{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T11:27:00Z","timestamp":1788262020489,"version":"build-2803163510"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T00:00:00Z","timestamp":1745798400000},"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. Immunol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>The aim of this study was to compare the clinical presentations, nerve conduction studies, neuroimaging findings of subacute combined degeneration (SCD) caused by N<jats:sub>2<\/jats:sub>O abuse and primary vitamin B12 deficiency. The goal is to improve diagnostic accuracy, tailored therapeutic interventions, and ultimately enhancing patient outcomes in cases of SCD caused by N<jats:sub>2<\/jats:sub>O abuse.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This study was a retrospective case-control study which enrolled 23 patients diagnosed with N<jats:sub>2<\/jats:sub>O-induced subacute combined degeneration (N<jats:sub>2<\/jats:sub>O-SCD) and 20 patients with vitamin B12 deficiency-induced subacute combined degeneration (Vit B12-SCD) between 2015 and 2023. Clinical manifestations, physical examinations, laboratory tests, nerve conduction studies, and spinal cord MRI imaging results were collected. Additionally, age-matched healthy control groups were also included for comparative electrophysiological analysis, consisting of 23 young individuals and 21 elderly individuals corresponding to the N<jats:sub>2<\/jats:sub>O-SCD and Vit B12-SCD groups, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The study found that compared to Vit B12-SCD, N<jats:sub>2<\/jats:sub>O-SCD patients exhibited more severe and extensive neurological damage. Both N<jats:sub>2<\/jats:sub>O-SCD and Vit B12- SCD patients may present with numbness or abnormal sensations, limb weakness, difficulty walking and inability to walk, but these are more severe and widespread in N<jats:sub>2<\/jats:sub>O-SCD patients. N<jats:sub>2<\/jats:sub>O-SCD patients showed significant decreases in limb strength, with common walking difficulties and paralysis. Additionally, N<jats:sub>2<\/jats:sub>O abuse patients more frequently exhibited psychiatric symptoms, especially memory loss, hallucinations and confusion. Both Vit B12-SCD and N<jats:sub>2<\/jats:sub>O-SCD can cause peripheral nerve demyelination and axonal damage, but it is more severe in the N<jats:sub>2<\/jats:sub>O-SCD group, with more damage in the lower limbs than in the upper limbs. The extensive nature of axonal damage also indicated a poor prognosis. The degree of spinal cord damage in the N<jats:sub>2<\/jats:sub>O-SCD group was more severe and affected longer segments. These results suggest that in addition to affecting vitamin B12, N<jats:sub>2<\/jats:sub>O also causes neurological damage through other mechanisms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In summary, N<jats:sub>2<\/jats:sub>O-SCD leads to more severe clinical symptoms, peripheral nerve damage, and spinal cord injury than Vit B12-SCD. These differences guide the clinical treatment of N<jats:sub>2<\/jats:sub>O-SCD, requiring not only vitamin B12 supplementation but also an addition in neuroprotective treatments.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1567541","type":"journal-article","created":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T04:13:23Z","timestamp":1745813603000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Comparative study of subacute combined degeneration of the spinal cord due to nitrous oxide abuse and vitamin B12 deficiency"],"prefix":"10.3389","volume":"16","author":[{"given":"Sedine Marie Desiree Nina","family":"Agbo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohui","family":"Duan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingrui","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojing","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,4,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1525-1497.2006.00525.x","article-title":"Potential outcome factors in subacute combined degeneration: review of observational studies","volume":"21","author":"Vasconcelos","year":"2006","journal-title":"J Gen Intern Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3390\/nu5114521","article-title":"Cobalamin deficiency: clinical picture and radiological findings","volume":"5","author":"Briani","year":"2013","journal-title":"Nutrients"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1007\/BF03016309","article-title":"Potential of xenon to induce or to protect against neuroapoptosis in the developing mouse brain","volume":"55","author":"Cattano","year":"2008","journal-title":"Can J Anaesth"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2015.10.017","article-title":"Recreational nitrous oxide use: Prevalence and risks","volume":"73","author":"van Amsterdam","year":"2015","journal-title":"Regul Toxicol Pharmacol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.4103\/2045-9912.385941","article-title":"Nitrous oxide induces subacute combined degeneration by affecting vitamin B12 metabolism","volume":"14","author":"Hu","year":"2023","journal-title":"Med Gas Res"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jns.2010.10.033","article-title":"Nitrous