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We know that it is the most common neurological disease affecting the young-middle aged, that it affects two to three times more females than males, and that it is characterized as an autoimmune disease, in which autoreactive T lymphocytes cross the blood\u2013brain barrier, resulting in demyelinating lesions. But despite all the knowledge gained, a key question still remains; what is the initial event that triggers the inflammatory demyelinating process? While most research effort to date has focused on the immune system, more recently, another potential candidate has emerged: hypoxia. Specifically, a growing number of studies have described the presence of hypoxia (both \u2018virtual\u2019 and real) at an early stage of demyelinating lesions, and several groups, including our own, have begun to investigate how manipulation of inspired oxygen levels impacts disease progression. In this review we summarize the findings of these hypoxia studies, and in particular, address three\u00a0main questions: (i) is the hypoxia found in demyelinating lesions \u2018virtual\u2019 or real; (ii) what causes this hypoxia; and (iii) how does manipulation of inspired oxygen impact disease progression?<\/jats:p>","DOI":"10.1093\/brain\/awaa427","type":"journal-article","created":{"date-parts":[[2020,11,17]],"date-time":"2020-11-17T15:10:39Z","timestamp":1605625839000},"page":"402-410","source":"Crossref","is-referenced-by-count":61,"title":["Hypoxia in multiple sclerosis; is it the chicken or the egg?"],"prefix":"10.1093","volume":"144","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9472-3864","authenticated-orcid":false,"given":"Sebok K","family":"Halder","sequence":"first","affiliation":[{"name":"San Diego Biomedical Research Institute, 10865 Road to the Cure, Suite 100, San Diego, CA 92121, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Milner","sequence":"additional","affiliation":[{"name":"San Diego Biomedical Research Institute, 10865 Road to the Cure, Suite 100, San Diego, CA 92121, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,12,22]]},"reference":[{"key":"2021092108143675900_awaa427-B1","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s00401-004-0954-8","article-title":"Mitochondrial damage and histotoxic hypoxia: a pathway of tissue injury in inflammatory brain disease?","volume":"109","author":"Aboul-Enein","year":"2005","journal-title":"Acta Neuropathol"},{"key":"2021092108143675900_awaa427-B2","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1093\/jnen\/62.1.25","article-title":"Preferential loss of myelin-associated glycoprotein reflects hypoxia-like white matter damage in stroke and inflammatory brain diseases","volume":"62","author":"Aboul-Enein","year":"2003","journal-title":"J Neuropathol Exp Neurol"},{"key":"2021092108143675900_awaa427-B3","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1016\/j.neuroimage.2006.08.008","article-title":"Pattern of hemodynamic impairment in multiple sclerosis: dynamic susceptibility contrast perfusion MR imaging at 3.0 T","volume":"33","author":"Adhya","year":"2006","journal-title":"Neuroimage"},{"key":"2021092108143675900_awaa427-B4","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1136\/jnnp.50.11.1402","article-title":"Hyperbaric oxygen and multiple sclerosis: final results of a placebo-controlled, double-blind trial","volume":"50","author":"Barnes","year":"1987","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"2021092108143675900_awaa427-B5","doi-asserted-by":"crossref","first-page":"18351","DOI":"10.1073\/pnas.1318345110","article-title":"Hypoxia and inflammation are two sides of the same coin","volume":"110","author":"Bartels","year":"2013","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021092108143675900_awaa427-B6","doi-asserted-by":"crossref","first-page":"96","DOI":"10.2337\/dc13-1414","article-title":"Higher relative risk for multiple sclerosis in a pediatric and adolescent diabetic population: analysis from DPV database","volume":"37","author":"Bechtold","year":"2014","journal-title":"Diabetes Care"},{"key":"2021092108143675900_awaa427-B7","first-page":"CD003057","article-title":"Hyperbaric oxygen therapy for multiple sclerosis","volume":"1","author":"Bennett","year":"2004","journal-title":"Cochrane Database Syst Rev"},{"key":"2021092108143675900_awaa427-B8","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1111\/j.1755-5949.2009.00129.x","article-title":"Hyperbaric oxygen therapy for multiple sclerosis","volume":"16","author":"Bennett","year":"2010","journal-title":"CNS Neurosci Ther"},{"key":"2021092108143675900_awaa427-B9","first-page":"298","article-title":"Use of hyperbaric oxygen in various neurologic diseases. 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