Beyond the optic disc: Investigating gender-based differences in optic neuritis

Abstract

Optic neuritis (ON) is a focal inflammatory demyelinating disorder of the optic nerve. Although classically regarded as a sentinel event for multiple sclerosis (MS), ON also occurs in antibody-mediated entities such as aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) and myelin-oligodendrocyte-glycoprotein-antibody disease. In all these settings biological sex is a pivotal determinant of susceptibility, clinical expression, treatment response and long-term outcome. Data synthesized from an extensive literature analysis utilizing PubMed, Scopus, and Web of Science in this review shows that women experience ON far more frequently – with female-to-male ratios ranging from 3:1 in MS to almost 9:1 in AQP4-NMOSD – yet men, when affected, tend to accumulate irreversible neuro-axonal loss more rapidly. Sex-specific patterns arise at every biological stratum: X-linked gene dosage, epigenetic regulation, hormonal cycles from puberty through menopause, metabolic co-modifiers such as obesity and vitamin-D status, and psychosocial forces that influence healthcare utilization. By weaving these elements into an expanded narrative, the present review provides a detailed resource for clinicians and investigators aiming at gender-tailored management of ON.

Key Words: Optic neuritis; Gender differences; Neuromyelitis optica spectrum disorder; Myelin oligodendrocyte glycoprotein antibody disease; Optic nerve

Core Tip: Optic neuritis (ON) is affected by sex at all levels, from molecular biology to clinical outcomes. Women are considerably more predisposed to developing ON, particularly in aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder. Men frequently experience more severe long-term neuroaxonal damage. The interaction of genetic, hormonal, metabolic, and behavioral variables highlights the necessity for sex-specific strategies in the diagnosis, treatment, and research of ON. Comprehending these distinctions is crucial for enhancing individualized treatment in ON across various demyelinating conditions.

INTRODUCTION

Optic neuritis (ON) presents with sub-acute monocular visual loss, impaired color vision and peri-ocular pain exacerbated by eye movement. The classic dichotomy distinguishes a typical ON – strongly predictive of MS – from a spectrum of atypical forms that include neuromyelitis optica spectrum disorder (NMOSD), myelin-oligodendrocyte-glycoprotein-antibody disease (MOGAD), parainfectious optic neuritis and optic neuropathies secondary to systemic autoimmune diseases[1-8]. Diagnostic algorithms have evolved beyond simple clinical judgement: The multidimensional classification proposed by Petzold et al[9] integrates clinical presentation with orbital and brain magnetic resonance imaging (MRI), optical-coherence-tomography (OCT) metrics, cerebrospinal-fluid cytology and disease-specific auto-antibodies to label each episode as definite, possible or non-ON.

Sex differences constitute a persistent leitmotif. Women outnumber men in MS-related ON by roughly 3:1, and the imbalance reaches 9:1 in AQP4-NMOSD[4-7]. In MOGAD, by contrast, sex distribution is approximately equal[10]. Paradoxically women tend to recover vision better than men, whereas men – although less frequently affected – are more likely to develop neuro-degenerative sequelae or steroid-refractory relapses[11-13]. Deciphering these patterns requires an integrated appreciation of genetic, hormonal, metabolic, environmental and psychosocial factors. Every thematic block – epidemiology, immuno-genetics, hormonal modulation, metabolic co-morbidities, neuro-imaging correlates, auto-antibody profiles, reproductive counselling, psychosocial context, therapeutic response and prognosis – is therefore expanded below.

LITERATURE SEARCHING

Search strategy and selection criteria

A systematic literature search was performed across three major biological databases—PubMed, Scopus, and Web of Science—to create a thorough and representative synthesis of sex-based variations in ON. The search included all pertinent publications published until April 2025. Keywords and search phrases were chosen to encompass the complete clinical and immunological spectrum of ON and its demyelinating variations, with a specific focus on biological sex as a modifying variable. The strategy incorporated both controlled vocabulary and free-text terminology, amalgamating descriptors for ON and associated disorders—such as NMOSD and MOGAD—with terms denoting sex and gender distinctions, including “female”, “male”, “sex differences”, and “gender”. Boolean operators were employed to narrow the search and improve specificity. Alongside primary database queries, the reference lists of all obtained research were meticulously examined to uncover additional pertinent sources not identified via computerized indexing.

