Etiologic spectrum and predictors of visual acuity in non-glaucomatous optic atrophy

Abstract

Aim

To determine the prevalence and underlying causes of nonglaucomatous optic atrophy (NGOA) in a tertiary referral center in southeastern Iran and to identify predictors of current visual acuity in this population.

Methods

In this descriptive cross-sectional study, patients with a confirmed diagnosis of NGOA were included. All cases had a definitive etiologic diagnosis based on clinical evaluation, paraclinical investigations, and thorough review of medical records. Patients were classified into etiologic categories including hereditary or developmental disorders; secondary or consecutive optic atrophy; traumatic optic neuropathy (TON); compressive lesions; raised intracranial pressure–related involvement; inflammatory or demyelinating disease; infiltrative processes; toxic exposure; and ischemic causes.

Results

A total of 155 eyes from 155 patients with NGOA were analyzed, of whom 86 (55.5%) were male. Overall, 75 patients (48.4%) had a best-corrected visual acuity (BCVA) of ≥ 1.90 logMAR (logarithm of the minimum angle of resolution), corresponding to counting fingers vision or worse. Patients with toxic optic neuropathy demonstrated the poorest visual outcomes, with 5 of 6 cases (83.3%) having a BCVA of ≥ 1.90 logMAR. Ischemic causes were the most prevalent etiology, identified in 46 patients (29.7%), including 45 cases of non-arteritic anterior ischemic optic neuropathy (AION). TON was the second most common cause, observed in 37 patients (23.9%). In multivariate analysis, a longer duration from symptom onset was the sole independent predictor of poorer current visual acuity (β = 0.253, P = 0.010).

Conclusion

Previous non-arteritic AION was the most common cause of NGOA in this cohort, followed by TON. Toxic exposure was associated with the poorest visual acuities. Among all evaluated variables, the duration from symptom onset was the only independent predictor of current visual acuity.

Keywords

optic atrophy non-glaucomatous etiology visual acuity ischemic traumatic

Introduction

Optic nerve atrophy is a common long-term outcome of various disorders that result in damage to retinal ganglion cell axons. It represents a final clinical endpoint for a wide range of pathological processes affecting the optic nerve, optic tracts, brain, and, in some cases, the retina. With the exception of advanced glaucoma, which is a well-recognized cause of optic atrophy, other etiologies are classified as non-glaucomatous optic atrophy (NGOA). The underlying causes of NGOA are heterogeneous and include inflammatory, compressive, toxic, ischemic, and hereditary conditions that lead to optic neuropathy and subsequent axonal loss. Previous demographic and epidemiologic studies have demonstrated considerable variation in the prevalence of these etiologies across different populations and regions.^1–6 Regardless of the underlying cause, once optic atrophy has developed, axonal damage is largely irreversible and no disease-specific therapies are currently effective in restoring visual function.⁷ Therefore, determining the prevalence of etiologic factors is essential for identifying the most relevant acquired and genetic risk factors, as well as for guiding diagnostic and preventive strategies.

Several studies worldwide, including reports from Middle Eastern countries, have investigated the incidence and epidemiologic characteristics of NGOA.^1–3 However, no large-scale study has evaluated the prevalence and etiologic spectrum of NGOA in Iran. Optic atrophy is a significant cause of visual impairment; in Iran, diseases of the optic nerve and optic tract account for approximately 10% of all cases of visual impairment and blindness.^8,9 Given this relatively high burden and the lack of comprehensive national data, further investigation is warranted.

Accordingly, the present study was conducted to determine the prevalence and underlying causes of NGOA in patients evaluated at a tertiary referral center in southeastern Iran. In addition, we aimed to assess differences in current visual acuity among patients with NGOA based on etiologic factors, as well as to identify predictors of current visual acuity in this population.

Methods

Study design

This descriptive cross-sectional study was conducted between March 2024 and March 2025 at the Ophthalmology Department of Shafa Hospital, Kerman, Iran. The study protocol was approved by the Ethics Committee of Kerman University of Medical Sciences (approval code: IR.KMU.AH.REC.1402.211) and was performed in accordance with the tenets of the Declaration of Helsinki. Written informed consent was obtained from all participants or their legal guardians.

