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 concentrations in saliva over 30 days in 49 patients with episodic migraine, thus capturing changes during the different phases of attacks. Patients had higher CGRP concentrations interictally than did healthy controls. CGRP concentrations further increased slightly in the pre-ictal phase, increased more markedly during a genuine migraine attack, and then reverted to baseline values after the attack resolved. Even more interestingly, a subset of patients with episodic migraine did not have increased saliva CGRP concentrations, suggesting the existence of a non-CGRP-dependent migraine phenotype. Meanwhile, Al-Karagholi and colleagues6 showed, in patients with migraine, that the activation of a downstream cellular pathway, based on ATP-sensitive potassium channel opening, was able to induce a migraine attack in 14 (82%) of 17 patients. Of note, aura symptoms fulfilling ICHD-3 criteria were present in up to 60% (10 of 17) of patients who had migraine with aura, possibly providing the first model for the study of the aura phase in humans under well-controlled conditions. Cluster headache is a highly disabling and relatively rare primary headache, characterised by attacks of unilateral and excruciating pain associated with ipsilateral cranial autonomic symptoms and restlessness. Typically manifesting with active periods during which recurring attacks devastate patients’ quality of life, cluster headache is an enigmatic disorder whose pathophysiology is highly elusive. Occurrence in families suggests a genetic predisposition, but previous studies have not shown any such association. In 2021, two genome-wide association studies identified seven loci associated with cluster headaches.7, 8 Two pivotal observations strongly suggest that these loci might be risk loci for cluster headache: four loci were individually identified by both study groups in the two different cohorts; and five loci were not previously described in other primary headache disorders. Although not conclusive, these studies are a starting point for better understanding the genetic profile of cluster headache as well as the mechanisms of the disease. Notwithstanding relentless scientific advances, further research is still needed as too few people with primary headaches receive adequate care,9 and treatment resistance and refractoriness remain untackled issues.10 The findings summarised here show the importance of identifying solid clinical, biological, and genetic biomarkers for primary headaches—a crucial step for recognition of these diseases and for improving their management globally. RDI has received speaker honoraria for oral presentations from Eli-Lilly. CT has received fees for advisory boards or scientific lecturing from Allergan/AbbVie, Eli Lilly, Lundbeck, Novartis, and TEVA; and institutional payments for clinical trials from Allergan/AbbVie, Eli Lilly, Novartis Lundbeck, and TEVA.
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