The inclusion criteria were explicitly delineated and uniformly implemented. Only peer-reviewed, full-text studies in English that included sex-disaggregated data on ON or its atypical subtypes were deemed suitable. These comprised original research articles, meta-analyses, and systematic reviews. Studies were rejected if they were abstracts, conference proceedings, non-peer-reviewed, written in languages other than English, or did not include specific stratification by sex. The screening and selection process had methodological transparency and reproducibility; however, a formal meta-analytic synthesis was not conducted due to variability in outcome measures and study designs.

Data extraction and synthesis

Subsequent to the preliminary screening, pertinent data were separately retrieved by two reviewers and validated by a third to guarantee consistency and precision. The extracted data encompassed demographic variables, including age at onset and sex ratios; clinical outcomes, such as visual acuity scores, relapse frequency, and disability indices like the Expanded Disability Status Scale; imaging parameters obtained from OCT and MRI; and immunological data, including the presence of aquaporin-4 or MOG antibodies. Hormonal impacts, including life stages such as menarche, pregnancy, and menopause, were documented when accessible, with therapeutic response profiles, particularly to corticosteroids and monoclonal antibodies. Where relevant, psychosocial factors and quality-of-life indicators—such as pain perception, sexual dysfunction, and mental health burden—were included to offer a comprehensive knowledge of sex variations in disease impact.

Due to the diversity in research design, outcomes, and methodological rigor among the collected literature, a quantitative meta-analysis proved impracticable. Outcome metrics varied significantly among trials, encompassing high-precision imaging biomarkers and patient-reported outcome measures, hence hindering effective statistical aggregation (Table 1). A qualitative story synthesis was conducted, organized thematically to illustrate the multifaceted influence of sex on ON.

Table 1 Ratio female:male in different pathologies.

Condition	Female:male ratio	Ref.
Typical MS-related ON	2-3:1	Malik et al[5] and Arnett et al[4]
Multiple sclerosis (overall)	2.73:1 (95 %CI: 2.37-3.09)	Arnett et al[4]
AQP4-NMOSD (overall)	8.89:1	Arnett et al[4]
HIV-positive NMOSD	9-10:1	Borisow et al[6]
HIV-negative NMOSD	≈ 2:1	Borisow et al[6]
MOGAD	≈ 1:1 (some series female > male)	Jurynczyk et al[10] and de Mol et al[14]

MS: Multiple sclerosis; ON: Optic neuritis; AQP4-NMOSD: Aquaporin 4 IgG positive neuromyelitis optica spectrum disorder; NMOSD: Neuromyelitis optica spectrum disorder; MOGAD: Myelin oligodendrocyte glycoprotein antibody disease; HIV: Human immunodeficiency virus.

In the selection of the papers included in our review paper, we used several conceptual domains of the Newcastle-Ottawa Scale, encompassing sample representativeness, ascertainment of exposure and outcomes, duration and completeness of follow-up, and methodological control for potential confounders, to inform our internal evaluation of study quality. In instances of contradictory findings, precedence has been given to prospective research characterized by higher sample sizes, established outcome criteria, and rigorous statistical adjustments for sex as an independent variable. Redundant findings documented in both basic source materials were consolidated to guarantee coherence and eliminate redundancy. In instances of disparity, priority was assigned to research featuring bigger sample sizes, more precise definitions, and enhanced statistical analysis. The synthesis elucidates the intricate interaction of genetic, hormonal, metabolic, and psychosocial variables that influence the development, progression, and treatment response of optic neuritis in a sex-specific context.

EPIDEMIOLOGY AND DEMOGRAPHY

Sex ratios and historical trends

Typical MS-ON – Female:Male 2-3:1[4,5]. Multiple sclerosis (overall) – Pooled Female:Male 2.73:1 (95%CI: 2.37-3.09)[4,5]. AQP4-NMOSD – Female:Male 8.89:1; human immunodeficiency virus (HIV) -positive strata up to 10:1, HIV-negative ≈ 2:1[4]. MOGAD – Typically 1:1; occasional mild female excess[10,14].

Over the past seven decades MS incidence has climbed disproportionately among women. Several lifestyle factors have been hypothesized, including smoking, delayed childbearing and urbanization[15-18]. However, the temporal curve of tobacco use does not mirror the surge in female MS, because smoking rates in women peaked decades later than the incidence shift. Likewise, reduced parity and an older age at first pregnancy may contribute to risk but cannot fully explain the magnitude of the female predominance[19,20].