oxide-induced B12 deficiency myelopathy: Perspectives on the clinical biochemistry of vitamin B12","volume":"301","author":"Hathout","year":"2011","journal-title":"J Neurol Sci"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1097\/jcp.0000000000001151","article-title":"Psychiatric and other medical manifestations of nitrous oxide abuse: implications from case series","volume":"40","author":"Chien","year":"2020","journal-title":"J Clin Psychopharmacol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1111\/1742-6723.13997","article-title":"Review article: Clinical manifestations and outcomes of chronic nitrous oxide misuse: A systematic review","volume":"34","author":"Marsden","year":"2022","journal-title":"Emerg Med Australas"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.braindev.2018.12.003","article-title":"Recreational nitrous oxide abuse related subacute combined degeneration of the spinal cord in adolescents - A case series and literature review","volume":"41","author":"Lan","year":"2019","journal-title":"Brain Dev"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-021-10858-2","article-title":"Nitrous oxide-induced predominantly motor neuropathies: a follow-up study","volume":"269","author":"Berling","year":"2022","journal-title":"J Neurol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.2147\/SAR.S114404","article-title":"Psychiatric comorbidities in a young man with subacute myelopathy induced by abusive nitrous oxide consumption: a case report","volume":"7","author":"Mancke","year":"2016","journal-title":"Subst Abuse Rehabil"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1111\/ajad.12372","article-title":"Neurologic, psychiatric, and other medical manifestations of nitrous oxide abuse: A systematic review of the case literature","volume":"25","author":"Garakani","year":"2016","journal-title":"Am J Addict"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1080\/15563650.2022.2046772","article-title":"Nitrous oxide abuse induced subacute combined degeneration despite patient initiated B12 supplementation","volume":"60","author":"Temple","year":"2022","journal-title":"Clin Toxicol (Phila)"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-200010000-00034","article-title":"Effects of gaseous anesthetics nitrous oxide and xenon on ligand-gated ion channels. Comparison with isoflurane and ethanol","volume":"93","author":"Yamakura","year":"2000","journal-title":"Anesthesiology"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e3181870a17","article-title":"Biologic effects of nitrous oxide: a mechanistic and toxicologic review","volume":"109","author":"Sanders","year":"2008","journal-title":"Anesthesiology"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3390\/ijerph191811567","article-title":"A systematic review of recreational nitrous oxide use: implications for policy, service delivery and individuals","volume":"19","author":"Allan","year":"2022","journal-title":"Int J Environ Res Public Health"},{"key":"B17","volume-title":"Global Drug Survey (GDS) 2021 Key Findings Report","author":"Winstock","year":"2021"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fpubh.2022.854977","article-title":"Neurological and psychological characteristics of young nitrous oxide abusers and its underlying causes during the COVID-19 lockdown","volume":"10","author":"Wu","year":"2022","journal-title":"Front Public Health"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.revmed.2022.06.004","article-title":"Possible impact of the COVID-19 pandemic on the recreational use of nitrous oxide in the Paris area, France","volume":"43","author":"Dufayet","year":"2022","journal-title":"Rev Med Interne"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(03)13045-0","article-title":"Nitrous oxide use in first-year students at Auckland University","volume":"361","author":"Ng","year":"2003","journal-title":"Lancet"},{"key":"B21","volume-title":"2004 National Drug Strategy Household Survey: First Results","year":"2005"},{"key":"B22","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1177\/0269881116632375","article-title":"Up: The rise of nitrous oxide abuse. An international survey of contemporary nitrous oxide use","volume":"30","author":"Kaar","year":"2016","journal-title":"J\u00a0Psychopharmacol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-023-11570-z","article-title":"Comparison of biomarker for diagnosis of nitrous oxide abuse: challenge of cobalamin metabolic parameters, a retrospective study","volume":"270","author":"Grzych","year":"2023","journal-title":"J Neurol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.clineuro.2013.04.004","article-title":"Laughing gas abuse is no joke. An overview of the implications for psychiatric practice","volume":"115","author":"Cousaert","year":"2013","journal-title":"Clin Neurol Neurosurg"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2008.11.029","article-title":"Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression","volume":"65","author":"Miller","year":"2009","journal-title":"Biol Psychiatry"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1126\/science.1088417","article-title":"Inflammatory blockade restores adult hippocampal