Search Results (910)

Objective: Bacterial vaginosis is a dysbiosis of the vaginal microbiome, typically characterized by a loss of Lactobacillus. Lactobacillus plays a crucial role in vaginal immunity and protection against sexually transmitted infections. Herpes simplex virus 2, the primary cause of genital herpes, impacts 13% of people worldwide. We undertook this systematic review and meta-analysis to examine the risk of herpes simplex virus 2 acquisition in women with bacterial vaginosis. Secondarily, we examined the impact of bacterial vaginosis on herpes simplex virus 2 shedding, reactivation, and symptoms. Data sources: We searched PubMed, EMBASE, Cochrane, Web of Science, Google Scholar, and ClinicalTrials.gov for articles published before 1 July 2023 for microbiome and herpes simplex virus type 2. Studies were limited to human subjects and the English language. An updated search was performed in January 2026. This study was registered on PROSPERO (CRD42023439139). Methods of study selection: Studies on non-pregnant, reproductive-aged cisgender women that diagnosed bacterial vaginosis by Amsel Criteria, Nugent Scoring or used molecular techniques, and those that detected herpes simplex virus 2 by serological assay or PCR testing were included. Our search identified 863 results with four publications eligible for inclusion. For our secondary outcomes, 40 results were identified regarding herpes simplex virus 2 shedding, with two publications eligible for inclusion, which did not meet our threshold for meta-analysis. There were 21 results identified for herpes simplex virus 2 reaction and 115 results for herpes simplex virus 2 symptoms, with no articles being eligible for inclusion. Tabulation, integration, and results: Quality assessment was performed following data extraction using the quality assessment scales from the Joanna Briggs Institute. Results were extracted, and the pooled hazard ratio was calculated with 95% confidence interval. A total of 1906 women were included in this analysis, and 255 acquired herpes simplex virus 2. The pooled unadjusted hazard ratios produced an effect size of 1.91, (95% confidence interval 1.4649–2.4980), and a p-value of <0.0001, while the pooled adjusted hazard ratios produces an effect size of 1.85, (95% confidence interval of 1.3556–2.5162), and a p-value of 0.0001 indicating that bacterial vaginosis is associated with a increased risk of herpes simplex virus 2 acquisition. Conclusions: This systematic review with meta-analysis indicates that bacterial vaginosis is associated with a significantly increased risk (91% unadjusted, 85% adjusted) of herpes simplex virus 2 acquisition, indicating that bacterial vaginosis treatment may reduce herpes simplex virus 2 acquisition. A notable limitation of these findings is the relatively small number of studies eligible for inclusion in this systematic review and meta-analysis. Full article

A survey was carried out during 2023–2024, and 363 asymptomatic and symptomatic olive samples with deformed leaves, mosaic, and yellow spots were collected from different regions in Saudi Arabia. These samples were tested by ELISA against eight important olive viruses. To investigate the presence of these viruses in olive trees, PCR and RT-PCR techniques were employed using the virus-specific primers. The obtained results from serological tests indicated that 44.4% of the collected samples were found to be positive with at least one of the tested viruses. The most prevalent virus was OEGV (14.3%), followed by ArMV (11.9%), SLRSV (11.3%), CLRV (9.4%), TuYV (5%), TNV-D (4.4%), OMMV (3.6%), whereas OLV-1, OLV-2, CMV, TMV, OLV-3, OLYaV, and OLRSV were not positive in the tested samples. Single, as well as mixed infections, were observed in a number of samples with 9.4% and 34.7%, respectively. The nucleotide sequence analysis of PCR amplified fragments revealed 99.7–100% identity to OEGV, 95–99% to TuYV, 85–98% to OMMV, 83–93% to ArMV, 92–97% to CLRV, 84–98% to TNV-D, and 85–97% to SLRSV isolates, according to the pairwise nucleotide identity percentage calculated by SDT software. This is the first comprehensive survey to investigate the genetic diversity and phylogenetic relationship of seven olive viruses detected in olive trees in Saudi Arabia, which can provide the missing local epidemiological understanding. Full article