Study setting and population

All participants underwent a comprehensive ophthalmologic examination, including measurement of best-corrected visual acuity (BCVA), assessment of pupillary light reflex for detection of a relative afferent pupillary defect (RAPD), slit-lamp biomicroscopy, Goldmann applanation tonometry, and dilated fundus examination. BCVA was measured using a Snellen E-chart and converted to logarithm of the minimum angle of resolution (logMAR) units for statistical analysis. Visual acuity categories were assigned the following logMAR equivalents: no light perception (3.0), light perception (2.7), hand motion (2.3), and counting fingers (1.9).¹⁰ In patients with bilateral optic atrophy, the eye with worse visual acuity was selected for analysis to ensure inclusion of only one eye per patient.

A detailed history of symptom onset was obtained, including decreased visual acuity (blurred or reduced vision), visual field defects, color vision disturbances (e.g., washed-out colors), reduced contrast sensitivity (difficulty seeing in dim light or lack of visual sharpness), and altered brightness perception (objects appearing dimmer in the affected eye). The time of symptom onset was recorded. In young children, indirect indicators such as nystagmus, strabismus, incidental detection during routine ophthalmologic examination, or referral by a neurologist or pediatrician leading to the diagnosis of optic atrophy were considered.

Diagnostic criteria and etiologic classification

All patients with a confirmed diagnosis of NGOA were included. For both confirmation of NGOA diagnosis and etiologic classification, two independent examiners (A.S. and M.S.), who were blinded to each other’s assessments, evaluated each case and assigned it to the predefined etiologic categories. In cases of disagreement, a third senior assessor (A.Z.) was consulted for adjudication. The clinical diagnosis of optic atrophy was established based on funduscopic evidence of optic disc pallor, with or without disc cupping or blurred margins, along with supportive paraclinical findings. These included abnormalities on visual function tests such as characteristic visual field defects, color vision deficits, contrast sensitivity impairment, electrophysiological studies when available, and identification of a plausible underlying etiology. Optical coherence tomography (OCT) and automated perimetry were performed when indicated. Neuroimaging with brain and/or orbital computed tomography (CT) or magnetic resonance imaging (MRI) was obtained in cases with suspected compressive optic neuropathy, raised intracranial pressure, or space-occupying lesions involving the orbit or central nervous system affecting the visual pathway. Medical records of patients with hereditary non-glaucomatous optic atrophy (NGOA), including Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA), were reviewed for documented genetic testing results. Evaluated mutations included mitochondrial DNA mutations 11778 and 14484 for LHON and OPA1 gene mutations for ADOA. All included cases had a definitive etiologic diagnosis based on clinical findings, paraclinical investigations, and thorough review of medical records. Patients were classified into etiologic categories including hereditary or developmental disorders; chorioretinal degenerative or ischemic conditions resulting in secondary or consecutive optic atrophy; trauma-related optic nerve injury; compressive lesions; raised intracranial pressure–related involvement; inflammatory or demyelinating disease; infiltrative processes; toxic exposure; and ischemic or vascular causes. Detailed definitions for each category are provided in Table 1.

Table 1.

Diagnostic criteria for etiologic classification of non-glaucomatous optic atrophy (NGOA)¹¹.

