It is essential to study and quantify the burden of the post-COVID-19 symptoms in migraine patients to shape specific recommendations for such population upon recovery from infection. To our knowledge, this is the first study that investigated a broad range of post-COVID-19 symptoms in patients with a confirmed diagnosis of migraine. Among these symptoms, it was found that fatigue, anxiety, depression, insomnia, headache, and olfactory impairment were affected more in migraine patients than those without migraine. However, no difference in limitations of daily living activities was found between the two groups.
First, in order to prove or refute our hypothesis that migraine patients are more likely to have post-COVID-19 problems than others, several factors known to increase the risk of post-COVID-19 symptoms have been considered. In this study, the migraine and control groups were matched for age, gender, COVID-19 symptoms, infection severity, and vaccination status prior to infection, all of which have been shown to increase the risk of post-COVID-19 symptoms in previous reports [24, 25]. However, the matching could not be achieved regards headache during acute infection. In agreement with previous studies, migraine patients exhibited headache during the acute phase more frequently than those without headaches.
In the context of the current findings, as some post‐COVID-19 symptoms were more prevalent among migraine patients than those without migraine, we propose that shared neurobiological mechanisms are likely involved in the link between migraine and post-COVID-19.
Post-COVID-19 olfactory alterations are primarily attributed to neuroinflammation of the olfactory bulb being more robust in predisposed subjects . Migraine patients already have a higher baseline rate of olfactory bulb atrophy than healthy individuals in the same age range ; this may make migraine patients more susceptible to olfactory impairment as COVID-19 sequelae.
It is broadly accepted that a prolonged state of low-grade neuroinflammation mediated by elevated IL-1Beta and IL-6, along with central mechanisms represented by hypothalamic involvement and altered serotoninergic level, would eventually lead to post-COVID-19 fatigue [28,29,30]. Intriguingly, all these factors were previously described in migraine patients relative to healthy controls [7, 31], rendering them susceptible to chronic fatigue syndrome .
Of particular recent interest in pathogenic mechanisms of neuropsychiatric sequelae of COVID-19 infection is the role of biogenic amines. It has been demonstrated that cytokine storm induced by COVID-19 infection potentially may contribute to suppressed serotonin levels , a well-established biological basis of depression and anxiety . Given that low cerebral serotonin level during headache-free periods is a common feature in migraine patients , a high frequency of post-COVID-19 mood disorders in this population may seem expected.
In the same way, melatonin levels -a product of serotonin- were also altered in patients with COVID-19 infection [33, 36] as well as migraine patients , explaining the high vulnerability for sleep disturbance when the two conditions coincide.
The post-COVID-19 headache includes a multifaceted spectrum of presentations, best described by Membrilla et al.  and Caronna et al. , including worsening of a pre-existing migraine, persistent headache after COVID-19 infection, and late-onset new persistent headache without a prior history of a primary headache disorder. Yet, these distinct patterns have not been obeyed by studies estimating the prevalence of headaches after COVID-19. Yet, the rate conveyed by our study (12% of the whole study population) fell within the range reported by these studies (10.6- 19.0%) assessed at the same post-COVID-19 period [11, 39, 40].
Hyperexcitability of the trigeminovascular system mediated by a sustained pro-inflammatory response during the acute infection may lead to central sensitization of second-order neurons, promoting the development of persistent headache after COVID-19 infection . Further scientific efforts also consider an immune-mediated mechanism in the pathophysiology of post-COVID headaches based on a structural mimicry of the spike protein of SARS-CoV-2 with the CGRP receptor .
These justifications, combined with the pandemic's negative impact and fear of an unusually serious and potentially fatal illness, may also explain the higher frequency of depression, anxiety, insomnia, and headache exacerbation as post-COVID-19 symptoms in migraine patients [42, 43].
Another point worth discussing is that the prevalence of some neuropsychiatric symptoms in our study exceeded the range previously reported by epidemiological studies conducted before the pandemic among patients with episodic migraine. Chronic fatigue was previously estimated as (5.2%) , depression (5.2–17.2%) [44,45,46], and anxiety (13.4–18.8%) [44,45,46]. Such a notable increase in post-COVID-19 fatigue, depression, and anxiety warrants strenuous efforts to track these symptoms after recovery and to employ prudently directed rehabilitation programmes. On the other hand, the prevalence of other post-COVID-19 symptoms reported in our study fell within the previously reported range, such as insomnia (16–25.9%) [47, 48], pains (15.1–22.2%) [45, 49], and vestibular symptoms (12.2–17.8%) [49, 50].
In light of the previous findings, long-term rehabilitation policies should be employed to deliver appropriate care to migraine patients upon recovery from COVID-19 infection. Furthermore, the importance of the COVID-19 vaccine should be emphasized for individuals with migraine who appear to be vulnerable to the long-term consequences of COVID-19 infection.
The present study had some limitations that limited the generalizability of its results. Because this study targeted people who contracted COVID-19 during a single wave, the third wave, these findings are mainly limited to a specific viral variant that caused this wave. Also, most participants had a mild COVID-19 infection (n = 342, 83%8). Since the severity of COVID-19 infection strongly predicts post-COVID-19 symptoms, the current results can not be generalized. Furthermore, post-COVID-19 migraine chronification was based primarily on patients' self-report. Headache diaries might provide a more objective evaluation when headache characteristics of a pre-existing migraine were compared to those of the new headache pattern. Another limitation in this study was the marginal match between migraine patients and controls in age. Finally, adding another group of migraine patients not infected with COVID-19 to be compared to those who had contracted the virus might completely nullify the negative impact of the COVID-19 pandemic on migraine.