The circulation of viruses of medical and veterinary importance is monitored to evaluate risks to both human and animal health. Among the species most commonly used in surveillance programs, the wild boar (Sus scrofa) plays a key role due to its high population density and its contacts with rural swine herds in the areas under investigation. In the present study, molecular (real-time PCR) and serological analyses were conducted on wild boar samples collected in the regions of Apulia, Basilicata, Campania, and Calabria. Specifically, molecular detection was applied to IAVs, FLVs, and Porcine PCV-2, while serological testing was used to assess exposure to IAVs, FLVs, and ADV. Serological results showed an 8.31% positivity for IAVs, whereas viral presence detected by PCR was 1.17%. No active infections were detected for WNV, with only a single seropositive sample (0.30%), while ADV showed a seroprevalence of 2.61%. PCV-2 was detected exclusively by molecular analysis in 66 out of 223 tested animals (29.6%). The overall objective of the study is to deepen the understanding of virus circulation in the wildlife of Southern Italy, using the wild boar as an additional sentinel species for epidemiological surveillance activities. The distinctive feature of the project lies in its multi-pathogen approach applied to a reference population distributed across a particularly wide geographical area, allowing for the simultaneous assessment of the circulation of different viruses over a large territory. Full article

In recent years, outbreaks of inclusion body hepatitis (IBH) have been reported with increasing frequency worldwide. In Austria, the presence of fowl aviadenoviruses (FAdVs) and/or IBH has been documented sporadically. The present report describes a surge of natural IBH cases in fifteen Ross 308 broiler flocks. The clinical picture was characterized by the sudden onset of increased mortality in birds 3 to 15 days of age, persisting for approximately one week, resulting in cumulative flock mortality ranging from 2% to 27%. The main pathological findings were hepatitis with diffuse necrotic foci and petechial hemorrhages with intranuclear inclusion bodies by histology. FAdV was detected in liver samples from all affected flocks. Based upon partial hexon sequence analysis, FAdV serotype-11, species-D (FAdV-11, FAdV-D) was identified, showing complete sequence identity among broiler-derived strains and high identity with previous isolates from Austria and globally IBH-associated isolates. Furthermore, FAdV-11 DNA was detected in dead-in-shell embryos collected during the ongoing outbreak, originating from one suspect broiler breeder flock, confirming vertical transmission. Serological investigations of the suspect breeders confirmed the FAdV-11 infections within the studied timeframe. In conclusion, investigations confirmed vertical transmission of FAdV-11 and subsequent manifestation of IBH in broilers under field conditions, highlighting the epidemiological importance of broiler breeders in IBH outbreaks. Full article

Background: Anti-double-stranded DNA (anti-dsDNA) antibodies are a key serological marker for systemic lupus erythematosus (SLE) and are commonly assessed in conjunction with anti-nuclear antibody (ANA) testing by indirect immunofluorescence (IIF) on HEp-2 cells. However, their detection is influenced both by the heterogeneity of the autoimmune response and by the characteristics of the analytical method employed, thereby complicating diagnostic interpretation. Methods: In this retrospective single-center study, 3090 consecutive patients undergoing anti-dsDNA analysis were screened, and 138 positive individuals, with anti-dsDNA levels ≥ 15 IU/mL by fluoroenzyme immunoassay (FEIA), were included in the study. A control group of 29 anti-dsDNA-negative patients was also analyzed. Anti-dsDNA-positive patients were stratified by antibody level (low, mild, high), and the results were correlated with HEp-2 IIF titers and fluorescence patterns. Furthermore, in a subset of 30 positive patients, anti-dsDNA antibodies were evaluated using immunoblotting (IB) and the Crithidia luciliae indirect immunofluorescence test (CLIFT). Statistical analyses assessed associations and concordance among methods. Results: Higher anti-dsDNA levels were generally associated with higher HEp-2 IIF titers. However, a considerable percentage (35%) of patients with positive anti-dsDNA were negative by HEp-2 IIF. Notably, high anti-dsDNA levels were detected in 19% of HEp-2 IIF-negative patients (titer < 1:80), 18% of mildly HEp-2 IIF-positive patients (titer 1:80–1:160), and 25% of HEp-2 IIF-positive patients (titer > 1:320). In the subset of 30 positive patients, FEIA analysis showed high concordance with the immunoblot in both IIF-positive (81%) and -negative (100%) patients, while CLIFT demonstrated lower agreement with both FEIA and IB independently of the IIF. Conclusions: Our findings indicate that anti-dsDNA antibody detection may occur independently of HEp-2 IIF positivity and that FEIA, especially when confirmed by immunoblot, represents a reliable approach for anti-dsDNA assessment. The observed results in this study likely reflect differences in epitope recognition and assay sensitivity among methods, suggesting the use of a multi-step diagnostic strategy in the serological evaluation of SLE. Full article

