Headache in mitochondrial diseases: From migraine to stroke‐like episodes

Objective: 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. Background: Among the most frequent and disabling symptoms affecting patients with PMDs, headache occurs in approximately 55–71% of individuals. Those with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and related phenotypes are particularly affected. Compared to the general population, migraine prevalence in patients with PMD is up to three- to four-fold higher. Methods: 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 “mitochondrial disease,” “migraine,” “headache,” “MELAS,” and “stroke-like episodes,” with no date restrictions. Relevant references from identified articles were also reviewed. Results: In PMDs, migraine with or without aura is the most common type of headache disorder, especially among carriers of the m.3243A>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-occurring neurological and systemic manifestations, temporal relationship with stroke-like episodes, and variable response to conventional therapy. The use of mitochondrial cofactors such as riboflavin, coenzyme Q10, and L-arginine as adjuncts to standard preventive strategies has been supported by only limited evidence. Conclusions: Specialized diagnostic and therapeutic approaches are required for headache management in PMDs, combining mitochondrial-targeted interventions with evidence-based 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.