{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T05:05:01Z","timestamp":1780031101563,"version":"3.53.1"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T00:00:00Z","timestamp":1780012800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Ophthalmol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Tuberculosis (TB) and its treatment have been associated with significant neuro-ophthalmic morbidity; however, the magnitude and determinants of these complications remain incompletely characterized. This systematic review and meta-analysis aimed to evaluate the incidence and risk factors of ethambutol optic neuropathy (EON), neuro-ophthalmic manifestations of tuberculous meningitis (TBM), and prognostic biomarkers for visual outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Following PRISMA 2020 guidelines, we searched PubMed, Scopus, Embase, Web of Science, Cochrane Library, and Google Scholar up to the 30th of September 2025. Studies reporting EON incidence, TBM neuro-ophthalmic complications, or subclinical neurotoxicity biomarkers were included. Random-effects meta-analysis with generalized linear mixed models was performed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Twenty-two studies (N\u00a0=\u00a0260,430) were included. Pooled EON incidence was 1.54% (95% CI: 0.81-2.49%, I\u00b2=98.2%). Renal impairment (OR 3.73, 95% CI: 1.78-7.83) and hypertension (OR 2.37, 95% CI: 1.46-3.84) were significant risk factors. TBM neuro-ophthalmic manifestations included cranial nerve III palsy (17.4%), papilledema (12.5%), and optic atrophy (16.7%), with pediatric patients demonstrated significantly higher hydrocephalus rates (72.5% vs 13.0%, RR 5.56). Visual evoked potential (VEP) demonstrated better detection of subclinical changes over optical coherence tomography (OCT) (Hedges\u2019 g difference: 0.686, P-value = 0.001). Visual recovery occurred in 52.4% of clinical EON cases. Factors associated with improved recovery included younger age (MD= -3.8 years, P-value= 0.095) and earlier ethambutol discontinuation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>TB-related neuro-ophthalmic complications represent significant morbidity with identifiable risk factors. Visual evoked potentials offer superior subclinical detection and early intervention improves visual outcomes. Screening protocols targeting high-risk populations are recommended.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic review registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/www.crd.york.ac.uk\/PROSPERO\/<\/jats:ext-link>\n                      , identifier CRD420251141453.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fopht.2026.1818640","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T04:48:38Z","timestamp":1780030118000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Neuro-ophthalmic complications of tuberculosis and its treatment: a systematic review and meta-analysis"],"prefix":"10.3389","volume":"6","author":[{"given":"Ahmed A.","family":"Alessa","sequence":"first","affiliation":[{"name":"Faculty of Medicine, King Abdulaziz University","place":["Jeddah, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed Zuhier","family":"Awan","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, King Abdulaziz University","place":["Jeddah, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdulkarim B.","family":"Almutairi","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, King Abdulaziz University","place":["Jeddah, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim Ghassan","family":"Ajabnoor","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, King Abdulaziz University","place":["Jeddah, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed Marouf M.","family":"Jan","sequence":"additional","affiliation":[{"name":"School of Medicine, Trinity College Dublin","place":["Dublin, Ireland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed Y.","family":"Azzam","sequence":"additional","affiliation":[{"name":"Department of Clinical Research and Clinical Artificial Intelligence, ASIDE Healthcare","place":["Lewes, DE, United States"]},{"name":"Division of Global Health and Public Health, School of Nursing, Midwifery and Public Health, University of Suffolk","place":["Suffolk, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nooran","family":"Badeeb","sequence":"additional","affiliation":[{"name":"Ophthalmology Surgery, Division of Ophthalmology, College of Medicine, University of Jeddah","place":["Jeddah, Saudi Arabia"]},{"name":"Department of Ophthalmology, King Fahad Armed Forces Hospital","place":["Jeddah, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1038\/s41433-021-01619-6","article-title":"Neuro-ophthalmic manifestations of tuberculosis","volume":"36","author":"Dhiman","year":"2022","journal-title":"Eye"},{"key":"B2","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1080\/01658107.2023.2281435","article-title":"The neuro-ophthalmology of tuberculosis","volume":"48","author":"Shree","year":"2024","journal-title":"Neuro-Ophthalmology"},{"key":"B3","doi-asserted-by":"publisher","first-page":"3111","DOI":"10.1186\/s12889-024-20664-w","article-title":"Global, regional, and national burden of tuberculosis and attributable risk factors for 204 countries and territories, 1990\u20132021: a systematic analysis for the Global Burden of Diseases 2021 study","volume":"24","author":"Yang","year":"2024","journal-title":"BMC Public Health"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.7759\/cureus.79160","article-title":"Ethambutol-induced optic