Chagas disease remains a major public health concern in Latin America, with Bolivia reporting one of the highest burdens of infection. While congenital transmission has become the predominant route of new infections in several countries, vector-borne transmission persists in rural and peri-urban regions. Postrervalle, in the department of Santa Cruz, is officially classified as a low-infestation area; however, updated community-level data remain limited. We conducted a cross-sectional study in July 2023 involving 58 mothers and 104 of their children in Postrervalle. Participants underwent serological screening with three diagnostic assays, and epidemiological data were collected via structured maternal questionnaires. Logistic regression models were used to assess associations between child Trypanosoma cruzi seropositivity and maternal or household exposures during pregnancy. Seroprevalence was 15.5% among mothers and 3.8% among children. Notably, all seropositive children were born to mothers who tested seronegative, suggesting non-congenital transmission. In multivariable analysis, living in houses with mud walls during pregnancy was strongly associated with child seropositivity (adjusted OR = 38.566), while older child age also increased the odds of infection. Other maternal exposure variables showed elevated but imprecise associations. Despite its classification as a low-infestation area, Postrervalle shows serological patterns consistent with postnatal acquisition linked to domestic structural conditions that facilitate triatomine colonization. These findings overall highlight the need for integrated serological and entomological surveillance to better characterize and prevent Chagas transmission in rural communities. Full article

Background: Measles remains a global public health threat despite the availability of an effective vaccine and substantial progress toward elimination in many countries. Outbreaks in highly vaccinated settings suggest that waning vaccine-induced immunity, particularly among adults, may create silent susceptibility gaps capable of sustaining viral transmission. Aim: To evaluate age- and cohort-specific patterns of measles-specific antibody levels in Mexican adults and to examine evidence suggesting lower vaccine-induced antibody levels in younger vaccinated cohorts. Methods: A cross-sectional seroepidemiological study was conducted among 302 voluntary blood donors aged 18–70 years. Demographic, clinical, and vaccination data were collected through structured interviews. Serum anti-measles-virus (MV) IgG levels were quantified using a commercial ELISA. Antibody concentrations were analyzed according to age, sex, vaccination history, self-reported measles infection, and historical vaccination strategies. Multivariate linear models were applied to identify factors associated with IgG levels. Results: Anti-MV IgG seropositivity (>200 mIU/mL) was 67.2%, with a geometric mean concentration (GMC) of 270.43 mIU/mL. A positive correlation was observed between age and antibody levels (r_s = 0.161, p = 0.005). Individuals born before the introduction of the measles vaccine (pre-1970) had significantly higher GMCs (1096.63 mIU/mL) than younger cohorts. A history of natural infection tended to be associated with higher antibody levels (GMC: 428.38 vs. 257.24 mIU/mL; p = 0.051). In multivariate analysis, historical vaccination strategy emerged as the primary factor associated with antibody levels, whereas age alone was not significant. Conclusions: Cohort-specific differences in measles IgG levels suggest generational patterns of immunity and are consistent with diminished vaccine-induced antibody levels in younger adults in the absence of natural boosting. These findings highlight the importance of ongoing serological surveillance in post-elimination settings and underscore the need for targeted public health interventions. Full article

Background/Objectives: Helicobacter pylori infection induces a systemic humoral immune response that reflects both bacterial virulence and host immune regulation. While anti-H. pylori IgG is widely used as a marker of infection, its ability to predict the topographic distribution and biological activity of gastritis is limited. The objective of this study was to evaluate whether the relative predominance of systemic IgG versus IgA antibodies, IgG subclasses, and antigen-specific IgG reactivity could better reflect the features and topography of gastric inflammation. Methods: A total of 123 patients with dyspeptic symptoms, confirmed H. pylori infection, and histologically verified gastritis were included. Anti-H. pylori IgG and IgA levels were measured by ELISA, IgG1 and IgG2 subclasses by subclass-specific assays, and antigen-specific IgG reactivity (CagA, VacA, UreB66, 30 kDa, and UreA 26 kDa) by Western blot. Histopathological parameters of the antral and corpus mucosa were graded according to the updated Sydney system. Receiver operating characteristic (ROC) analysis and univariate and multivariate logistic regression were applied to identify predictors of gastritis topography. Results: Anti-H. pylori IgG levels correlated with the grade and activity of inflammation in the antrum, whereas IgA correlated with inflammatory parameters in the corpus. IgG1 and IgG2 showed limited associations with antral inflammatory activity. IgA showed the best diagnostic performance for pangastritis/corpus-predominant gastritis, while IgG2 best identified antrum-predominant gastritis. The combined serological profile defined as IgG > IgA together with 30 kDa antigen positivity was independently associated with antrum-predominant gastritis in multivariate analysis (OR 2.516; 95% CI 1.004–6.308). Conclusions: The systemic balance between IgG and IgA responses reflects the topographic distribution of H. pylori-associated gastritis. IgG predominance combined with 30 kDa antigen seropositivity represents an independent serological predictor of antrum-predominant gastritis and may improve non-invasive stratification of gastric inflammation. Full article

