{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T21:39:58Z","timestamp":1770673198312,"version":"3.49.0"},"reference-count":58,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2019,11,14]],"date-time":"2019-11-14T00:00:00Z","timestamp":1573689600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["headachejournal.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Headache"],"published-print":{"date-parts":[[2020,1]]},"abstract":"<jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>This basic review is intended to summarize the current knowledge of methemoglobinemia as an important cause of secondary headache with the hope of generating a growing interest in studying this phenomenon.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>We describe the pathological underpinnings of headaches generated by hypoxia. Possible mechanisms include cerebral vasodilation\u2010associated stretching of the vessel nociceptors, sensitization of perivascular nociceptors mediated by nitric oxide, cerebral calcitonin gene\u2010related peptide, activation of the cyclic adenosine monophosphate pathway, cortical spreading depression, disruption of the blood\u2010brain barrier, and neurogenic inflammation.<\/jats:p>\n                    <jats:p>We review the clinical features, pathophysiology, and management of methemoglobinemia. We conducted a literature review of reports of symptomatic methemoglobinemia with headache. In addition, we describe a case report of a patient who presented with an acute onset of severe holocranial headache associated with rapidly progressive perioral paresthesia, cyanosis in lips and hands, nausea, and mild dyspnea on exertion. These features can be misinterpreted as an acute attack of migraine with pain\u2010related hyperventilation syndrome and anxiety leading to clinically detrimental delay in the management of the progressive hypoxia. Her symptoms resolved following treatment with methylene blue.<\/jats:p>\n                    <jats:p>The complex relationship of migraine and hypoxia\u2010related headaches is also reviewed. We propose that methemoglobinemia\u2010associated headaches are possibly generated by stretching of the nociceptor nerve endings during cerebral vasodilation and hypoxia\u2010mediated oxidative stress.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The case highlights the need to broaden the formulated differential diagnosis of an acute onset severe holocranial headache and pay careful attention to other signs and symptoms that may provide hints on potential mechanism(s) for secondary headaches.<\/jats:p>\n                    <jats:p>We provide justification for the need to incorporate \u201cHeadache attributed to Methemoglobinemia\u201d as a subtype under the section \u201cHeadache attributed to hypoxia and\/or hypercapnia\u201d of the International Classification of Headache Disorders to support clinical decision making.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/head.13696","type":"journal-article","created":{"date-parts":[[2019,11,14]],"date-time":"2019-11-14T07:44:11Z","timestamp":1573717451000},"page":"291-297","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Headache and Methemoglobinemia"],"prefix":"10.1111","volume":"60","author":[{"given":"Fawad Ahmed","family":"Khan","sequence":"first","affiliation":[{"name":"The McCasland Family Comprehensive Headache Center Ochsner Neuroscience Institute Ochsner Clinic Foundation New Orleans LA USA"},{"name":"The University of Queensland School of Medicine Ochsner Clinical School New Orleans LA USA"},{"name":"Tulane University School of Medicine New Orleans LA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caley","family":"McIntyre","sequence":"additional","affiliation":[{"name":"The University of Queensland School of Medicine Ochsner Clinical School New Orleans LA USA"},{"name":"Department of Hospital Medicine Ochsner Clinic Foundation New Orleans LA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdul Mukhtadir","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine Ochsner Clinic Foundation New Orleans LA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Maslov","sequence":"additional","affiliation":[{"name":"The University of Queensland School of Medicine Ochsner Clinical School New Orleans LA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,11,14]]},"reference":[{"key":"e_1_2_12_2_1","first-page":"133","article-title":"Methemoglobin pathophysiology","volume":"51","author":"Jaff\u00e9 ER","year":"1981","journal-title":"Prog Clin Biol Res"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.2830420104"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1345\/aph.1Q139"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0196-0644(99)70167-8"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2008.07017.x"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198603203141206"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1080\/08998280.2006.11928171"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.md.0000141096.00377.3f"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.2344\/0003-3006(2005)52[136:BM]2.0.CO;2"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1136\/pgmj.63.742.643"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.2.4887.575"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0025-6196(12)61794-7"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1097\/SMJ.0b013e318232139f"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamainternmed.2013.75"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.167.18.1977"},{"key":"e_1_2_12_17_1","first-page":"977","volume-title":"Goldfrank's