Age of onset and life-phase modifiers

MS-ON – Women debut in early adulthood; men a few years later and transition more rapidly to progressive forms[8,21,22]. AQP4-NMOSD – Mean onset approximately 40 years; some series show later onset in men[4]. MOGAD – Pediatric onset twice as common as adult onset[10,23,24].

Early menarche (13–15 years of age) is associated with earlier MS onset (approximately 35 years of age)[25,26]. Since obesity accelerates menarche via aromatase-derived estrogen, adolescent body mass index (BMI) indirectly modulates risk[27-29]. Conversely, menopause – characterized by estrogen withdrawal – may aggravate neurodegeneration, although evidence remains sparse[15,30].

Pregnancy, puerperium and parity

High estrogen and progesterone levels (Figure 1) during the third trimester confer a temporary immunological sanctuary: MS relapse rates fall[29-31], OCT demonstrates reduced RNFL loss[5,12,13,32], and NMOSD may remain quiescent in individual cases[27,33,34]. The puerperium is an immunological “snap-back”: Abrupt hormone withdrawal drives a surge in MS and NMOSD relapses[8,35,36]. Exclusive breastfeeding shows conflicting data; some series report protective effects, others note no benefit[8,37,38]. Low parity and delayed first pregnancy, prevalent in modern societies, may partially account for the growing female bias in MS[39-41].

Figure 1 Hormonal changes at different stages of life and optic neuritis.

Ageing and elderly ON

Older ON patients display less optic-disc oedema and more extensive brain plaques, possibly reflecting immunosenescence and lower inflammatory vigor. Seropositivity for AQP4 is more common in the elderly, and age correlates inversely with relapse frequency, supporting the hypothesis of a hypo-immune late-onset phenotype[42-45].

GENETIC AND EPIGENETIC UNDERPINNINGS

X-chromosome gene dosage and escape from inactivation

Numerous factors contribute to NMOSD (Figure 2). The X chromosome is enriched in immune-regulatory genes[46-48]. In women, incomplete inactivation allows double-dose expression of TLR-7/8 and other pattern recognition receptors, enhancing viral sensing but increasing autoantibody production. FOXP3 – also X-linked – governs regulatory-T-cell development; sex-biased methylation alters its transcriptional accessibility, influencing susceptibility to experimental autoimmune encephalomyelitis (EAE) and, by extension, MS and NMOSD[8,49-51].

Figure 2 Neuromyelitis optica spectrum disorder summary diagram. NMOSD: Neuromyelitis optica spectrum disorder; AQP4-IgG: Aquaporin-4 immunoglobulin G antibodies.

Micro-RNAs, epigenetic memory and X-reactivation

Sex-specific micro-RNAs and Foxp3-locus methylation fine-tune T-cell thresholds. Cellular stress can trigger partial X-reactivation in female lymphocytes, releasing silenced alleles and fueling systemic autoimmunity – a mechanism invoked to explain the higher prevalence of Sjögren’s syndrome and SLE, conditions that share epidemiological patterns with NMOSD[52-55].

HLA and non-HLA loci

Robust HLA associations exist for AQP4-NMOSD, whereas MOGAD lacks consistent genetic anchors. Emerging non-HLA loci involve cytokine regulators and complement components, yet most findings await replication[8,56-59].

HORMONAL MODULATION ACROSS THE LIFESPAN

Estrogens

There are several hormonal factors to consider (Table 2). Estradiol (E2) and estriol (E3) suppress Th1 cytokines [tumour necrosis factor-α (TNF-α), interferon-γ] and up-regulate interleukin (IL)-10. ER-β activation in microglia dampens iNOS expression, while ER-β signaling in CD11c⁺ cells reduces nitric-oxide-mediated damage[8,60-62]. In oligodendrocytes ER-β promotes differentiation and remyelination. These mechanisms underpin the clinical observation that high-hormone states (pregnancy, mid-cycle peak) coincide with fewer relapses and milder RNFL thinning[8,13,60,61].

Table 2 Main hormones and their immunomodulating action.

