tumor that most commonly occurs in children. Approximately 40% of RB patients carry germline mutations in the RB1 gene. RB survivors with germline mutations are at increased risk of passing on the disease to future offspring and of secondary cancer in adulthood. This highlights the importance of genetic testing in disease management and counseling. This study aimed to identify germline RB1 mutations and to correlate the mutations with clinical phenotypes of RB patients. Methods: Genomic DNA was extracted from peripheral blood mononuclear cells isolated from 52 RB patients (27 unilaterally and 25 bilaterally affected probands). Mutations in the RB1 gene, including the promoter and exons 1-27 with flanking intronic sequences, were identified by direct sequencing. The samples with negative test results were subjected to multiplex ligation-dependent probe amplification (MLPA) to detect any gross mutations. A correlation of germline RB1 mutations with tumor laterality or age at diagnosis was determined for RB patients. Age at diagnosis was examined in regard to genetic test results and the presence of extraocular tumor extension. Results: Germline RB1 mutations were detected in 60% (31/52) of patients. RB1 mutations were identified in 92% (22/25) of bilateral RB patients, and a high rate of germline RB1 mutations was found in unilateral RB cases (33% or 9/27). Whole gene and exon deletions were reported in five patients. Twenty-three distinct mutations as a result of base substitutions and small deletions were identified in 26 patients; seven mutations were novel. Nonsense and splicing mutations were commonly identified in RB patients. Furthermore, a synonymous mutation was detected in a patient with familial RB; affected mutation carriers in this family exhibited differences in disease severity. The types of germline RB1 mutations were not associated with age at diagnosis or laterality. In addition, patients with positive and negative test results for germline RB1 mutations were similar in age at diagnosis. The incidence of extraocular tumors was high in patients with heritable RB (83% or 5/6), particularly in unilateral cases (33% or 3/9); the mean age at diagnosis of these patients was not different from that of patients with intraocular tumors. Conclusions: This study provides a data set of an RB1 genotypic spectrum of germline mutations and clinical phenotypes and reports the distribution of disease-associated germline mutations in Thai RB patients who attended our center. Our data and the detection methods could assist in identifying a patient with heritable RB, establishing management plans, and informing proper counseling for patients and their families.
Subject(s)
Germ-Line Mutation , Phenotype , Retinal Neoplasms/genetics , Retinoblastoma Binding Proteins/genetics , Retinoblastoma/genetics , Ubiquitin-Protein Ligases/genetics , Adult , Base Sequence , Child , Child, Preschool , Exons , Female , Gene Expression , Genotype , Humans , Infant , Inheritance Patterns , Male , Multiplex Polymerase Chain Reaction , Pedigree , Promoter Regions, Genetic , Retinal Neoplasms/diagnosis , Retinal Neoplasms/pathology , Retinoblastoma/diagnosis , Retinoblastoma/pathology , Severity of Illness Index , ThailandABSTRACT
PURPOSE: To determine the rate of progression and optimal follow-up time in patients with advanced-stage retinitis pigmentosa (RP) comparing the use of fundus autofluorescence imaging and spectral-domain optical coherence tomography. DESIGN: Retrospective analysis of progression rate. METHODS: Longitudinal imaging follow-up in 71 patients with retinitis pigmentosa was studied using the main outcome measurements of hyperautofluoresent ring horizontal diameter and vertical diameter along with ellipsoid zone line width from spectral-domain optical coherence tomography. Test-retest reliability and the rate of progression were calculated. The interaction between the progression rates was tested for sex, age, mode of inheritance, and baseline measurement size. Symmetry of left and right eye progression rate was also tested. RESULTS: Significant progression was observed in >75% of patients during the 2-year mean follow-up. The mean annual progression rates of ellipsoid zone line and hyperautofluorescent ring horizontal diameter and vertical diameter were 0.45 degree (4.9%), 0.51 degree (4.1%), and 0.42 degree (4.0%), respectively. The ellipsoid zone line width and hyperautofluorescent ring horizontal diameter and vertical diameter had low test-retest variabilities of 8.9%, 9.5%, and 9.6%, respectively. This study is the first to demonstrate asymmetrical structural progression rate between right and left eye, which was found in 19% of patients. The rate of progression was significantly slower as the disease approached the fovea, supporting the theory that RP progresses in an exponential fashion. No significant interaction between progression rate and patient age, sex, or mode of inheritance was observed. CONCLUSIONS: Fundus autofluorescence and optical coherence tomography detect progression in patients with RP reliably and with strong correlation. These parameters may be useful alongside functional assessments as the outcome measurements for future therapeutic trials. Follow-up at 1-year intervals should be adequate to efficiently detect progression.