neuropathy: a retrospective study of incidences and risk factors","volume":"17","author":"Singh","year":"2025","journal-title":"Cureus"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1080\/01658107.2022.2100916","article-title":"The genetics of ethambutol- induced optic neuropathy: a narrative review","volume":"46","author":"Kaur","year":"2022","journal-title":"Neuro-Ophthalmology"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3390\/toxics12080549","article-title":"Risk factors of optic neuropathy in ethambutol users: interaction with isoniazid and other associated conditions of toxic optic neuropathy","volume":"12","author":"Kim","year":"2024","journal-title":"Toxics"},{"key":"B7","doi-asserted-by":"publisher","first-page":"178","DOI":"10.12688\/wellcomeopenres.15516.1","article-title":"Neurocognitive and functional impairment in adult and paediatric tuberculous meningitis","volume":"4","author":"Davis","year":"2019","journal-title":"Wellcome Open Res"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1136\/bcr-2017-221170","article-title":"Optic disc swelling in a patient with tuberculous meningitis: a diagnostic challenge","volume":"2017","author":"Zuhaimy","year":"2017","journal-title":"Case Rep"},{"key":"B9","doi-asserted-by":"publisher","first-page":"49","DOI":"10.2147\/eb.s516393","article-title":"Recent advances in visual dysfunction and ocular biomarkers in neurological disorders","volume":"17","author":"Cheng","year":"2025","journal-title":"Eye Brain"},{"key":"B10","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1212\/wnl.0b013e3181aaea32","article-title":"Optical coherence tomography is less sensitive than visual evoked potentials in optic neuritis","volume":"73","author":"Naismith","year":"2009","journal-title":"Neurology"},{"key":"B11","first-page":"538","article-title":"Optical coherence tomography versus visual evoked potentials in detecting subclinical visual impairment in multiple sclerosis","volume":"7","author":"Grecescu","year":"2014","journal-title":"J Med Life"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.31222\/osf.io\/v7gm2_v1","article-title":"The PRISMA 2020 statement: an updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"bmj"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1097\/ede.0000000000001232","article-title":"Meta-analysis of proportions using generalized linear mixed models","volume":"31","author":"Lin","year":"2020","journal-title":"Epidemiology"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2020.09.018","article-title":"GRADE Guidelines 30: the GRADE approach to assessing the certainty of modeled evidence\u2014an overview in the context of health decision-making","volume":"129","author":"Brozek","year":"2021","journal-title":"J Clin Epidemiol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwae332","article-title":"Assessing the certainty of the evidence in systematic reviews: importance, process, and use","volume":"194","author":"Brignardello-Petersen","year":"2025","journal-title":"Am J Epidemiol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1097\/icu.0000000000000416","article-title":"Ethambutol optic neuropathy","volume":"28","author":"Chamberlain","year":"2017","journal-title":"Curr Opin Ophthalmol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.5588\/ijtld.11.0766","article-title":"Incidence of ethambutol-related visual impairment during treatment of active tuberculosis","volume":"17","author":"Ezer","year":"2013","journal-title":"Int J Tuberculosis Lung Disease: Off J Int Union Against Tuberculosis Lung Dis"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1097\/wno.0b013e31818e3c6b","article-title":"Incidence and clinical features of ethambutol- induced optic neuropathy in Korea","volume":"28","author":"Lee","year":"2008","journal-title":"J Neuro-Ophthalmology"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.kjms.2015.05.004","article-title":"Incidence and prognostic factor of ethambutol-related optic neuropathy: 10-year experience in southern Taiwan","volume":"31","author":"Chen","year":"2015","journal-title":"Kaohsiung J Med Sci"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1136\/bjophthalmol-2012-301870","article-title":"Ethambutol-induced optic neuropathy a nationwide population-based study from Taiwan","volume":"96","author":"Chen","year":"2012","journal-title":"Br J Ophthalmol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fopht.2023.1152215","article-title":"Incidence, risk factors and ophthalmic clinical characteristic of ethambutol-induced optic neuropathy: 7-year experience","volume":"3","author":"Chaitanuwong","year":"2023","journal-title":"Front Ophthalmol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejim.2011.01.007","article-title":"Incidence, predictors and prognostic value of cranial nerve involvement in patients with tuberculous meningitis: a retrospective evaluation","volume":"22","author":"Sharma","year":"2011","journal-title":"Eur J Internal Med"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.clineuro.2019.105443","article-title":"Clinical characteristics of tuberculous meningitis combined with cranial nerve palsy","volume":"184","author":"Li","year":"2019","journal-title":"Clin Neurol Neurosurg"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.2147\/idr.s396022","article-title":"Incidence and risk factors of cranial nerve palsy in patients with tuberculous meningitis: A retrospective evaluation","volume":"16","author":"Wen","year":"2023","journal-title":"Infection Drug Resistance"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.1983.04050090081014","article-title":"Visual