Lymphatic filariasis (LF) is a mosquito-borne neglected tropical disease targeted by the World Health Organization (WHO) for global elimination as a public health problem. Sixteen Pacific Island countries and territories were historically endemic, and eight have now met the WHO criteria for elimination as a public health problem. Elimination as a public health problem does not imply zero transmission. Rather, it denotes that LF prevalence has been reduced below a defined threshold at which community transmission can be sustained. Following validation of elimination, the WHO recommends post-validation surveillance (PVS) to detect potential re-emergence of LF as a public health problem. However, implementing PVS is challenging in Small Island Developing States with dispersed populations, limited workforce capacity, resource constraints, and competing health priorities. The ‘Voices and Visions: Building Partnerships for Integrated Serosurveillance of LF and Other Infectious Diseases in the Pacific Islands’ meeting was held in Brisbane, Australia, from 8–10 July 2025. Fifty-one delegates, including Pacific LF programme managers, WHO representatives, global health partners, and academic researchers, reviewed regional PVS progress, discussed the newly released WHO guidelines for the implementation, monitoring, and evaluation of PVS, planned for PVS implementation, and explored novel multiplex bead assay (MBA) serological analysis methods to strengthen regional coordination for its development as a public health tool. Five broad themes emerged. First, the new WHO Monitoring and Epidemiological Assessment of Mass Drug Administration in the Global Programme to Eliminate Lymphatic Filariasis: A Manual for National Elimination Programmes, 2nd edn needs to be operationalised to meet decision-making needs across diverse Pacific settings. Second, integrating LF-PVS with existing surveys and health service activities could improve efficiency and long-term sustainability. Third, regional coordination and alignment of funding cycles will require high-level collaboration. Fourth, community engagement is essential to strengthen demand for PVS. Finally, while at an early stage and with further evidence needed, MBA laboratory methods hold promise for cost-effective, feasible integrated multi-pathogen serosurveillance. Full article

Hepatitis E virus (HEV) is a global public health concern, causing over 20 million infections annually. It is primarily transmitted via the fecal–oral route, with wild boars and domestic swine as major reservoirs involved in zoonotic transmission. Bahía de Samborombón is an important natural reserve in Argentina characterized by a high population of wild boars, located in a livestock-intensive region near major urban centers. As part of a wild boar control program, 11 sampling campaigns were carried out between 2022 and 2023. Fecal, blood, and liver samples were systematically collected from 80 captured animals for the detection and characterization of HEV through antibody and RNA testing. Serological analysis revealed a positivity rate of 42.4%, whereas RT-qPCR detected HEV RNA in 9.1% of fecal samples and 12.5% of liver samples. From the positive samples, seven viral sequences were recovered using RT-nested PCR, including six from ORF1 and one from ORF2. Phylogenetic analysis clustered these sequences within zoonotic HEV genotype 3, showing a close relationship with human sequences from Buenos Aires and neighboring provinces. This study confirms the presence of HEV in wild boars from Argentina, highlighting the circulation of genotype 3, clade abchijklmno and the associated zoonotic risk. Full article