Toxicologic Emergencies","author":"Price DP","year":"2015"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1097\/00045391-200307000-00009"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.2165\/00139709-200322010-00003"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajem.2009.10.014"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.jvca.2013.02.005"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0196-0644(82)80502-7"},{"key":"e_1_2_12_23_1","volume-title":"FDA Drug Safety Communication: Updated Information About the Drug Interaction Between Methylene Blue (Methylthioninium Chloride) and Serotonergic Psychiatric Medications","author":"U. S. Food and Drug Administration"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0223(199601)16:1<39::AID-PD789>3.0.CO;2-P"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1526-4610.1990.hed3002052.x"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/head.13300"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awt369"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1468-2982.1993.1306395.x"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3770"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1177\/0333102416651453"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv359"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv402"},{"key":"e_1_2_12_33_1","first-page":"321","article-title":"Prolonged hemolysis and methemoglobinemia following organic copper fungicide ingestion","volume":"46","author":"Yang CC","year":"2004","journal-title":"Vet Hum Toxicol"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.3109\/15563657909030116"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1080\/15459624.2016.1229484"},{"key":"e_1_2_12_36_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4103\/jpp.JPP_79_17","article-title":"The blood blues: A review on methemoglobinemia","volume":"9","author":"David SR","year":"2018","journal-title":"J Pharmacol Pharmacother"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1183\/16000617.0096-2016"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0404.2005.00372.x"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10194-006-0264-8"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1177\/0333102415610876"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/nbm.3026"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1177\/0333102416647037"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1468-2982.2005.00867.x"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00616.2001"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-0115(02)00129-5"},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(99)02308-2"},{"key":"e_1_2_12_47_1","doi-asserted-by":"publisher","DOI":"10.1111\/head.12725"},{"key":"e_1_2_12_48_1","doi-asserted-by":"publisher","DOI":"10.1097\/WCO.0b013e32833821c1"},{"key":"e_1_2_12_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410230214"},{"key":"e_1_2_12_50_1","doi-asserted-by":"publisher","DOI":"10.1177\/0333102417738202"},{"key":"e_1_2_12_51_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000006697"},{"key":"e_1_2_12_52_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13312-017-1050-1"},{"key":"e_1_2_12_53_1","first-page":"211","article-title":"Assessment of severity of methaemoglobinemia following fibreoptic bronchoscopy with lidocaine","volume":"53","author":"Sajal D","year":"2011","journal-title":"Indian J Chest Dis Allied Sci"},{"key":"e_1_2_12_54_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12245-018-0208-5"},{"key":"e_1_2_12_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jemermed.2016.07.113"},{"key":"e_1_2_12_56_1","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/670979"},{"key":"e_1_2_12_57_1","doi-asserted-by":"publisher","DOI":"10.5505\/1304.7361.2014.79990"},{"key":"e_1_2_12_58_1","doi-asserted-by":"publisher","DOI":"10.1345\/aph.1E212"},{"key":"e_1_2_12_59_1","first-page":"625","article-title":"Benzocaine\u2010induced methemoglobinemia: A condition of which all endoscopists should be aware","volume":"18","author":"Armstrong C","year":"2004","journal-title":"Can J Gastroenterol Hepatol"}],"container-title":["Headache: The Journal of Head and Face Pain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/head.13696","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/head.13696","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/headachejournal.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/head.13696","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T09:25:39Z","timestamp":1762075539000},"score":1,"resource":{"primary":{"URL":"https:\/\/headachejournal.onlinelibrary.wiley.com\/doi\/10.1111\/head.13696"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,14]]},"references-count":58,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,1]]}},"alternative-id":["10.1111\/head.13696"],"URL":"https:\/\/doi.org\/10.1111\/head.13696","archive":["Portico"],"relation":{},"ISSN":["0017-8748","1526-4610"],"issn-type":[{"value":"0017-8748","type":"print"},{"value":"1526-4610","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,14]]},"assertion":[{"value":"2019-10-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-11-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}