Headache in 2021: clinical, biological, and genetic advances

In the past decade, the strenuous efforts of the scientific community have substantially advanced our understanding of primary headaches. This research has promoted the development of novel disease-specific treatments, such as monoclonal antibodies and small molecules targeting the calcitonin gene-related peptide (CGRP) pathway, and agonists of the 5-HT1F receptor. However, despite these major advances, primary headaches still constitute a challenge for clinicians and a major burden for patients and society. Among primary headaches, chronic migraine is the leading cause of disability and economic burden. Chronic migraine is defined by the recurrence of 15 or more headache days per month, with at least 8 days with a migraine phenotype, for at least 3 months. This definition assumes that the cutoff of 15 days adequately separates two different subtypes of migraine: episodic (less aggressive and burdensome) and chronic (more severe and disabling). Ishii and colleagues1 have now challenged the validity of the 15-day cutoff by showing that patients with 8–14 monthly headache days (ie, high-frequency episodic migraine) endure a similar loss of productivity, due to absenteeism, presenteeism, depression, and anxiety, as do patients with 15–23 monthly headache days. This observation is a clarion call to extend allocation of health-care and research resources to subtypes of migraine that have previously been thought of as less burdensome. In the International Classification of Headache Disorders (ICHD-3), primary headaches are framed according to their phenotypical manifestations, while almost no consideration is given to their neurobiological determinants. This apparently oversimplified approach has been validated within the Finnish Migraine Genome Project, where the main ICHD-3 categories were remarkably correlated with a polygenic risk score.2 The association with polygenic risk showed two striking features: first, it intensified across the proposed categories, being weaker in non-migraine headache and probable migraine, and becoming stronger in migraine without aura, migraine with aura, and hemiplegic migraine; and second, it was linked to specific migraine features—namely, the presence of nausea or vomiting, longer headache duration, and higher headache intensity. Altogether, these findings demonstrate a link between the ICHD-3 categories and biological mechanisms. They represent a steppingstone towards the development of a more individualised approach to the management of primary headaches based on two powerful tools: the ICHD-3 classification and polygenic risk score. Further advances in genetics were provided by a large cohort study (comprising 860 patients with hemiplegic migraine) that clarified the genotype–phenotype connection between autosomal dominant mutations in PRRT2 and hemiplegic migraine. PRRT2 mutations were present in 12 (7·4%) of 163 patients with hemiplegic migraine who previously tested negative for CACNA1A, ATP1A2, and SCN1A mutations, and in 18 (2·6%) of 697 patients who had not previously had genetic testing. PRRT2 mutations accounted for 18 (17%) of 103 pathogenic variants identified in this latter group. In 16 of 30 patients, hemiplegic migraine was the only clinical manifestation, but other phenotypes included epilepsy, cognitive impairment, sleep disturbances, and movement disorders.3 PRRT2 mutations lead to altered neuronal excitability, mainly through dysregulation of transmembrane calcium and sodium channels.4 Hemiplegic migraine is a rare migraine subtype, but unveiling the functional correlates of PRRT2 mutations might also shed light on novel pathways involved in less rare forms of migraine. In the context of migraine biomarkers, Alpuente and colleagues5 assessed CGRP concentration