{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T07:11:19Z","timestamp":1784099479975,"version":"3.55.0"},"reference-count":109,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["headachejournal.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Headache"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Headaches in primary mitochondrial diseases (PMDs) present distinctive features that warrant differentiation from primary headache disorders. Current knowledge on clinical manifestations, pathophysiology, diagnosis, and treatment is here reviewed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Among the most frequent and disabling symptoms affecting patients with PMDs, headache occurs in approximately 55\u201371% of individuals. Those with mitochondrial encephalomyopathy, lactic acidosis, and stroke\u2010like episodes (MELAS) and related phenotypes are particularly affected. Compared to the general population, migraine prevalence in patients with PMD is up to three\u2010 to four\u2010fold higher.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To examine headache across the full spectrum of PMDs, a narrative literature review was conducted. PubMed, Scopus, and Web of Science databases were searched using the terms \u201cmitochondrial disease,\u201d \u201cmigraine,\u201d \u201cheadache,\u201d \u201cMELAS,\u201d and \u201cstroke\u2010like episodes,\u201d with no date restrictions. Relevant references from identified articles were also reviewed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In PMDs, migraine with or without aura is the most common type of headache disorder, especially among carriers of the m.3243A&gt;G mutation, the most prevalent pathogenic variant found in MELAS syndrome. Recent data from Mendelian randomization studies have suggested a potential causal link between low mitochondrial DNA copy number and migraine without aura. The clinical characteristics that help differentiate headache in PMDs include protracted or atypical aura, co\u2010occurring neurological and systemic manifestations, temporal relationship with stroke\u2010like episodes, and variable response to conventional therapy. The use of mitochondrial cofactors such as riboflavin, coenzyme Q10, and L\u2010arginine as adjuncts to standard preventive strategies has been supported by only limited evidence.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Specialized diagnostic and therapeutic approaches are required for headache management in PMDs, combining mitochondrial\u2010targeted interventions with evidence\u2010based headache treatments. When atypical migraine features are present, particularly prolonged aura or aura occurring with epileptic seizures or encephalopathy, evaluation for underlying mitochondrial disease should be considered.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/head.70180","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T06:55:12Z","timestamp":1784098512000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Headache in mitochondrial diseases: From migraine to stroke\u2010like episodes"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-7333-6046","authenticated-orcid":false,"given":"Matteo","family":"Azzimonti","sequence":"first","affiliation":[{"name":"Neurodegenerative Diseases Unit Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico  Milan 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Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomo Pietro","family":"Comi","sequence":"additional","affiliation":[{"name":"Neurology Unit Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico  Milan Italy"},{"name":"Dino Ferrari Center, Department of Pathophysiology and Transplantation University of Milan  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5425-969X","authenticated-orcid":false,"given":"Stefania","family":"Corti","sequence":"additional","affiliation":[{"name":"Neurology Unit Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico  Milan Italy"},{"name":"Neuromuscular and Rare Diseases Unit Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico  Milan 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