Etiologic category	Definition
Hereditary/Developmental	Includes patients with confirmed genetic diagnosis of hereditary optic neuropathies such as LHON (mitochondrial mutations e.g., m.11778G>A, m.14484T>C) or ADOA (OPA1 mutations), based on documented genetic testing. Optic nerve hypoplasia was diagnosed clinically by a small optic disc, double-ring sign, and increased disc–macula distance (>3 disc diameters) on fundus examination.
Secondary/Consecutive (Chorioretinal causes)	Optic atrophy secondary to chorioretinal disease, including retinitis pigmentosa and similar degenerations. Diagnosis was based on fundus findings (bone-spicule pigmentation, retinal pigment epithelium atrophy, vascular attenuation), symptoms such as nyctalopia, family history, disease progression, and supportive ERG findings (reduced/absent amplitudes). Other chorioretinal diseases were confirmed by clinical examination, OCT imaging, and medical records.
Traumatic	Optic atrophy following head or orbital trauma, typically associated with sudden visual loss, RAPD, and absence of other retinal or compressive causes on imaging. Diagnosis was based on documented history of trauma and clinical correlation.
Compressive	Optic atrophy due to compressive lesions along the visual pathway (intraorbital, intracranial, or optic nerve). Diagnosis was confirmed by CT and/or MRI demonstrating mass effect (e.g., tumors, meningioma, pituitary adenoma), without alternative retinal or primary optic nerve disease explaining the findings.
Raised intracranial pressure (Papilledema-related)	Optic atrophy following chronic papilledema due to increased intracranial pressure. Diagnosis required bilateral optic disc swelling with CSF opening pressure ≥25 cmH₂O on LP, consistent with idiopathic or secondary intracranial hypertension.
Inflammatory/Demyelinating	Optic atrophy secondary to optic neuritis, typically associated with acute or subacute visual loss. Diagnosis was supported by MRI findings of optic nerve enhancement or enlargement and/or brain MRI features suggestive of demyelinating disease (e.g., MS), confirmed by neurologic evaluation. No alternative retinal or compressive pathology was present.
Infiltrative	Optic atrophy due to malignant or infiltrative disease affecting the optic nerve. Diagnosis was based on MRI findings of optic nerve thickening and enhancement in the context of a known systemic malignancy or radiologically confirmed metastatic disease involving the orbit or central nervous system.
Toxic	Optic atrophy following exposure to toxic substances, including methanol, alcohol abuse, or neurotoxic medications. Diagnosis required a clear exposure history and bilateral or subacute visual impairment with no evidence of retinal or compressive pathology.
Ischemic/Vascular (AION-related)	Optic atrophy following anterior ischemic optic neuropathy (non-arteritic or arteritic), characterized by acute painless monocular vision loss, optic disc edema at onset, and absence of compressive causes on neuroimaging.

LHON: Leber hereditary optic neuropathy, ADOA: Autosomal dominant optic atrophy, OPA1: Optic atrophy 1 gene, m.11778G>A/m.14484T>C: Mitochondrial DNA point mutations associated with LHON, RPE: Retinal pigment epithelium, ERG: Electroretinography, OCT: Optical coherence tomography, RAPD: Relative afferent pupillary defect, CT: Computed tomography, MRI: Magnetic resonance imaging, CSF: Cerebrospinal fluid, LP: Lumbar puncture, AION: Anterior ischemic optic neuropathy, MS: Multiple sclerosis.

Patients in whom a definite etiology for optic atrophy could not be established were excluded from the study.

Systemic risk factors for ischemic or vascular events, including diabetes mellitus and hypertension, were evaluated based on documented medical history, current medication use, or contemporaneous laboratory results.

Patients were excluded if they had incomplete medical records, optic nerve or central nervous system pathologies that had not progressed to optic atrophy (such as acute optic neuritis without atrophic changes), or glaucomatous optic nerve atrophy. Glaucomatous optic atrophy was differentiated from NGOA based on characteristic features, including relatively preserved neuroretinal rim coloration, less prominent pallor, deeper and more focal optic disc cupping, and the presence of peripapillary atrophy, which supported a glaucomatous etiology.²

Data analysis

Statistical analyses were performed using SPSS software version 24 (IBM Corp., Chicago, IL, USA). Continuous variables were summarized using mean, standard deviation, and range, while categorical variables were presented as frequencies and percentages. Multiple linear regression analysis was performed to identify predictors of current BCVA. Variables with a variance inflation factor greater than 5 were considered to exhibit excessive multicollinearity and were excluded from the model. Independence of residuals was assessed using the Durbin–Watson statistic, with values between 1.5 and 2.5 indicating acceptable independence. A two-tailed p-value less than 0.05 was considered statistically significant.

