Breaking the cycle: unraveling the diagnostic, pathophysiological and treatment challenges of refractory migraine

BackgroundRefractory migraine is a poorly described complication of migraine in which migraine has chronified and become resistant to standard treatments. The true prevalence is unknown, but medication resistance is common in headache clinic patient populations. Given the lack of response to treatment, this patient population is extremely difficult to treat with limited guidance in the literature.ObjectiveTo review the diagnostic, pathophysiological, and management challenges in the refractory migraine population.DiscussionThere are no accepted, or even ICHD-3 appendix, diagnostic criteria for refractory migraine though several proposed criteria exist. Current proposed criteria often have low bars for refractoriness while also not meeting the needs of pediatrics, lower socioeconomic status, and developing nations. Pathophysiology is unknown but can be hypothesized as a persistent “on” state as a progression from chronic migraine with increasing central sensitization, but there may be heterogeneity in the underlying pathophysiology. No guidelines exist for treatment of refractory migraine; once all guideline-based treatments are tried, treatment consists of n-of-1 treatment trials paired with non-pharmacologic management.ConclusionRefractory migraine is poorly described diagnostically, its pathophysiology can only be guessed at by extension of chronic migraine, and treatment is more the art than science of medicine. Navigating care of this refractory population will require multidisciplinary care models and an emphasis on future research to answer these unknowns

Schizophrenia is a later-onset feature of PCDH19 Girls Clustering Epilepsy

Objective To investigate the occurrence of psychosis and serious behavioral problems in females with protocadherin 19 gene (PCDH19) pathogenic variants. Methods We evaluated whether psychosis and serious behavioral problems had occurred in 60 females (age 2-75 years) with PCDH19 pathogenic variants belonging to 35 families. Patients were identified from epilepsy genetics databases in Australia, New Zealand, the United States, and Canada. Neurologic and psychiatric disorders were diagnosed using standard methods. Results Eight of 60 females (13%) from 7 families developed a psychotic disorder: schizophrenia (6), schizoaffective disorder (1), or an unspecified psychotic disorder (1). Median age at onset of psychotic symptoms was 21 years (range 11-28 years). In our cohort of 39 females aged 11 years or older, 8 (21%) developed a psychotic disorder. Seven had ongoing seizures at onset of psychosis, with 2 continuing to have seizures when psychosis recurred. Psychotic disorders occurred in the setting of mild (4), moderate (2), or severe (1) intellectual disability, or normal intellect (1). Preexisting behavioral problems occurred in 4 patients, and autism spectrum disorder in 3. Two additional females (3%) had psychotic features with other conditions: an adolescent had recurrent episodes of postictal psychosis, and a 75-year-old woman had major depression with psychotic features. A further 3 adolescents (5%) with moderate to severe intellectual disability had onset of severe behavioral disturbance, or significant worsening.