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

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.

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.

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.

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.

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.