82 Chapter 4 technique by solely using a RNA strand coding for the antigenic sequence of the spike protein (S-protein), modified to increase mRNA translation in vivo.15 After mRNA translation, this newly synthesized S-proteins are presented on the surface of the APCs, activating the immune system cascade mentioned above. The mRNA vaccines thus bypass the need for viral DNA to be integrated into the nucleus, and instead directly provide the instructions for the body to produce the S-protein fragment of the SARS-CoV-2 virus. Various side effects of the COVID-19 vaccines have been reported, among which injection site pain, swelling, fever and headache.16 Headache is the most common neurological symptom reported, with an incidence of headache in the days after vaccination of >50% with rates varying between vaccine types and reports.9, 13, 17 Headache incidence after vaccination with Pfizer/BioNTech was significantly higher in patients with a migraine diagnosis compared to a healthy control group (69.2% and 37.9%, respectively, p = 0.012).18 Other studies reported a higher pain intensity and duration of the post-vaccine headache in patients with a history of migraine for both Pfizer/BioNTech and AstraZeneca.19, 20 Finally, a questionnaire study found migraine attacks to have a higher pain intensity, longer duration and reduced responsiveness to usually effective migraine attack medication after vaccination.21 Important to note is that these studies should be interpreted with care due to their small retrospective nature and therefore a liability to recall bias. Migraine attacks are considered to be the result of natural fluctuations in neuronal excitability and trigger factors.22 Inflammatory mediators, such as peptides (predominantly calcitonin gene-related peptide (CGRP), substance P and neurokinin A), cytokines, metabolites (prostaglandins), nitric oxide and other molecules involved in the inflammatory response, have been implicated in the pathophysiology of migraine. These mediators are thought to play a role in the sensitization of trigeminal neurons, leading to the development of the migraine headache.23, 24 However, the relationship between inflammatory mediators and migraine is complex and still not fully understood. While the general population may experience an increase in other non-migrainous headache days post-vaccination, patients with migraine may have a higher impact, possibly leading to an increase in migraine or other headache days.18 The objective of this study was to determine whether COVID-19 vaccination or infection affects the number of monthly migraine days in individuals with migraine by merging E-headache diary information with the dates of infection and vaccination, which can be easily obtained through our national registration system.
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