evoked potentials in the detection of subclinical optic toxic effects secondary to ethambutol","volume":"40","author":"Yiannikas","year":"1983","journal-title":"Arch Neurol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3109\/15569527.2015.1079784","article-title":"Visual function test for early detection of ethambutol induced ocular toxicity at the subclinical level","volume":"35","author":"Kim","year":"2016","journal-title":"Cutaneous Ocul Toxicol"},{"key":"B27","article-title":"Visual evoked responses in ethambutol induced optic neuritis","volume":"45","author":"Srivastava","year":"1997","journal-title":"J Assoc Physicians India"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0215297","article-title":"Longitudinal evaluation of visual function and structure for detection of subclinical Ethambutol-induced optic neuropathy","volume":"14","author":"Jin","year":"2019","journal-title":"PloS One"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1136\/bjophthalmol-2020-316897","article-title":"Prospective study to evaluate incidence and indicators for early detection of ethambutol toxicity","volume":"105","author":"Mandal","year":"2021","journal-title":"Br J Ophthalmol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2025.03.002","article-title":"Ethambutol optic neuropathy surveillance: variations in real-world screening practices and associated factors in a nationwide cohort study","volume":"47","author":"Kim","year":"2025","journal-title":"Clin Ther"},{"key":"B31","article-title":"The ocular manifestations of systemic tuberculosis \u2013a hospital based observational study","volume":"15","author":"Deepa","year":"2024","journal-title":"J Cardiovasc Dis Res"},{"key":"B32","doi-asserted-by":"crossref","DOI":"10.1093\/ofid\/ofae686","article-title":"Incidence and risk factors of ophthalmic nerve palsy in patients with tuberculous meningitis: a retrospective study and literature review","author":"Fei","year":"2024"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2024.1461111","article-title":"Nationwide usage of ethambutol and incidence and screening practices of optic neuropathy","volume":"15","author":"Kim","year":"2024","journal-title":"Front Pharmacol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.4103\/ijo.ijo_2996_21","article-title":"Visual outcomes of toxic optic neuropathy secondary to ethambutol: a retrospective observational study from India, an endemic country","volume":"70","author":"Ambika","year":"2022","journal-title":"Indian J Ophthalmol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1111\/resp.14226","article-title":"Ethambutol ocular toxicity and risk factors, a single centre review","volume":"27","author":"Fattore","year":"2022","journal-title":"Respirology"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/s41433-019-0748-9","article-title":"Presumed ocular tuberculosis in the United Kingdom: a British ophthalmological surveillance unit (BOSU) study","volume":"34","author":"Shirley","year":"2020","journal-title":"Eye"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcjo.2018.06.013","article-title":"Ethambutol-induced optic neuropathy in renal disorder: a clinico-electrophysiological study","volume":"54","author":"Kanaujia","year":"2019","journal-title":"Can J Ophthalmol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2377-14-33","article-title":"Association between neuromyelitis optica and tuberculosis in a Chinese population","volume":"14","author":"Li","year":"2014","journal-title":"BMC Neurol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1007\/s12348-012-0079-5","article-title":"Clinical spectrum of tuberculous optic neuropathy","volume":"2","author":"Davis","year":"2012","journal-title":"J Ophthalmic Inflammation Infection"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1111\/j.1755-3768.2009.01579.x","article-title":"Complications of presumed ocular tuberculosis","volume":"88","author":"Hamade","year":"2010","journal-title":"Acta Ophthalmologica"},{"key":"B41","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.jns.2009.12.012","article-title":"Vision impairment in tuberculous meningitis: predictors and prognosis","volume":"290","author":"Sinha","year":"2010","journal-title":"J Neurol Sci"},{"key":"B42","doi-asserted-by":"crossref","DOI":"10.3928\/0191-3913-20010701-10","article-title":"Neuro-ophthalmic features in pediatric tubercular meningoencephalitis","volume-title":"Slack incorporated thorofare, NJ","author":"Amitava","year":"2001"},{"key":"B43","doi-asserted-by":"crossref","DOI":"10.3928\/0191-3913-19860501-06","article-title":"Ocular manifestations of tubercular meningitis: a clinico- biochemical study","volume-title":"SLACK incorporated thorofare, NJ","author":"Lamba","year":"1986"},{"key":"B44","article-title":"Optic nerve involvement in tuberculous meningitis","volume":"22","author":"Kalra","year":"1985","journal-title":"Indian Pediatr"}],"container-title":["Frontiers in Ophthalmology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fopht.2026.1818640\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T04:49:00Z","timestamp":1780030140000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fopht.2026.1818640\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,29]]},"references-count":44,"alternative-id":["10.3389\/fopht.2026.1818640"],"URL":"https:\/\/doi.org\/10.3389\/fopht.2026.1818640","relation":{},"ISSN":["2674-0826"],"issn-type":[{"value":"2674-0826","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,29]]},"article-number":"1818640"}}