Hormone (life-phase)	Key immunomodulatory actions	Principal experimental/clinical observations
Estradiol/estriol (mid-cycle, pregnancy)	↓ TNF-α, IFN-γ; ↑ IL-10; ER-β activation quiets microglia and CD11c+ cells; promotes oligodendrocyte maturation and remyelination	Third-trimester pregnancy sharply lowers MS/ON relapse rates; women retain more RNFL after ON in high-estrogen states
Progesterone (luteal phase, gestation)	Shifts immunity Th1 → Th2; expands T-regs; suppresses iNOS and Toll-like-receptor signaling; fosters myelin repair	Color-Doppler shows ↑ central-retinal-artery resistance; progesterone analogues ameliorate EAE lesions and enhance remyelination
Testosterone/DHT (male dominance, peri-puberty)	Down-regulates Th1/Th17; induces thymic AIRE; inhibits NF-κB & p38-MAPK in microglia; curtails IL-1β, IL-6, TNF-α; modulates Bax/Bcl-2, caspase-3	Androgen supplementation dampens EAE severity; low testosterone correlates with aggressive MS & greater ON severity in men; DHT shields SH-SY5Y neurons from inflammatory apoptosis
Prolactin (lactation, immune-cell secretion)	Dual role – may boost inflammation yet stimulates oligodendrocyte progenitors	Human data inconclusive; experimental models show both aggravation of EAE and promotion of remyelination

AIRE: Autoimmune regulator; Bax/Bcl-2: Bcl-2–associated X protein / B-cell lymphoma 2; CD11c⁺: Cluster of differentiation 11c–positive immune cells; DHT: Dihydrotestosterone; EAE: Experimental autoimmune encephalomyelitis; ER-β: Estrogen receptor beta; IFN-γ: Interferon gamma; IL: Interleukin; iNOS: Inducible nitric oxide synthase; MAPK: Mitogen-activated protein kinase; MS: Multiple sclerosis; NF-κB: Nuclear factor kappa B; ON: Optic neuritis; RNFL: Retinal nerve fiber layer; SH-SY5Y: Human neuroblastoma cell line SH-SY5Y; Th1/Th2/Th17: T helper cell subsets 1, 2, and 17; TNF-α: Tumor necrosis factor alpha; Tregs: Regulatory T cells.

Progesterone

Progesterone shifts immunity toward a Th2 phenotype, augments T-reg numbers, suppresses Toll-like-receptor signaling and promotes myelin repair. Color Doppler studies reveal that progesterone increases central-retinal-artery resistive index, likely by antagonizing estrogen-induced nitric-oxide synthesis[32,33,63-65].

Androgens and molecular neuroprotection

Multiple pathophysiological mechanisms have been suggested to elucidate the relatively poorer visual and neurological outcomes seen in male patients with ON[8,66]. Relative androgen deficit, resulting from either chronic neuroinflammation or intrinsic endocrine dysfunction, may hinder microglial suppression, central immune tolerance, and remyelination. Epidemiological studies indicate that men are less inclined to pursue prompt ophthalmologic or neurological assessments, resulting in delayed diagnoses and inadequate treatment commencement. Additionally, structural variations in axonal resilience, such as diminished baseline RNFL thickness and decreased production of neuroprotective trophic factors, may render men more susceptible to significant neuroaxonal loss after a solitary inflammatory incident. These factors may converge to expedite the accumulation of permanent disability in male ON patients, despite their lower overall illness incidence.

Testosterone and 5α-dihydrotestosterone (DHT) quell Th1/Th17 differentiation and induce thymic AIRE, broadening central tolerance[8]. In vitro DHT reduces IL-1β, IL-6 and TNF-α release, suppresses COX-2 and NOS, and down-regulates NF-κB and p38-MAPK signaling in microglia, thereby protecting SH-SY5Y neurons from inflammatory damage. DHT also modulates neuronal expression of IL-10, IL-13, Aβ, caspase-3, Bax/Bcl-2 and synaptophysin, collectively curtailing apoptosis and synaptic loss[65-72]. Despite these benefits, epidemiological data show lower serum testosterone in men with aggressive MS, suggesting either consumption by chronic inflammation or an intrinsic endocrine deficit[73].

Prolactin and hormone-replacement therapy

Prolactin’s role is ambivalent: Experimental data implicate it in disease exacerbation, yet oligodendrocyte-culture studies show enhanced remyelination[8]. Hormone-replacement therapy (HRT) in menopausal women with MS has been insufficiently studied; preliminary surveys hint at subtle immunomodulatory effects but firm recommendations await randomized trials[8,29].

METABOLIC AND ENVIRONMENTAL MODIFIERS

Obesity, adipokines and low-grade inflammation

There are several factors involved in the genesis of optic neuritis (Figure 3). Obesity elevates leptin and decreases adiponectin, fostering a chronic inflammatory milieu characterized by high IL-6 and C-reactive-protein (CRP)[74-78]. Mendelian-randomization studies demonstrate a bidirectional causal loop between BMI and CRP. In clinical cohorts higher BMI correlates with more severe ON attacks, greater steroid non-responsiveness and accelerated disability, especially in men[79,80].