Results

A total of 165 patients with non-glaucomatous optic atrophy (NGOA) were initially identified. Among them, 10 patients were excluded due to indeterminate etiology despite full clinical and paraclinical evaluation, as specified in the exclusion criteria. Therefore, 155 patients met the inclusion criteria and were enrolled in the final analysis for this descriptive cross-sectional study. Among these patients, 86 (55.5%) were male. Patients were categorized into nine etiologic groups based on the primary cause of optic atrophy. Demographic characteristics, duration of symptoms, laterality, visual acuity, and detailed underlying pathologies for each group are presented in Table 2. Ischemic/vascular optic neuropathy was the most prevalent cause of NGOA, identified in 46 patients (29.7%), followed by TON in 37 patients (23.9%). Together, these two etiologies accounted for more than half of all NGOA cases. Among the 17 patients with hereditary or developmental disorders, hereditary optic neuropathies—including LHON and ADOA—were the most common causes, accounting for 13 cases (76.5%). In the secondary or consecutive optic atrophy group (23 cases), retinitis pigmentosa (RP) was the predominant underlying condition, identified in 15 patients (65.2%). Intracranial tumors were the most common cause of compressive optic neuropathy, accounting for 10 of 13 cases (76.9%). Among these intracranial tumors, pituitary macroadenoma was the most frequent subtype, identified in 6 of 10 cases. Among patients with inflammatory or demyelinating optic neuropathy, 5 of 6 (83.3%) had a history of multiple sclerosis (MS)–related optic neuritis. All cases of toxic optic neuropathy were attributable to methanol toxicity. In the ischemic/vascular group, non arteritic anterior ischemic optic neuropathy (AION) accounted for 45 of 46 cases, with one case related to carotid artery dissection. Further etiologic details are provided in Table 2. Among the 45 patients with non arteritic AION, 18 (40.0%) had arterial hypertension and 12 (26.7%) had diabetes mellitus.

Table 2.

Demographic characteristics, clinical features, and etiologies of nonglaucomatous optic atrophy.

Etiology	Prevalence, n (%)	Age (years)	Male, n (%)	Duration of symptoms (months)	Bilaterality, n (%)	BCVA (logMAR)	Detailed underlying causes
Hereditary/Developmental	17 (11.0)	28.6 ± 16.5 (5–63)	8 (47.1)	330.0 ± 205.3 (12–756)	17 (100)	2.04 ± 0.97 (0.20–3.00)	Hereditary optic neuropathies including LHON or ADOA: 13; optic nerve hypoplasia: 2; childhood encephalitis: 1; Friedreich ataxia syndrome: 1
Secondary/Consecutive	23 (14.8)	47.0 ± 15.0 (14–72)	14 (60.9)	165.9 ± 158.2 (4–468)	17 (73.9)	2.16 ± 0.82 (0.00–3.00)	RP: 15; retinal ischemic/vaso-occlusive disorders: 7; other retinal dystrophies: 1
Traumatic	37 (23.9)	43.6 ± 17.7 (11–78)	29 (78.4)	157.2 ± 130.1 (2–600)	10 (27.0)	1.40 ± 1.29 (0.00–3.00)	Trauma including falls, vehicle accidents, or assault: 36; electrical shock: 1
Compressive	13 (8.4)	41.2 ± 17.3 (15–69)	4 (30.8)	183.8 ± 173.3 (5–492)	12 (92.3)	2.24 ± 1.02 (0.20–3.00)	Intracranial tumors: 10 (6 cases with pituitary macroadenoma); orbital tumors: 2; osteopetrosis: 1
Raised ICP–related	5 (3.2)	40.8 ± 6.2 (32–49)	2 (40.0)	276.0 ± 225.6 (24–540)	5 (100)	1.74 ± 1.15 (0.30–2.70)	IIH: 3; hydrocephalus: 2
Inflammatory/Demyelinating	6 (3.9)	43.5 ± 16.4 (27–71)	4 (66.7)	18.4 ± 16.5 (2–36)	1 (16.7)	0.58 ± 0.66 (0.00–1.70)	MS–related optic neuritis: 5; viral-related optic neuritis: 1
Infiltrative	2 (1.3)	45.0 ± 8.5 (39–51)	1 (50.0)	12.0	1 (50.0)	1.50 ± 2.12 (0.00–3.00)	Metastatic infiltration from distant malignancies: 2
Toxic	6 (3.9)	34.0 ± 9.0 (21–43)	5 (83.3)	14.2 ± 13.5 (2–36)	5 (83.3)	2.30 ± 1.20 (0.00–3.00)	Methanol toxicity: 6
Ischemic/Vascular	46 (29.7)	67.4 ± 10.8 (41–89)	19 (41.3)	42.8 ± 41.6 (2–168)	6 (13.0)	1.16 ± 0.92 (0.00–3.00)	Non arteritic AION: 45; carotid artery dissection: 1

Values are presented as mean ± standard deviation (range) unless otherwise stated.