neurogenesis","volume":"302","author":"Monje","year":"2003","journal-title":"Science"},{"key":"B27","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/j.bbi.2010.10.015","article-title":"Immune modulation of learning, memory, neural plasticity and neurogenesis","volume":"25","author":"Yirmiya","year":"2011","journal-title":"Brain Behav Immun"},{"key":"B28","doi-asserted-by":"publisher","first-page":"73","DOI":"10.3390\/brainsci4010073","article-title":"The neurotoxicity of nitrous oxide: the facts and \u201cputative\u201d mechanisms","volume":"4","author":"Savage","year":"2014","journal-title":"Brain Sci"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2003.tb07518.x","article-title":"Neurotoxicity of nitrous oxide and ketamine is more severe in aged than in young rat brain","volume":"993","author":"Beals","year":"2003","journal-title":"Ann N Y Acad Sci"},{"key":"B30","doi-asserted-by":"publisher","first-page":"e16076","DOI":"10.1111\/ene.16076","article-title":"Nitrous-oxide-induced polyneuropathy and subacute combined degeneration of the spine: clinical and diagnostic characteristics in 70 patients, with focus on electrodiagnostic studies","volume":"31","author":"Hassing","year":"2024","journal-title":"Eur J Neurol"},{"key":"B31","article-title":"Nitrous oxide-induced subacute combined degeneration presenting with dystonia and pseudoathetosis: A case report","volume":"25","author":"Chen","year":"2016","journal-title":"Acta Neurol Taiwan"},{"key":"B32","doi-asserted-by":"publisher","first-page":"44","DOI":"10.3988\/jcn.2023.19.1.44","article-title":"Electrophysiologic characteristics of nitrous-oxide-associated peripheral neuropathy: A retrospective study of 76 patients","volume":"19","author":"Fang","year":"2023","journal-title":"J Clin Neurol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2019.00704","article-title":"Elucidating unique axonal dysfunction between nitrous oxide abuse and vitamin B12 deficiency","volume":"10","author":"Tani","year":"2019","journal-title":"Front Neurol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1136\/practneurol-2014-001071","article-title":"Whippits, nitrous oxide and the dangers of legal highs","volume":"15","author":"Thompson","year":"2015","journal-title":"Pract Neurol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.12.038","article-title":"Myelin formation and remodeling","volume":"156","author":"Fields","year":"2014","journal-title":"Cell"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines12020429","article-title":"Understanding neuropathy features in the context of nitrous oxide abuse: A combined electrophysiological and metabolic approach","volume":"12","author":"Grzych","year":"2024","journal-title":"Biomedicines"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.jemermed.2010.04.020","article-title":"Severe myeloneuropathy from acute high-dose nitrous oxide (N2O) abuse","volume":"41","author":"Alt","year":"2011","journal-title":"J Emerg Med"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.13.14.2083","article-title":"Epidermal growth factor as a local mediator of the neurotrophic action of vitamin B(12) (cobalamin) in the rat central nervous system","volume":"13","author":"Scalabrino","year":"1999","journal-title":"FASEB J"},{"key":"B39","doi-asserted-by":"publisher","first-page":"9","DOI":"10.2344\/0003-3006(2007)54[9:AIUTAO]2.0.CO;2","article-title":"Advances in understanding the actions of nitrous oxide","volume":"54","author":"Emmanouil","year":"2007","journal-title":"Anesth Prog"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1097\/CND.0000000000000108","article-title":"Clinical manifestations of isolated elevated homocysteine-induced peripheral neuropathy in adults","volume":"17","author":"Shandal","year":"2016","journal-title":"J Clin Neuromuscul Dis"},{"key":"B41","article-title":"The role for oxidative stress in neurodegenerative diseases","volume":"60","author":"Shibata","year":"2008","journal-title":"Brain and Nerve"},{"key":"B42","article-title":"Spinal myoclonus in subacute combined degeneration caused by nitrous oxide intoxication","volume":"16","author":"Wu","year":"2007","journal-title":"Acta Neurol Taiwan"},{"key":"B43","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1111\/bjh.12959","article-title":"Guidelines for the diagnosis and treatment of cobalamin and folate disorders","volume":"166","author":"Devalia","year":"2014","journal-title":"Br J Haematol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1172\/jci110155","article-title":"Nitrous oxide has multiple deleterious effects on cobalamin metabolism and causes decreases in activities of both mammalian cobalamin-dependent enzymes in rats","volume":"67","author":"Kondo","year":"1981","journal-title":"J Clin Invest"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1567541\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T04:13:24Z","timestamp":1745813604000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1567541\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,28]]},"references-count":44,"alternative-id":["10.3389\/fimmu.2025.1567541"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1567541","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,28]]},"article-number":"1567541"}}