Figure 3 Main factors involved in the genesis of optic neuritis.

Vitamin-D status

A Thai case-control study revealed significantly lower 25(OH)D in all immune-mediated ON subtypes compared with age- and sex-matched controls. Vitamin-D deficiency is more prevalent in women due to estrogen deficits that hamper vitamin-D metabolism and precipitate osteoporosis, thus intersecting with the hormonal axis to modulate demyelinating risk[81,82].

Smoking and environmental exposures

Historical smoking patterns cannot fully explain the female up-swing in MS incidence: Male smoking peaked mid-20^th century, whereas female smoking rose later, unaligned with the earlier shift in MS sex ratio. Nonetheless, tobacco remains an adjuvant risk factor, synergizing with HLA-sensitive immune activation[16,17,83].

AUTO-ANTIBODIES: BEYOND AQP4 AND MOG

Poly-Autoimmunity in NMOSD

AQP4-positive NMOSD patients often harbor additional auto-antibodies (ANA, anti-thyroid). Female preponderance mirrors patterns in SLE and Sjögren’s, suggesting systemic immune dysregulation rather than organ-specific autoimmunity[46-48,55,84].

Hormonal fine-tuning of antibody production

Bidirectional Mendelian-randomization links higher serum progesterone to increased NMOSD susceptibility, independent of AQP4 status[33]. In contrast, elevated sex-hormone-binding globulin (SHBG) and reduced bioavailable testosterone correlate inversely with disease risk, underlining sex-hormone orchestration of B-cell activity[85,86].

Reproductive biology and AQP4

AQP4 expression in ovarian and testicular tissue implies a potential for antibody-mediated reproductive disturbances[8]. Female NMOSD patients display lower anti-Müllerian-hormone (AMH) levels, warning of diminished ovarian reserve. In mice, AQP4 knockout reduces fertility, supporting a causal link[87-90].

NEUROIMAGING AND OPTICAL-COHERENCE TOMOGRAPHY

MRI metrics

Men with MS show more pronounced whole-brain and brain-stem atrophy than women. In NMOSD sex-stratified MRI data are scarce; one retrospective review noted higher extra-optic lesion burden in elderly patients, hinting at age-driven hypo-immunity[91-95].

Ocular hemodynamic and OCT phenotypes

Progesterone elevates central-retinal-artery resistance (Doppler study) by engaging smooth-muscle receptors and suppressing endothelial nitric-oxide. Studies have documented sex-dependent differences in optic-nerve-head pulse waveforms, with women showing more stable perfusion[45]. OCT studies confirm that women lose less RNFL and macular-ganglion-cell thickness after ON. Disc oedema is common in younger women – likely reflecting robust inflammation – and rare in older men, aligning with immunosenescence[13,45,96-98].

PAIN PERCEPTION AND PSYCHOSOCIAL CONTEXT

Sex-specific nociceptive pathways

Rodent models reveal that neuropathic pain in males hinges on microglial activation and disinhibition of spinal neurons, whereas in females it depends on T-cell-derived mediators and macrophage-sensitization of nociceptors. In ON cohorts women report higher pain intensity, supporting a biological divergence[99-103].

Mental health, sexual dysfunction, and social-support disparities

Women with ON and demyelinating disease experience higher rates of depression, fatigue and pain, partly linked to fluctuating sex hormones. Men face elevated suicide risk after diagnosis, may be less inclined to participate in rehabilitation, and often receive less social support[64,104,105]. In NMOSD, both sexes can develop sexual dysfunction, but reduced bioavailable testosterone and elevated SHBG have been specifically correlated with decreased libido, mood disturbance, and diminished quality of life[8,12,66,40,106].

REPRODUCTIVE COUNSELLING AND LIFE-COURSE MANAGEMENT

Contraception and hormonal modulation

A multicentre survey found that women who had ever used hormonal contraception developed NMOSD at a younger age than non-users, suggesting hormonally modulated disease initiation. Counselling should discuss potential interactions without discouraging effective contraception where clinically necessary[107,108].