BCVA: best-corrected visual acuity; logMAR: logarithm of the minimum angle of resolution; ICP: intracranial pressure; LHON: Leber hereditary optic neuropathy; ADOA: autosomal dominant optic atrophy; RP: retinitis pigmentosa; IIH: idiopathic intracranial hypertension; MS: multiple sclerosis; AION: anterior ischemic optic neuropathy.

BCVA ranged from 0.00 to 3.00 logMAR. Overall, 75 patients (48.4%) had a BCVA ≥ 1.90 logMAR, corresponding to counting fingers vision or worse. The detailed distribution of BCVA across logMAR categories according to etiologic groups is presented in Table 3. The BCVA category thresholds used in this table were primarily based on the International Statistical Classification of Diseases (ICD) criteria.¹² Patients with toxic optic neuropathy demonstrated the poorest visual outcomes, with 5 of 6 cases (83.3%) having a BCVA of ≥ 1.90 logMAR.

Table 3.

Distribution of best-corrected visual acuity (BCVA) in logMAR ranges across etiologies of nonglaucomatous optic atrophy (NGOA).

BCVA (logMAR range)	Hereditary/Developmental (n=17)	Secondary/Consecutive (n=23)	Traumatic (n=37)	Compressive (n=13)	Raised ICP–related (n=5)	Inflammatory/Demyelinating (n=6)	Infiltrative (n=2)	Toxic (n=6)	Ischemic (n=46)	Total (n=155)
0.00–0.50	2 (11.8)	1 (4.3)	16 (43.2)	2 (15.4)	1 (20.0)	3 (50.0)	1 (50.0)	1 (16.7)	12 (26.1)	39 (25.2)
0.50–1.00	1 (5.9)	1 (4.3)	1 (2.7)	0 (0.0)	1 (20.0)	1 (16.7)	0 (0.0)	0 (0.0)	7 (15.2)	12 (7.7)
1.00–1.30	1 (5.9)	1 (4.3)	1 (2.7)	0 (0.0)	0 (0.0)	1 (16.7)	0 (0.0)	0 (0.0)	12 (26.1)	16 (10.3)
1.30–1.80	1 (5.9)	3 (13.0)	2 (5.4)	1 (7.7)	0 (0.0)	1 (16.7)	0 (0.0)	0 (0.0)	5 (10.9)	13 (8.4)
1.80–3.00	8 (47.1)	13 (56.5)	8 (21.6)	4 (30.8)	3 (60.0)	0 (0.0)	0 (0.0)	2 (33.3)	5 (10.9)	43 (27.7)
3.00	4 (23.5)	4 (17.4)	9 (24.3)	6 (46.2)	0 (0.0)	0 (0.0)	1 (50.0)	3 (50.0)	5 (10.9)	32 (20.6)

Values are presented as number (percentage within each etiologic group).

BCVA: best-corrected visual acuity; logMAR: logarithm of the minimum angle of resolution; ICP: intracranial pressure.

Eleven patients (7.1%) were aged 18 years or younger and were classified as the pediatric subgroup. In this subgroup, the most common etiologies were hereditary causes (4 cases, 36.4%), traumatic optic neuropathy (3 cases, 27.3%), secondary/consecutive causes (2 cases, 18.2%), and compressive optic neuropathy (2 cases, 18.2%).

In univariate regression analysis, both the etiology of optic atrophy (β = −0.258, P = 0.001) and the duration from symptom onset (β = 0.327, P < 0.001) were significantly associated with current BCVA. However, in multivariate analysis, only the duration of symptoms remained independently associated with current BCVA (β = 0.253, P = 0.010). Accordingly, among all evaluated baseline variables, a longer duration from symptom onset emerged as the sole independent predictor of poorer current visual acuity (Table 4).

Table 4.

Univariate and multivariate regression analyses evaluating the effect of demographic and clinical variables on current BCVA (LogMAR).

Variable	Univariate analysis			Multivariate analysis
Variable	Standard partial regression coefficient (ß)	Unstandardized ß (CI 95%)	P	Standard partial regression coefficient (ß)	Unstandardized ß (CI 95%)	P
Age (per 1 year)	-0.114	-0.007 (-0.016, 0.003)	0.162	-0.008	0.000 (-0.012, 0.011)	0.936
Gender (male vs. female)	-0.011	-0.025 (-0.387, 0.336)	0.890	-0.001	-0.001 (-0.369, 0.366)	0.994
Duration (per 1 month)	0.327	0.002 (0.001, 0.003)	< 0.001	0.253	0.002 (0.000, 0.003)	0.010
Etiology (9 predefined categories)	-0.258	-0.095 (-0.152, -0.038)	0.001	-0.136	-0.051 (-0.135, 0.034)	0.241

BCVA: best-corrected visual acuity, CI: confidence interval.

