Cluster headache and migraine are strongly associated with the circadian system and have significant genetic components, according to the results of a systematic review and meta-analysis published in Neurology.
The timing of cluster headache and migraine attacks appear to follow a 24-hour pattern, which suggests a circadian component in these disorders. Understanding the role of the circadian system in cluster pain attacks may expand understanding and allow for additional preventative or treatment approaches to be elucidated.
Researchers from UT Health Houston in the United States searched publication databases through April 2021 for studies about the timing of cluster headache and migraine attacks. In addition, recent genetic data about susceptibility to cluster headache and migraine attacks were evaluated through April 2022.
The review and meta-analysis included 72 studies and the genetic analysis, 16.
In cluster headache, a circadian pattern was observed in 70.5% of attacks. In 3 studies, cluster headache was reported to occur between 21:00-03:00. In addition, 5 studies reported that headache peaked in the Spring and Autumn.
Data from 8 studies indicated that patients with cluster headache had higher corticosteroid blood levels and lower nocturnal urinary melatonin levels compared with control individuals.
The genetic analysis found that period circadian regulator 3 (PERIOD3) and 1 single nucleotide polymorphism (SNP) in clock circadian regulator (CLOCK) were associated with cluster headache. Cycling of UFM1-specific ligase 1 (UFL1) expression in 15 of 64 brain tissues and MER proto-oncogene, tyrosine kinase (MERTK) expression in 6 brain tissues associated with cluster headache. The brain areas with most cluster headache clock controlled genes (CCGs) were the paraventricular nucleus of the hypothalamus and the aorta.
In cluster migraine, 50.1% of attacks had a circadian pattern. In 4 studies, a lower rate of migraine was reported between 23:00-07:00. In 4 studies, cluster migraine was observed to peak in April to October.
Data from 14 studies indicated that patients with migraine had lower cerebrospinal fluid cortisol, higher morning salivary cortisol, and lower nocturnal urinary melatonin levels compared with control individuals. Although, some conflicting findings in corticosteroid and melatonin patterns were reported.
There was some evidence of positive relationships between migraine and 2 alleles of the casein kinase 1 delta (CK1d) gene, 1 SNP in RAR-related orphan receptor A (RORa), and 1 SNP in CLOCK. Cycling of UFL1 was observed in 6 brain areas and LDL receptor-related protein 1 (LRP1), mediator complex subunit 14 (MED14), SMG6 nonsense-mediated mRNA decay factor (SMG6), and SURP and G-patch domain containing 1 (SUGP1) were observed to have relevant cycling patterns in 5 brain regions. The areas with most CCGs were thyroid, prefrontal cortex, and stomach fundus.
The major limitation of this review was that the definition of circadian pattern was not clear in most studies.
This review found evidence that cluster headache and migraine have circadian components, although with differing trends. The researchers concluded, “These data suggest that both headache disorders are highly circadian at multiple levels, especially cluster headache. The inherent circadian nature of these disorders reinforces the importance of the hypothalamus (where the SCN [suprachiasmatic nucleus] is located) and its role in both cluster headache and migraine. The inherent circadian nature also raises the question about the genetics of triggers.”
Disclosures: One study author declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
Benkli B, Kim SY, Koike N, et al. Circadian features of cluster headache and migraine: a systematic review, meta-analysis, and genetic analysis. Neurology. Published online March 29, 2023. doi:10.1212/WNL.0000000000207240