Subject(s)
Retina/pathology , Retinitis Pigmentosa/diagnosis , Adolescent , Adult , Aged , Aged, 80 and over , Child , Disease Progression , Electroretinography , Female , Fluorescein Angiography , Follow-Up Studies , Humans , Male , Middle Aged , Multimodal Imaging , Retinal Photoreceptor Cell Outer Segment , Retinitis Pigmentosa/genetics , Tomography, Optical Coherence , Visual Acuity , Visual Field Tests , Visual Fields , Young AdultABSTRACT
PURPOSE: To report the results of an acetazolamide (Diamox(®)) treatment regimen in a genetically confirmed case of X-linked juvenile retinoschisis (XLRS). METHODS: A patient with XLRS was prescribed acetazolamide (Diamox(®)) at a dose of 500 mg/day, then discontinued the treatment due to non-compliance for 4 days, and finally resumed the course of treatment. Best-corrected visual acuity, retinal structure, and function were monitored with autofluorescence, spectral domain-optical coherence tomography (SD-OCT), adaptive optics scanning laser ophthalmoscopy (AOSLO), and full-field electroretinogram (ERG). Full-field ERG was performed using DTL recording electrodes and Ganzfeld stimulation according to ISCEV standards. RESULTS: Serial monitoring of the cysts by SD-OCT revealed a strong association between the effects of acetazolamide administration and the size of the schisis. A reduction in foveal cyst size was significant in as rapid as 6 days after acetazolamide initiation. AOSLO data revealed that the resolution of cone cell images improves as the foveal schisis decreases in size. CONCLUSIONS: Efficacy of acetazolamide in patients with XLRS can be apparent in as rapid as a week of therapy. AOSLO can be a good method to evaluate the cone cells after acetazolamide treatment in the early stages of XLRS.
Subject(s)
Acetazolamide/therapeutic use , Carbonic Anhydrase Inhibitors/therapeutic use , Retinoschisis/drug therapy , Electroretinography , Humans , Male , Ophthalmoscopy , Retina/physiopathology , Retinoschisis/physiopathology , Tomography, Optical Coherence/methods , Visual Acuity/physiology , Young AdultABSTRACT
BACKGROUND: It has long been assumed that in retinitis pigmentosa, disease presentation and progression are symmetrical. This study investigated whether hyperautofluorescent ring size, one known marker of disease progression, is symmetrical in typical RP patients. MATERIALS AND METHODS: A total of 88 patients with typical retinitis pigmentosa were enrolled in the study. Each presented with a hyperautofluorescent ring when imaged at baseline with fundus autofluorescence (AF). Vertical and horizontal diameters were analyzed according to mode of inheritance and age group. Seven of 88 patients had data missing in one eye and were excluded from further analysis. RESULTS: There was no significant relationship between hyperautofluorescent ring diameter and inheritance mode. There was a tendency toward smaller ring size with age and 3.7% of subjects displayed marked asymmetry in ring size between right and left eyes, although their electroretinogram results did not differ. Overall, when patients were considered as a group, there was a high correlation between right and left eyes' horizontal and vertical diameters (r=0.99, p<0.0001; r=0.98, p<0.0001). Comparing individual patients' eyes, and accounting for measurement error, a smaller majority of patients displayed symmetry of the hyperautofluorescent ring in both dimensions (85.7% in the vertical dimension, 87.3% in the horizontal dimension). CONCLUSION: This study confirmed the highly symmetrical nature of the hyperautofluorescent ring in RP patients, except in a small subgroup. AF results, which provide less variability per image, and are consistently interpreted between different observers, may be a more sensitive and reliable method for testing symmetry than many functional tests.
Subject(s)
Retina/pathology , Retinitis Pigmentosa/diagnosis , Adolescent , Adult , DNA Mutational Analysis , Disease Progression , Electroretinography , Female , Fluorescein Angiography , Humans , Male , Middle Aged , Observer Variation , Optical Imaging , Retinitis Pigmentosa/genetics , Retinitis Pigmentosa/physiopathology , Tomography, Optical Coherence , Visual Acuity/physiology , Visual Field Tests , Visual Fields/physiology , Young AdultABSTRACT
Retinitis pigmentosa (RP), a genetically heterogeneous group of retinopathies that occur in both non-syndromic and syndromic forms, is caused by mutations in â¼100 genes. Although recent advances in next-generation sequencing have aided in the discovery of novel RP genes, a number of the underlying contributing genes and loci remain to be identified. We investigated three siblings, born to asymptomatic parents of Italian-American descent, who each presented with atypical RP with systemic features, including facial dysmorphologies, psychomotor developmental delays recognized since early childhood, learning disabilities and short stature. RP-associated ophthalmological findings included salt-and-pepper retinopathy, attenuation of the arterioles and generalized rod-cone dysfunction as determined by almost extinguished electroretinogram in 2 of 3 siblings. Atypical for RP features included mottled macula at an early age and peripapillary sparing of the retinal pigment epithelium. Whole-exome sequencing data, queried under a recessive model of inheritance, identified compound heterozygous stop mutations, c.C199T:p.R67* and c.C322T:p.R108*, in the retinol dehydrogenase 11 (RDH11) gene, resulting in a non-functional protein, in all affected children. In summary, deleterious mutations in RDH11, an important enzyme for vision-related and systemic retinoic acid metabolism, cause a new syndrome with RP.