Discussion

Although previous studies have reported etiologic distributions of NGOA in various populations, including some Middle Eastern countries, large cohort data from Iran remain limited.^2–6,8 Furthermore, previous studies have not evaluated independent predictors of current visual acuity using multivariate models incorporating etiology, disease duration, and demographic variables. Therefore, this study provides novel insights into both the etiologic spectrum and determinants of visual acuity in NGOA in southeastern Iran.

The most common cause of optic atrophy in the present study was ischemic/vascular optic neuropathy (29.7%), with non arteritic AION accounting for nearly all cases (45 of 46). Similarly, Kılıçarslan et al. reported that 29.2% of NGOA cases in Turkey were attributable to AION, including both arteritic and non-arteritic forms.² In our cohort, this etiologic group had the highest mean age (67.4 ± 10.8 years), which is consistent with existing literature indicating that AION is the most common optic neuropathy in individuals over 50 years of age.^13,14 Thus, our results align well with prior epidemiologic studies.

TON was the second most common cause of optic atrophy in our study, accounting for 23.9% of cases. The frequency and etiologic distribution of TON vary widely across regions and countries.^2,4,15–17 In Nepal, Shrestha et al. reported trauma as the leading cause of optic atrophy (25.8%),⁴ which is comparable to our findings. The relatively high frequency of TON in our study may be explained by the high burden of road traffic accidents in Iran, which remains a major cause of trauma-related injuries and mortality.¹⁸ Since most TON cases in our cohort were associated with traffic-related accidents, TON constituted one of the leading etiologies of NGOA in our region and was the second most common cause in our study population. Therefore, compared with studies from other countries, the higher prevalence of TON in our cohort may reflect the greater incidence of traffic-related trauma in Iran.¹⁸ The mean age of patients with traumatic optic atrophy in our study (43.6 ± 17.7 years) was slightly higher than that reported in several previous studies, in which the majority of patients were younger than 40 years.^2,4,15–17 The higher mean age of patients in our study compared with previous reports may be related to the broader age distribution of individuals involved in road traffic accidents in our population.¹⁸ In contrast, studies from other countries may include fewer trauma cases and may involve predominantly younger age groups. Male predominance was evident (78.4%), consistent with earlier reports, likely reflecting higher exposure of males to high-risk activities. Road traffic accidents were the most common cause of trauma in our cohort, in agreement with previous studies.^2,4,15–17

Hereditary and developmental disorders constituted the most common etiologic category among pediatric patients. Previous studies have similarly reported hereditary optic neuropathies (such as LHON and ADOA) and developmental brain or optic nerve disorders as leading causes of NGOA in children.^19,20 This explains the relatively younger mean age observed in this etiologic group in our study.

Several studies have reported intracranial tumors as a leading cause of optic atrophy. For instance, Kılıçarslan et al. found that central nervous system–related causes, particularly intracranial tumors, accounted for 27.2% of NGOA cases,² while Mbekeani et al. reported tumors as the predominant etiology (55.4%) in a Saudi Arabian cohort.³ Our findings are in agreement with Kılıçarslan et al., as pituitary adenoma was the most frequent intracranial tumor associated with NGOA in both studies. However, in our cohort, compressive optic neuropathy accounted for only 8.4% of cases. This discrepancy may be attributed to referral patterns, selection bias, differences in study populations, and variability in access to specialized neurosurgical services across centers.

Consecutive optic atrophy related to chorioretinal diseases constituted a substantial proportion of NGOA cases in our cohort. Studies from India and underdeveloped African countries have similarly reported a high prevalence of consecutive optic atrophy, with RP being the most common underlying cause.^5,6 Consistent with these findings, RP was the leading cause within this category in our study.

Toxic optic neuropathy accounted for 3.9% of cases, with all affected patients having methanol toxicity and a strong male predominance. This finding closely parallels results from Turkey, where toxic causes accounted for 3.5% of optic atrophy cases, with methanol ingestion responsible for approximately half.²The high prevalence of severe visual loss in this group underscores the devastating visual consequences of methanol poisoning.

