{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T17:10:14Z","timestamp":1790097014685,"version":"4.0.1"},"reference-count":35,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Oxidative stress is implicated in epilepsy, but seizures, disease severity, diet, comorbidity and treatment all influence circulating redox biomarkers. We systematically reviewed human evidence on levetiracetam (LEV) under three estimands: within-person change, LEV-treated epilepsy versus healthy controls, and LEV versus other antiseizure medications. PubMed\/MEDLINE, Cochrane Library, Web of Science and Scopus were searched from inception to 15 July 2026 (PROSPERO CRD420261448016; OSF HXA4U). Eleven non-randomized studies contributed 297 participants\u2014the sum of LEV subgroups with analysable biomarker data, not the total enrolled populations. Effect estimates with 95% confidence intervals were calculated here wherever reporting permitted; none could be derived for four studies, and those derived are wide, inconsistent in direction, or from designs that cannot attribute change to LEV. Meta-analysis was inappropriate: definitions, matrices, assays, estimands and variance reporting were incompatible. Certainty was very low for every outcome-domain\/comparator body, and a sensitivity analysis excluding one report failing a post hoc source-verifiability check (10 studies, 265 participants) changed no conclusion. This review\u2019s contribution is not an estimate of LEV\u2019s redox effect but a demonstration of why the literature cannot establish one: the human evidence is not of sufficient validity to support or refute such an effect.<\/jats:p>","DOI":"10.3390\/ijms27188410","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:32:12Z","timestamp":1790083932000},"page":"8410","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Levetiracetam and Peripheral Oxidative Stress Biomarkers in Epilepsy: A Systematic Review of Human Evidence"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-3140-2274","authenticated-orcid":false,"given":"Robert","family":"M\u00eendreanu","sequence":"first","affiliation":[{"name":"Department of Physiology, Iuliu Ha\u021bieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0046-0803","authenticated-orcid":false,"given":"Simona","family":"Clichici","sequence":"additional","affiliation":[{"name":"Department of Physiology, Iuliu Ha\u021bieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2919-4551","authenticated-orcid":false,"given":"Bianca","family":"Buleteanu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Victor Babe\u0219 University of Medicine and Pharmacy, 300173 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7200-6169","authenticated-orcid":false,"given":"Mario","family":"Badea","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Victor Babe\u0219 University of Medicine and Pharmacy, 300173 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihaela","family":"Pop","sequence":"additional","affiliation":[{"name":"Department of Public Law and Private Law, Faculty of Law and Economic Sciences T\u00e2rgu Jiu, Titu Maiorescu University of Bucharest, 210102 T\u00e2rgu Jiu, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u0103zvan Mircea","family":"Chereche\u0219","sequence":"additional","affiliation":[{"name":"HIVE Health Innovation Centre, Babe\u0219-Bolyai University, 400132 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cezar","family":"Login","sequence":"additional","affiliation":[{"name":"Department of Physiology, Iuliu Ha\u021bieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1111\/epi.12550","article-title":"ILAE Official Report: A Practical Clinical Definition of Epilepsy","volume":"55","author":"Fisher","year":"2014","journal-title":"Epilepsia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1016\/j.freeradbiomed.2004.08.021","article-title":"Mitochondrial Dysfunction and Oxidative Stress: Cause and Consequence of Epileptic Seizures","volume":"37","author":"Patel","year":"2004","journal-title":"Free Radic. Biol. Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Pearson-Smith, J., and Patel, M. (2017). Metabolic Dysfunction and Oxidative Stress in Epilepsy. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18112365"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"9861","DOI":"10.1073\/pnas.0308208101","article-title":"The Synaptic Vesicle Protein SV2A Is the Binding Site for the Antiepileptic Drug Levetiracetam","volume":"101","author":"Lynch","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Contreras-Garc\u00eda, I.J., C\u00e1rdenas-Rodr\u00edguez, N., Romo-Mancillas, A., Bandala, C., Zamudio, S.R., G\u00f3mez-Manzo, S., Hern\u00e1ndez-Ochoa, B., Mendoza-Torreblanca, J.G., and Pichardo-Mac\u00edas, L.A. (2022). Levetiracetam Mechanisms of Action: From Molecules to Systems. Pharmaceuticals, 15.","DOI":"10.3390\/ph15040475"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Ignacio-Mej\u00eda, I., Contreras-Garc\u00eda, I.J., Mendoza-Torreblanca, J.G., Medina-Campos, O.N., Pedraza-Chaverri, J., Garc\u00eda-Cruz, M.E., Romo-Mancillas, A., G\u00f3mez-Manzo, S., Bandala, C., and S\u00e1nchez-Mendoza, M.E. (2023). Evaluation of the Antioxidant Activity of Levetiracetam in a Temporal Lobe Epilepsy Model. Biomedicines, 11.","DOI":"10.3390\/biomedicines11030848"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"51","DOI":"10.55782\/ane-2024-2537","article-title":"Effect of Levetiracetam on DNA Oxidation and Glutathione Content in a Temporal Lobe Epilepsy Model","volume":"84","author":"Bandala","year":"2024","journal-title":"Acta Neurobiol. Exp."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.ab.2016.10.021","article-title":"Assessment of Lipid Peroxidation by Measuring Malondialdehyde (MDA) and Relatives in Biological Samples: Analytical and Biological Challenges","volume":"524","author":"Tsikas","year":"2017","journal-title":"Anal. Biochem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1080\/13547500500216546","article-title":"F2-Isoprostanes as Markers of Oxidative Stress in Vivo: An Overview","volume":"10","author":"Milne","year":"2005","journal-title":"Biomarkers"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 Statement: An Updated Guideline for Reporting Systematic Reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"l6890","DOI":"10.1136\/bmj.l6890","article-title":"Synthesis without Meta-Analysis (SWiM) in Systematic Reviews: Reporting Guideline","volume":"368","author":"Campbell","year":"2020","journal-title":"BMJ"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"i4919","DOI":"10.1136\/bmj.i4919","article-title":"ROBINS-I: A Tool for Assessing Risk of Bias in Non-Randomised Studies of Interventions","volume":"355","author":"Sterne","year":"2016","journal-title":"BMJ"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Higgins, J.P.T., Thomas, J., Chandler, J., Cumpston, M., Li, T., Page, M.J., and Welch, V.A. (2019). Assessing Risk of Bias in a Non-randomized Study. Cochrane Handbook for Systematic Reviews of Interventions, Wiley.","DOI":"10.1002\/9781119536604"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1136\/bmj.39489.470347.AD","article-title":"GRADE: An Emerging Consensus on Rating Quality of Evidence and Strength of Recommendations","volume":"336","author":"Guyatt","year":"2008","journal-title":"BMJ"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1097\/WNF.0b013e3181d1e133","article-title":"Effects of Valproate, Carbamazepine, and Levetiracetam on the Antioxidant and Oxidant Systems in Epileptic Patients and Their Clinical Importance","volume":"33","author":"Varoglu","year":"2010","journal-title":"Clin. Neuropharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1016\/j.seizure.2010.07.010","article-title":"The Effects of Levetiracetam on Urinary 15f-2t-Isoprostane Levels in Epileptic Patients","volume":"19","author":"Ozden","year":"2010","journal-title":"Seizure"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1007\/s12013-015-0683-8","article-title":"The Effects of Levetiracetam on Cerebrospinal Fluid and Plasma NPY and GAL, and on the Components of Stress Response System, Hs-CRP, and S100B Protein in Serum of Patients with Refractory Epilepsy","volume":"73","author":"Chen","year":"2015","journal-title":"Cell Biochem. Biophys."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.eplepsyres.2019.03.009","article-title":"Effects of Levetiracetam and Valproic Acid Treatment on Liver Function Tests, Plasma Free Carnitine and Lipid Peroxidation in Childhood Epilepsies","volume":"153","author":"Haznedar","year":"2019","journal-title":"Epilepsy Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"984","DOI":"10.4314\/ahs.v20i2.55","article-title":"Effect of Levetiracetam Drug on Antioxidant and Liver Enzymes in Epileptic Patients: Case-Control Study","volume":"20","author":"Mahdavi","year":"2020","journal-title":"Afr. Health Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"057","DOI":"10.1055\/s-0036-1586728","article-title":"Effects of Antiepileptic Drugs on Oxidative Stress Enzymes in Children with Epilepsy: Correlation with Child Psychopathology","volume":"14","author":"Elsayed","year":"2016","journal-title":"J. Pediatr. Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1515\/tjb-2018-0218","article-title":"Plasma Homocysteine and Aminothiol Levels in Idiopathic Epilepsy Patients Receiving Antiepileptic Drugs","volume":"44","author":"Anadol","year":"2019","journal-title":"Turk. J. Biochem."