COVID-19 infection and related-pandemic
Worsening of migraine throughout the pandemic has been shown previously. Al-Hashel et al have studied 1018 patients with migraine using an online survey and showed that more than half of them experienced an increase in migraine frequency and severity, in comparison to the pre-pandemic period (25). However, many studies included few patients diagnosed with COVID-19 (9). As a main finding of our study, almost half of migraineurs reported worsening headache pattern during the COVID-19 pandemic, irrespectively of COVID-19 diagnosis, and treatment intensification was needed in most. The majority reported worsening before the COVID-19 diagnosis. This suggests that other important triggers other than SARS-CoV-2 might have had a significant role in migraine symptoms exacerbation during the pandemic period. In fact, we found that patients who reported worsening headache pattern had significantly higher levels of anxiety and depression, as well as higher frequency of sleep pattern change, especially with chronic insomnia.
In contrast, a fifth of our cohort reported a reduction in headache intensity or frequency. One might speculate that reduction of work-related stress and/or healthier lifestyle routines adopted during the lockdown period may have contributed to this observation (26). Other studies have described similar improvements in migraine severity. A previous study reported a similar reduction in headache days per month since the beginning of the pandemic (16%) (27). Verhagen et al reported a decrease in daily use of acute treatment and improvement in well-being scores after the lockdown due to the COVID-19 outbreak in spite of unchanged number of headache days per month (10).
The rate of symptomatic headache was high among migraine patients, many with migraine-like features and persistent headache (27,28). As in our study, a case-control study demonstrated an association between worsening of migraine-related pain after infection and incidence of acute symptomatic headache related with COVID-19 (58.6% vs. 34.3%, p<0.001) (27). In our study, migraine patients with persistent symptomatic headache also tended to experience a worsening headache pattern. The fact that about half of our cohort had a disabling migraine (52.8% with baseline MIDAS score IV) may partly explain the high rate of persistent symptomatic rate we observed (27.8%).
In our study, a change in pain quality was noticeable in patients diagnosed with COVID-19. This finding is in line with those of Membrilla J. A. et al and Uygun O. et al (11,29). Although this change after infection has been described, the pathophysiology is still unclear. It has been speculated that the proinflammatory state induced by the release of large amounts of pro-inflammatory cytokines during the SARS-CoV-2 infection might alter the perception of pain (30,31).
Despite differences in migraine symptom’ severity, no differences were found regarding the average number of first-line preventive drugs tried and less than a quarter were given second-line preventive treatment. Moreover, around 1/4 patients were not effectively taking any first-line preventive drug during the pandemic. However, this does not reflect well-controlled migraine symptoms. In reality, many patients had had to discontinue more than one oral drug due to adverse effects before the therapeutical trial was deemed effective. Others were transitioning to a second-line treatment at the time of the survey and conclusions regarding treatment effectiveness could not be ascertained. Additionally, in our centre it is not uncommon for several oral drugs to be tried before escalating to a second-line treatment.
Half of the participants in our cohort revealed symptoms of abnormally elevated levels of anxiety and a third reported depressive symptoms; of note, more than half in those reporting a worsened headache pattern. While anxiety and depression might trigger more migraine attacks, more severe headaches might result in higher incidence of mood disorders in migraineurs (4). It has been previously shown that migraine patients are more likely to have experienced severe psychological distress during the COVID-19 outbreak compared to the general population (25). Importantly, these symptoms were well-balanced among patients diagnosed with COVID-19 and those who remained COVID-free.
Sleep dysfunction is more common in migraine patients than controls, insomnia being the main symptom (32). The evidence in the last decades suggests that several areas in the brainstem and diencephalon (mostly the ventrolateral periaqueductal gray matter and the posterior hypothalamus) processes integral to both headache and sleep interact. Also, physiologic data showed the involvement of adenosine, melatonin, and orexin in both sets of disorders, and a dysregulation of either REM sleep or underlying arousal mechanisms in many headache disorders (33). A high prevalence of sleep disorders was shown during COVID-19 quarantine and lockdown periods (possibly explained by fear of COVID-19, changes in sleep-wake habits, less lights off-time and delayed sleep onset time) (34). We showed a statistically significant higher frequency of chronic insomnia in patients with a worsened headache pattern. These patients also had a higher severity insomnia index during the pandemic. A significantly greater change in sleep pattern was identified in patients diagnosed with COVID-19, with a trend over higher incidence of middle insomnia. We found no significant differences in insomnia severity between the groups (COVID-19 vs non-COVID-19). Hence, COVID-19-related sleep dysfunction might be part of the causal pathway of the worsening headache pattern in migraine patients after the acute symptomatic phase and even further in time, as sleep dysfunction was shown to be a long persistent symptom in COVID-19 patients (34).
COVID-19 vaccination
Despite not being yet listed in the International Classification of Headache Disorders, headache after vaccination was one of the most frequently reported adverse events after vaccination against SARS-CoV-2. Previously reported incidences among vaccine types and doses ranged from 1.4% after Moderna’s vaccine administration to 52% after Pfizer’s and 57% after AstraZeneca’s, respectively (35). Increased headache duration and pain intensity, as well as increased need to intensify preventive treatment after COVID-19 vaccine administration has also been previously reported in patients with pre-existing primary headache disorders including migraine (36–38). Silvestro M. et al also showed that most patients perceived the headache attacks as “different” from those usually experienced, being characterized by higher pain intensity, longer duration, and reduced responsiveness to usually effective analgesic treatment (39). In our study, headache pattern change was predominantly reported shortly after a vaccine administration, although with much lower frequency than acute symptomatic headache related with COVID-19 or during the pandemic overall. Moreover, this pattern change was transient (within the first 3 weeks) in almost half of patients. The pathophysiological mechanisms of headache attributed to vaccination against COVID-19 remain unclear. A previously proposed mechanism highlights the possibility that intracellular synthetization of the S glycoprotein of SARS-CoV-2 (by transcription of the gene supplied by the vaccine) might trigger an immune response resulting in migraine exacerbation (40). Another explanation postulates that transient hyper-excitability of trigemino-vascular neurons results in increased pain sensitivity even in patients without an underlying primary headache (40). In patients with already sensitized trigemino-vascular neurons, this trigger might result in pain with further increased duration and intensity.
Our study intended to address whether COVID-19 diagnosis and vaccines administration were significant triggers for migraine symptoms worsening during the pandemic. Major strengths of our study are the high number of included patients diagnosed with SARS-CoV-2-proven infection and description of mood disorder symptoms and insomnia using validated self-reported scales. Furthermore, our study included patients form a well-characterized cohort of migraineurs according to diagnosis subtype and symptom severity.
This study has, however, several limitations. Firstly, patients recruited from the outpatient clinic are likely to have more severe migraine symptoms. This undermines the extrapolation of results to all migraine patients. One additional challenge is the wide temporal window of symptom fluctuations throughout three years of pandemic. Indeed, establishing a temporal relationship between changes in pain pattern and quality with changes in sleep pattern, anxiety, and depressive symptoms is difficult to ascertain. Pre-lockdown period data is lacking, thus further complicating comparisons and recall bias might have influenced our findings. Finally, negative information processing during the lockdown period might have negatively influenced self-perceived worsening.