Background: Climate change represents a major global health challenge, with rising temperatures and altered precipitation patterns influencing the spread of infectious diseases. This study investigated the association between climatic factors (average temperature and precipitation) and the monthly proportion of laboratory-confirmed Legionella pneumophila serogroup 1 and West Nile Virus infections among clinically suspected patients in a large teaching hospital in Northern Italy. Methods: We retrospectively analyzed data from 2021 to 2024. The primary outcome was the monthly proportion of positive tests (standardized per 1000 clinically suspected patients) for Legionella pneumophila serogroup 1 (urinary antigen) and West Nile Virus (serology). Associations with climatic variables were assessed using linear and multivariate regression models, as well as Generalized Additive Models (GAMs). Seasonal effects were evaluated through ANOVA. Results: For Legionella pneumophila, precipitation was not significantly associated with the proportion of positive tests (p = 0.1438; R² = 0.049). In contrast, average temperature was a significant predictor: each 1 °C increase was associated with +0.52 positive cases per 1000 tested patients (p = 0.000283; R² = 0.267). Multivariate models confirmed temperature as the dominant factor. For West Nile Virus, precipitation showed no meaningful effect (p = 0.914). However, average temperature demonstrated a significant positive association with the proportion of positive cases (p = 0.00293; coefficient = 9.33), with seasonal analysis highlighting a marked summer peak (mean = 399.68 positive cases per 1000 tested; p = 0.00653). Conclusions: Our findings underline the predominant role of temperature over precipitation in driving the burden of both Legionella pneumophila and West Nile Virus infections among hospitalized patients. These results strengthen the evidence that the life cycles of these pathogens are tightly climate-dependent. Developing effective adaptation strategies is essential to mitigate climate-related health risks. Full article

Background: Human parvovirus B19 causes a broad spectrum of clinical manifestations, ranging from the classic “fifth disease” to severe presentations. Clinical presentation varies considerably across age groups. In 2023–2024, a notable increase in parvovirus B19 cases was reported across Europe. Methods: We retrospectively analyzed pediatric patients with serum serology and/or plasma PCR-confirmed parvovirus B19 infection treated at the tertiary infectious diseases center (University Hospital for Infectious Diseases, Zagreb) in 2023 (January–August). Demographic, laboratory, viral load, and clinical characteristics were assessed, with emphasis on cutaneous manifestations. Results: A total of 102 patients were included (median age 10 years; 54.9% male), of whom 7.8% required hospitalization. Rash was present in 94 (92.2%) of the patients of whom 75 had erythema infectiosum and petechiae, while the rest had a combination of both. Patients with petechial rash were significantly older (p = 0.013) and exhibited lower platelet counts (p < 0.001) compared with those with erythema. A higher proportion of anti-B19V IgM (p = 0.027) and IgG (p < 0.001) antibodies was detected in patients with erythema. Petechial rash was associated with higher viral loads (p < 0.001). In univariate analysis, the presence of anti-B19V IgG antibodies was correlated with the absence of petechial rash (OR = 0.09; p < 0.001), whereas higher viral load was associated with its presence (OR = 1.7; p < 0.001). In multivariate analysis, viral load emerged as the only predictor of petechial rash (aOR = 1.4, p = 0.042). Conclusions: Parvovirus B19 remains a self-limiting illness in healthy children, despite frequent atypical presentations. Higher viremia is associated with atypical rash morphology and suggests age-related differences in immune clearance. Full article

Background and Clinical Significance: Pediatric autoimmune gastritis (AIG) is a rare and frequently underdiagnosed disorder characterized by chronic immune-mediated inflammation and atrophy of the gastric mucosa. In children, AIG typically presents with iron-deficiency anemia (IDA) refractory to oral iron supplementation, in contrast to the pernicious anemia more commonly observed in adults. Diagnosis relies on a combination of serological markers, such as anti-parietal cell antibodies, and histopathological confirmation, with gastric biopsies demonstrating oxyntic mucosal atrophy and lymphocytic infiltration. Early recognition is essential, particularly in patients with personal or familial autoimmune backgrounds, to prevent long-term complications including nutritional deficiencies and increased gastric neoplasia risk. Case Presentation: An 11-year-old boy was referred for evaluation of severe microcytic anemia. He was clinically asymptomatic, with normal growth and physical examination except for mucocutaneous pallor. Celiac disease, thyroid dysfunction, hemoglobinopathies, and infectious or inflammatory gastrointestinal causes were excluded. Despite six months of high-dose oral iron therapy, anemia persisted. Upper gastrointestinal endoscopy showed macroscopically normal mucosa; however, histopathological analysis of gastric body biopsies revealed chronic atrophic gastritis. Serological testing confirmed autoimmune etiology, with positive anti-parietal cell antibodies and hypergastrinemia. Since diagnosis, the patient has required two courses of intravenous iron supplementation, and remains under close follow-up for associated autoimmune and hematologic conditions. Conclusions: Refractory IDA may represent the sole clinical manifestation of AIG in pediatric patients, even in the absence of gastrointestinal symptoms. Histological assessment is crucial, as endoscopic findings may be normal. Early diagnostic suspicion allows timely management focused on correction of nutritional deficiencies and long-term surveillance to mitigate neoplastic risk. AIG should therefore be considered in children with anemia unresponsive to conventional iron therapy. Full article