},{"key":"ref_22","first-page":"224","article-title":"The Effect of Levetiracetam on Depression and Anti-Oxidant Activity in Patients with Epilepsy","volume":"21","author":"Zare","year":"2022","journal-title":"Curr. J. Neurol."},{"key":"ref_23","first-page":"10","article-title":"Evaluation of Antioxidant Effects of Antiepileptic Drugs in Adult Epileptic Patients: An Open Label, Non Randomised Interventional Study","volume":"16","author":"Swathi","year":"2022","journal-title":"J. Clin. Diagn. Res."},{"key":"ref_24","first-page":"101558","article-title":"Thermal Infrared Imaging in the Clinical Treatment of Ferroptosis with Different Antiepileptic Drugs: Biomedical Imaging Assistance","volume":"18","author":"Wang","year":"2025","journal-title":"J. Radiat. Res. Appl. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"106439","DOI":"10.1016\/j.yebeh.2019.07.040","article-title":"Assessment of Psychiatric and Behavioral Adverse Effects of Antiepileptic Drugs Monotherapy: Could They Have a Neuroendocrine Correlation in Persons with Epilepsy?","volume":"100","author":"Sarangi","year":"2019","journal-title":"Epilepsy Behav."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"106352","DOI":"10.1016\/j.eplepsyres.2020.106352","article-title":"Determination of Levels of Oxidative Stress and Nitrosative Stress in Patients with Epilepsy","volume":"164","author":"Ersan","year":"2020","journal-title":"Epilepsy Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Martinc, B., Grabnar, I., Milosheska, D., Lorber, B., and Vovk, T. (2024). A Cross-Sectional Study Comparing Oxidative Stress in Patients with Epilepsy Treated with Old and New Generation Antiseizure Medications. Medicina, 60.","DOI":"10.3390\/medicina60081299"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.jcma.2016.10.005","article-title":"A Study of Oxidative Stress and the Newer Antiepileptic Drugs in Epilepsy Associated with Severe Motor and Intellectual Disabilities","volume":"80","author":"Morimoto","year":"2017","journal-title":"J. Chin. Med. Assoc."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1016\/j.eplepsyres.2014.08.007","article-title":"An Evaluation of Serum Paraoxonase Together with Arylesterase Activities and Oxidative Stress in Children with Intractable Epilepsy: A Cross-Sectional Study","volume":"108","author":"Calik","year":"2014","journal-title":"Epilepsy Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Szo\u0142tysek-Bo\u0142dys, I., Zieli\u0144ska-Danch, W., Gajowska, \u0141., Kopyta, I., and Sarecka-Hujar, B. (2025). Comparison of Glutathione, Retinol and \u03b1- and \u03b3-Tocopherols Concentrations Between Children with and Without Epilepsy: A Single-Center Case\u2013Control Study. Brain Sci., 15.","DOI":"10.3390\/brainsci15060655"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"398","DOI":"10.4103\/0972-2327.144008","article-title":"Low Plasma Antioxidant Status in Patients with Epilepsy and the Role of Antiepileptic Drugs on Oxidative Stress","volume":"17","author":"Menon","year":"2014","journal-title":"Ann. Indian Acad. Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"82969","DOI":"10.1039\/C6RA15777G","article-title":"Antiepileptic Drugs Affect Lipid Oxidative Markers\u2014Neuroprostanes and F2-Dihomo-Isoprostanes\u2014In Patients with Epilepsy: Differences among First-, Second-, and Third-Generation Drugs by UHPLC-QqQ-MS\/MS","volume":"6","author":"Medina","year":"2016","journal-title":"RSC Adv."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Sarecka-Hujar, B., Szo\u0142tysek-Bo\u0142dys, I., and Kopyta, I. (2022). Serum Levels of Lipids and Selected Aminothiols in Epileptic Children\u2014A Pilot Case-Control Study. Brain Sci., 12.","DOI":"10.3390\/brainsci12010120"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1111\/j.1528-1167.2009.02024.x","article-title":"Long-Term Antiepileptic Drug Therapy Contributes to the Acceleration of Atherosclerosis","volume":"50","author":"Tan","year":"2009","journal-title":"Epilepsia"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1080\/00207454.2022.2140426","article-title":"Assessment of Oxidative\/Nitrosative Stress and Antioxidant Capacity in Children with Epilepsy","volume":"134","author":"Kopan","year":"2024","journal-title":"Int. J. Neurosci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/18\/8410\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T16:38:23Z","timestamp":1790095103000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/18\/8410"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,21]]},"references-count":35,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ijms27188410"],"URL":"https:\/\/doi.org\/10.3390\/ijms27188410","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,21]]}}}