Subject(s)
Codon, Nonsense , Oxidoreductases/genetics , Retinitis Pigmentosa/genetics , Adolescent , Child , Female , Humans , Male , Pedigree , Phenotype , Retinitis Pigmentosa/diagnosis , Syndrome , Vision Tests , Visual Acuity , Young AdultABSTRACT
PURPOSE: To report the phenotypes caused by a novel mutation in the PDE6B gene in a family with two affected siblings and one affected cousin with a 2-year follow-up. DESIGN: Three patients from a family with a history of retinitis pigmentosa underwent clinical evaluations. The affected patients' DNA was analyzed using next-generation sequencing and segregation analyses were performed for the family. SETTING: Edward S. Harkness Eye Institute, New York Presbyterian Hospital. PARTICIPANTS: Two siblings, one cousin, and five unaffected family members. MAIN OUTCOME MEASURES: Macular appearance assessed by funduscopy, autofluorescence imaging, spectral-domain optical coherence tomography and visual function assessed by electroretinography. RESULTS: The proband, brother, and cousin had rod-cone degeneration with cystoid macular edema. Fundus autofluorescence showed hyperautofluorescent ring constriction over time. Spectral-domain optical coherence tomography revealed retinal pigment epithelium atrophy, loss of external limiting membrane, retinal layer thinning, and reduction in ellipsoid zone length over time. Next-generation whole exome sequencing revealed a homozygous c.1923_1969ins6del47 nonsense PDE6B mutation, which has not been previously described, that segregated with the disease in the family. CONCLUSIONS: The homozygous PDE6B mutation causes retinitis pigmentosa. Acetazolamide treatment improved visual acuity but rod degeneration continued. Despite having the same mutation and living in the same environment, the proband's brother progressed at a faster rate starting at a younger age, suggesting that gene modifiers may influence the expressivity of the phenotype. Next-generation sequencing, used to discover this mutation, is a practical new technology that can detect novel disease-causing alleles, where previous arrayed primer extension (APEX) technology could not.
Subject(s)
Codon, Nonsense , Cyclic Nucleotide Phosphodiesterases, Type 6/genetics , High-Throughput Nucleotide Sequencing , Retinitis Pigmentosa/genetics , Adolescent , Carbonic Anhydrase Inhibitors/therapeutic use , Consanguinity , DNA Mutational Analysis , Electroretinography , Exome/genetics , Fluorescein Angiography , Genetic Association Studies , Humans , Male , Methazolamide/therapeutic use , Pedigree , Polymorphism, Single Nucleotide , Retina/physiology , Retinitis Pigmentosa/drug therapy , Retinitis Pigmentosa/physiopathology , Tomography, Optical Coherence , Visual Acuity , Young AdultABSTRACT
Ocular involvement after primary infection with varicella zoster virus is very rare. We report a case of a healthy 18-year-old man who presented with unilateral ischemic retinal vasculitis 10 days after the onset of chickenpox. He developed acute severe visual loss and a relative afferent pupillary defect in his right eye. Fundus imaging, optical coherence tomography, fundus fluorescence angiography, and electrophysiologic studies confirmed the diagnosis of retinal vasculitis, which led to generalized retinal ischemia. Although aggressive treatment with systemic steroids and antiviral drugs was administered, a poor visual outcome still resulted.
ABSTRACT
Vigabatrin is an effective antiepileptic drug (AED) typically used in the treatment of refractory partial seizures and infantile spasms. Its use, however, is limited due to the concern of retinal toxicity and subsequent visual field defects. Herewith in we describe a case of vigabatrin toxicity that illustrates electroretinographic (ERG) changes occur before imaging and visual field deterioration. Decrease in maximal ERG b: a ratio was observed before thinning of the retinal nerve fiber layer (RNFL) on optical coherence tomography (OCT).