Mitochondrial migraine: A multicenter study based on mitochondrial diseases presenting as encephalopathy and/or myopathy.

Abstract

Objective: This study aimed to investigate the clinical features of migraine in a cohort of patients with mitochondrial disease (MD) presenting as encephalopathy and/or myopathy, and to explore the potential association between migraine and mitochondrial dysfunction.

Background: MDs comprise a heterogeneous group of disorders characterized by impaired mitochondrial oxidative phosphorylation. The high frequency of migraine among patients with MD presenting as encephalopathy and/or myopathy suggests a potential connection between migraine pathogenesis and mitochondrial dysfunction.

Methods: In this multicenter cross-sectional real-world study, 48 genetically confirmed patients with MD presenting as encephalopathy and/or myopathy were included from seven medical centers in China between January 2020 and March 2023. A structured questionnaire was utilized to collect demographic data, comprehensive clinical information related to MD, and detailed headache information. The frequency, clinical characteristics, and potential factors associated with migraine were analyzed. Furthermore, the frequency and characteristics were compared with data from a population-based survey on primary headaches. According to ICHD-3, the concept of "acute headache preceding or associated with focal neurological deficits and/or seizures (AHF)" was introduced under ICHD-3 6.8.2 Headache attributed to mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). In patients with MELAS, the frequency and characteristics of migraine in AHF-positive patients were further evaluated and contrasted with those in AHF-negative patients.

Results: The 1-year frequency of migraine in this cohort was 48% (23/48) (95% confidence interval [CI]: 34%-62%), markedly higher than the 1-year prevalence in the general population (9%, 95% CI: 9%-10%). Epilepsy (adjusted odds ratio: 5.73, 95% CI: 1.11-43.67, p = 0.036) and elevated resting blood lactate concentration (adjusted odds ratio : 1.54, 95% CI: 1.05-2.43, p = 0.026) were independently associated with migraine. Additionally, ancillary tests performed in specific patient subgroups revealed a higher incidence of electroencephalography abnormalities in the migraine-positive group (p = 0.025). Among 29 patients with MELAS, 12 experienced AHF and all were diagnosed with migraine (12/12, 100%), exhibiting a notably high incidence of typical migraine aura (6/12, 50%). In contrast, five of the 17 AHF-negative patients were diagnosed with migraine (5/17, 29%), and only one of these patients had typical migraine aura (1/5, 20%). The mean Numerical Rating Scale score for migraine was higher in AHF-positive patients than in AHF-negative patients (7.3 ± 1.3 vs. 5.7 ± 1.5; t = 2.23, p = 0.042).

Conclusion: In patients with MD presenting as encephalopathy and/or myopathy, the 1-year frequency of migraine was more than five times higher than that in the general population. Epilepsy and elevated resting blood lactate concentration were identified as factors independently associated with migraine. In patients with MELAS, AHF positivity was associated with distinct and severe migraine phenotypes. Collectively, these findings offer clinical evidence supporting the potential link between migraine and mitochondrial dysfunction.