Fertility preservation

Lower AMH in NMOSD signals reduced ovarian reserve. Fertility counselling – encompassing cryopreservation, timing of immunosuppression, and contraceptive planning – is essential. Men with ON and concurrent hypogonadism may require endocrinology referral for testosterone replacement, which could confer neuroprotection and improve mood and sexual function[74,90].

Pregnancy planning and postpartum care

Optimal strategies include achieving disease stability for ≥ 6 months, correcting vitamin-D insufficiency, and avoiding teratogenic agents (teriflunomide, cladribine). High-risk NMOSD patients may benefit from low-dose prednisolone or continuation of compatible monoclonal antibodies through pregnancy. Postpartum relapse surveillance is critical, with early re-initiation of maintenance immunotherapy[36,109-112].

Hormone-replacement therapy in menopause

Data are limited, but HRT could theoretically restore estrogen-mediated neuroprotection. Until randomized trials clarify risks and benefits, HRT decisions should be individualized, balancing vasomotor symptom relief against potential immune activation[29,113].

THERAPEUTIC RESPONSE AND SEX DIFFERENCES

First-line disease-modifying therapies in MS

Interferons/Glatiramer Acetate – Equal efficacy, but men more prone to transaminase elevation[114]. S1P Receptor Modulators – Severe lymphopenia predominantly in women; hepatotoxicity in men[115,116]. Teriflunomide/Cladribine – Highly teratogenic; strict contraception required for both sexes[117,118].

High-efficacy therapies

Natalizumab – Greater reduction of disability accumulation in women[119]. Anti-CD20 Monoclonal Antibodies – Particularly efficacious in primary-progressive MS (male-biased); necessitate breast-cancer surveillance in women[120,121].

NMOSD-specific agents and steroid responsiveness

Eculizumab and satralizumab markedly lower relapse risk. Male NMOSD patients exhibit higher rates of high-dose steroid non-response, reinforcing the need for timely biologic escalation[121-124].

MOGAD management

Evidence derives from off-label use of MS/NMOSD agents (mycophenolate, azathioprine, rituximab). To date no sex-specific differences in efficacy or safety are apparent, but sample sizes remain small[10].

Side-effect profiles and monitoring

In light of the identified sexual dimorphisms in pathogenesis and therapeutic efficacy, we advocate for customized monitoring strategies. Male patients with ON should have first endocrinological assessment for hypogonadism, especially in the presence of symptoms like fatigue, sad mood, or diminished libido, due to the possible advantages of testosterone replacement on neuroimmune modulation and overall quality of life[67]. Counseling for female patients should focus on cumulative estrogen exposure, mammographic monitoring during extended anti-CD20 medication, and vigilant assessment of bone mineral density in cases of corticosteroid administration or amenorrhea. These approaches, integrated within a sex-aware care strategy, may reduce long-term consequences and enhance disease progression across the ON spectrum.

Lymphopenia with S1P modulators warrants closer surveillance in women, while transaminase monitoring is prioritized in men on interferons. Breast-cancer screening is mandatory for women on chronic anti-CD20 therapy. Conversely, bone-density monitoring should not be neglected in men exposed to prolonged corticosteroids, given their under-recognized osteoporosis risk[125-127].

LIMITATIONS OF CURRENT EVIDENCE

Sex Imbalance – Women dominate NMOSD and MS cohorts, restricting male-specific inferences. Outcome Heterogeneity – Visual and neurological endpoints vary, hampering meta-analysis. Centre Bias – Tertiary-care recruitment over-represents severe phenotypes. Era Effects – Therapeutic innovations rolled out unevenly across sexes and regions. Age-by-Sex Interactions – Pediatric and geriatric data scarce.

CONCLUSION

Gender influences every dimension of optic neuritis – from genetic predisposition and hormonal modulation to metabolic co-risk factors, pain perception, reproductive decisions and therapeutic side-effect profiles. Women are more susceptible yet often recover vision better; men experience fewer attacks but accumulate disability faster and may respond less robustly to corticosteroids. Hormonal transitions (menarche, pregnancy, puerperium, menopause) and environmental factors (vitamin-D insufficiency, obesity, smoking) further modulate risk and outcome. Auto-antibody patterns, ocular hemodynamic, MRI signatures and psychosocial variables all display sex bias. Addressing these nuances demands sex-powered clinical trials, inclusive registries and mechanistic studies that bridge immunology, endocrinology and neuro-ophthalmology. Only through such multidimensional research can clinicians achieve genuinely personalized, gender-responsive care for every individual with optic neuritis.