Inflammatory or demyelinating optic neuropathy accounted for 5.6% of NGOA cases in our study, with MS being the most common underlying cause. This is consistent with previous reports.² Although MS-related optic neuritis is more prevalent among females, male patients may experience greater retinal nerve fiber layer thinning and more pronounced neuroaxonal loss following inflammation,²¹ which may explain the male predominance observed in our cohort.

We excluded cases with unknown or idiopathic optic atrophy, which accounted for 10 patients. Other studies have reported varying proportions of idiopathic optic atrophy, often attributed to limited diagnostic resources or incomplete investigations.¹ Differences in environmental exposure, genetic background, access to advanced diagnostic tools (such as genetic testing), and heterogeneity in etiologic classification systems likely contribute to the wide variation in reported NGOA etiologies across regions.

Optic atrophy is a major cause of visual impairment and blindness worldwide.^22,23 In our study, toxic optic neuropathy was associated with the poorest visual acuity outcomes, with 83.3% of cases having BCVA ≥ 1.90 logMAR, consistent with previous reports.² However, in multivariate analysis, the etiology of NGOA was not independently associated with current visual acuity. Instead, the duration from symptom onset was the only significant predictor of worse current visual acuity. This finding suggests that optic atrophy represents a progressive process of axonal degeneration, in which prolonged disease duration leads to cumulative neuroaxonal loss and worsening visual acuity, even when the optic disc appearance remains relatively stable over time.²⁴

Although reduced visual acuity is the most common presenting symptom of optic atrophy, some patients may primarily exhibit deficits in other visual functions, such as visual field, contrast sensitivity, or color vision. In our study, 9.7% of patients had normal or near-normal BCVA (0.00–0.10 logMAR), which is consistent with previous reports.^2,3,20 Visual acuity reflects foveal function, whereas optic atrophy reflects axonal loss that may spare the papillomacular bundle, preserving central vision. Additionally, in cases of post-inflammatory or post-edematous optic atrophy following resolved optic neuritis or chronic papilledema, visual acuity may recover fully despite residual optic disc pallor.²⁵ Therefore, clinicians should not rely solely on visual acuity when evaluating suspected optic atrophy; comprehensive assessment of visual fields, contrast sensitivity, and color vision, along with fundus examination, OCT, and neuroimaging when indicated, is essential.

This study has some strengths, including a relatively large sample size and access to neuroimaging and laboratory investigations, which enhanced diagnostic accuracy. However, several limitations should be acknowledged. The single-center design and the absence of a formal sample size calculation may limit the generalizability of the findings. The relatively small pediatric sample limits age-stratified analyses. Additionally, not all visual functions or structural parameters, including retinal nerve fiber layer and ganglion cell layer thickness on OCT, were assessed in every patient, as advanced testing was primarily performed in cases with near-normal visual acuity or atypical clinical presentations. Future multicenter, population-based studies with comprehensive functional and structural assessments are needed to better characterize NGOA in Iran and clarify regional differences.

Conclusion

In this cohort, the most common cause of NGOA was previous AION, followed by TON. The poorest visual acuity was observed in patients with toxic optic neuropathy secondary to methanol poisoning. Among all evaluated variables, the duration from symptom onset was the only independent predictor of current visual acuity, underscoring the importance of early recognition and evaluation of optic nerve disorders.

Footnotes

ORCID iDs

Meraj Sharifi

Amin Zand

Mohammad Sharifi

Ali Sharifi

Ethical considerations

The study was approved by the ethics committee of Kerman University of Medical Sciences, Kerman, Iran (ethics code: IR.KMU.AH.REC.1402.211). The study was explained to eligible participants and written informed consents were obtained. The study was in accordance with Declaration of Helsinki and the national guidelines and regulations.

Consent to participate

Written informed consent was obtained from all participants or their legal guardians, regarding any research use of medical information without disclosing their identity.

Author contributions

Me.Sharifi and A.Sharifi designed the study. Mo.Sharifi and A.Sharifi collected data. A.Zand and Me.Sharifi analyzed and reported the data. Mo.Sharifi and Me.Sharifi wrote the first draft of the paper. A.Sharifi and A.Zand contributed to the writing and revision of the manuscript. All authors read and approved the final manuscript.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.*

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