89 Effect of COVID vaccination on monthly migraine days 4 DISCUSSION Our longitudinal cohort study examined the relationship between COVID-19 vaccination or infection and the frequency of migraine. We observed a rise in the number of MMD, MHD and MAMD during the first month after vaccination compared to the preceding month. Interestingly, there was a decrease in MMD during the second month after vaccination, indicating that the effect is temporary. These findings may suggest that the vaccine may decrease the threshold for migraine attacks, possibly because of an increase in circulating inflammatory mediators. Inflammation plays a crucial role in migraine pathophysiology, as indicated by the increased prevalence of chronic inflammatory diseases such as multiple sclerosis and inflammatory bowel disease in patients with migraine.26 During a migraine attack, plasma levels of inflammatory cytokines such as IL-6, IL-10 and TNF-α are increased.26, 27 The release of neuropeptides, such as CGRP, pituitary adenylate cyclase-activating polypeptide, substance P and neurokinin-A, along with neurogenic inflammation, are also implicated in migraine pathophysiology.24, 28, 29 Activation of trigeminal nociceptors by inflammatory cytokines can lead to the release of these peptides, initiating a sterile meningeal inflammatory reaction.30 This eventually leads to the release of nitric oxide, activation of glial cells and mast cell degranulation, resulting in sustained activation and sensitization of meningeal nociceptors, possibly contributing to migraine headache.31 Apart from inflammation, inflammatory cytokines have also been implicated in modulation of the pain threshold and activation of trigeminal nociceptors.24 Therefore, it is hypothesized that COVID-19 vaccination may initiate the release of inflammatory mediators, which in turn may trigger migraine headaches.32 Our study has some limitations. First, the infection analysis was limited by a smaller sample size with less diary days and a low incidence of reported COVID-19 infections among our cohort of subjects with migraine. To ensure reliability of the results, we applied an E-diary compliance criterion of ≥80% per month, which further reduced our sample size. Despite this inherent limitation, the high compliance rate enabled us to precisely capture changes in migraine frequency and medication usage around the time of COVID-19 infection. However, this may explain why we found a significant increase in MAMD but not in MMD and MHD, because we had less statistical power compared to the vaccination data. Although the exact day and method of diagnosis of the infection may have differed between participants, leading to less accurate estimation exact infection date compared to the vaccination date, this potential limitation is mitigated by the fact that we analyzed the data on a monthly scale. By contrast, a strength of the vaccination analysis was that our participants could easily
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