Background: Multiple myeloma (MM) is a hematologic malignancy characterized by clonal plasma cell expansion and diverse genomic rearrangements, including immunoglobulin heavy chain (IGH) translocations. Although RNA sequencing enables the comprehensive detection of IGH-associated fusions, routine molecular monitoring remains limited, particularly in non-secretory MM (NSMM), which lacks measurable serologic markers. Methods: Here, we contracted an integrated system combining RNA sequencing (RNA-seq) and reverse transcription quantitative polymerase chain reaction (RT-qPCR) to identify and validate fusion gene-based molecular markers for minimal residual disease (MRD) monitoring. Results: The global fusion landscape was delineated by the sequencing analysis of bone marrow samples from 22 newly diagnosed patients with MM. A total of 362 fusion events were identified, of which 190 non-immunoglobulin fusions were selected for detailed characterization. Recurrent breakpoints were concentrated on chromosomes 1 and 19, and five recurrent fusions, DDX5::EEF1A1, OAZ1::KLF2, OAZ1::KLF16, PFKFB3::LINC02649, and PLXNB2::SCO2, were detected across nine patients. Functional enrichment analyses indicated the significant involvement of these genes in RNA splicing regulation, transcriptional misregulation in cancer-related pathways, and focal adhesion processes. Twenty-three fusion transcripts were validated using RT-PCR and Sanger sequencing, demonstrating high specificity for MM. Longitudinal monitoring revealed that the quantitative assessment of fusion transcript levels enabled earlier relapse detection than flow cytometry, including in NSMM, where conventional MRD tools are ineffective. Conclusions: These findings suggest that individualized fusion transcripts serve as robust molecular markers for MRD surveillance. The proposed RNA-seq–RT-qPCR pipeline offers a clinically practical strategy to enhance precision diagnosis and personalized treatment in MM. Full article

Optic neuritis (ON) has been recognized since antiquity, but its modern clinical identity emerged only in the late 19th century and was definitively shaped by the Optic Neuritis Treatment Trial (ONTT). The ONTT established the natural history, visual prognosis, association with multiple sclerosis (MS), and therapeutic response to corticosteroids, building the foundation for contemporary ON management. Subsequent discoveries—most notably aquaporin-4 IgG-associated ON (AQP4-ON), myelin oligodendrocyte glycoprotein antibody-associated ON (MOG-ON), and double-negative ON—have fundamentally transformed this paradigm, shifting ON from a seemingly uniform demyelinating syndrome to a group of biologically distinct disorders. These subtypes differ in immunopathology, clinical course, MRI features, retinal injury patterns, CSF profiles, and long-term outcomes, making early and accurate differentiation essential. MRI provides key distinctions in lesion length, orbital tissue inflammation, bilateral involvement, and chiasmal or optic tract extension. Optical coherence tomography (OCT) offers complementary structural biomarkers, including severe early ganglion cell loss in AQP4-ON, relative preservation in MOG-ON, and variable patterns in double-negative ON. CSF analysis further refines diagnosis, with oligoclonal bands strongly supporting MS-ON. Together, these modalities enable precise early stratification and timely initiation of targeted immunotherapy, which is critical for preventing irreversible visual disability. Despite major advances, significant unmet needs persist. Access to high-resolution MRI, OCT, cell-based antibody assays, and evidence-based treatments remains limited in many regions, contributing to global disparities in outcomes. The understanding of the pathogenesis of double-negative optic neuritis, the identification of reliable biomarkers of relapse and visual recovery, and the determination of standardized cut-off values for multimodal diagnostic tools—including MRI, OCT, CSF analysis, and serological assays—remain unresolved challenges. Future research must expand biomarker discovery, refine imaging criteria, and ensure equitable global access to cutting-edge diagnostic platforms and therapeutic innovations. Four decades after the ONTT, ON remains a dynamic field of investigation, with ongoing advances holding the potential to transform care for patients worldwide. Together, these advances expose a fundamental tension between historically MS-centered diagnostic frameworks and the emerging biological heterogeneity of ON, a tension that underpins the structure and critical perspective of the present review. Full article