Introduction
Coronavirus disease-19 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) that first emerged in Wuhan by the end of 2019 [
1].
Patients with SARS-CoV-2 infection can experience a wide range of clinical manifestations, from no symptoms to critical illness. Approximately 33% of people with SARS-CoV-2 infection never develop symptoms [
2]. The most common clinical symptoms of COVID-19 infection involve fever, cough, myalgia, and fatigue [
3].
However, various neurologic manifestations such as headache, dizziness, anosmia, impaired consciousness, and acute cerebrovascular disease have been also reported [
4]. Although Headache was included by the Centre for Disease Control and Prevention [
5] as one of the main symptoms of COVID-19, a better definition of COVID-19 related headache and its characteristics are lacking and no definite data on its evolution are available at present.
Headache attributed to systemic viral infection is included in the International Classification of Headache Disorders third edition (ICHD-3) [
6] and, although commonly reported [
7], specific data are lacking.
It is estimated that with the COVID-19 pandemic there has been a five-fold increase in the incidence of headache in the affected regions [
8]. The prevalence of headache was calculated at 10.9% (8.6–13.5%) in a meta-analysis of 6486 patients included in 21 studies, in which the prevalence ranged from 3.5–34% [
9]. In most studies, the prevalence of headache in patients with COVID-19 is around 12% [
10]. Little information is known about the characteristics of these headaches.
During the pandemic, we noticed frequent clinical visits to our headache clinic with complaints of worsening of previous headache or new onset Headache following COVID-19.
This study aimed to investigate the frequencies, features, and course of pre-existing primary headaches (migraine and tension type headache) as well as the characteristics of the de-novo headache in participants with RT-PCR-confirmed COVID-19.
Discussion
COVID-19 is a systemic inflammation affecting all age groups, with high mortality rate and severe adverse outcomes. It involves nervous system, blood vessels, lung, heart, liver, gastrointestinal system, kidney, eyes, and other organs [
14].
The present study showed that COVID-19 has a significant negative impact on patients with pre-existing primary headache disorder either migraine or tension type headache. De novo primary headache is frequent post COVID-19. Occurrence of headache during the symptomatic phase of COVID-19 can be consider as headache attributed to systemic viral infection [
6].
The de novo headache post COVID-19 has migraineurs features like i.e., throbbing in nature with associated symptoms like photophobia and phonophobia. Migraine features of de novo headache post COVID-19 could be hypothesised that there is a meningeal peripheral senstisation and an activation of the trigemino- vascular system underlying this headache type [
15].
Within 3 months after the COVID-19, significant number of patients in this cohort with primary headache had worsening of their headache in form of increased headache attack severity and/ or frequency with subsequent increased analgesics use. Stress during COVID-19 could be a trigger of migraine attacks and may have a role in this worsening. In the other hand worsening of primary headaches could be explained by viral diseases [
16].
Long COVID was defined in previous study as the set of symptoms that accompanies the patient even for months after recovery from COVID-19. These symptoms include persistent headache, y fatigue, moderate breathlessness, foggy head, and psychiatric disorders [
17]. In our cohort, headache resolved in most of patients within 1 month after COVID-19 and in resolved in the others after 3 months. Persistent headache for at least 6 months, both as a new onset or worsening/ chronicization of a pre-existing migraine should not be underestimated [
18].
Post-COVID-19, while the increase in migraine attack severity was noticed more among females and those who had more severe headache attack before COVID-19, the increase in headache attack frequency and analgesic use were more among patients with migraine who had more frequent migraine attacks before infection. For the patients with tension type headache, while the younger patients had significantly increased attack severity, the female patients had significantly increase in analgesics use post-infection. Our results are consistent with those of Magdy et al. [
19] who found that patients with pre-existing primary headache disorder had significantly more frequent headache attacks post- COVID-19 infection. On the other hand, in the study by Uygun et al. [
20] about headache characteristics in COVID-19 pandemic, which included a total of 3458 participants and 262 participants had confirmed COVID-19 diagnosis, the majority of patients did not report a worsening of previous primary headaches. The better outcomes in Uygun et al. cohort could be explained by avoiding stressful social interactions, consumption of a healthy diet, practicing mild sports activities and reducing the stress of daily work life during the pandemic among his study population.
Previous Studies found that pre-existing primary headache disorders are usually associated with atypical pain process [
21] due to atypical release of pro-inflammatory cytokines and chemokines [
22], such changes lead to sensitization of central and peripheral nociceptive pathways with a subsequent reduction in pain threshold [
23]. That might explain the increased intensity of headache in those with primary headache disorders in our study population.
It is important to keep in mind that as the COVID-19 pandemic rapidly sweeps across the world, it is inducing a considerable degree of negative economic and psychosocial consequences that may contribute to poor mental health. COVID-19 related headache was a commonly reported symptom in many studies, but there was a great diversity in its frequency, severity, character, and duration [
24]. The prevalence of headache was ranged from 3.5–34% in previous studies [
9]. We reported here a de novo post-COVID-19 headache in 26.4% of patients; their headache started during the active phase of SARS-COV2 Infection. Headache resolved in 56.3% within 1 month while 28.1% have headache for more than 3 months. The headache characters were of migraine phenotype Analgesics use for three or more days was noted among 72.2% of the patients. Longer attack duration was noted among younger patients ≤40 years, while the higher attack severity was noted among males and the those who had more severe COVID-19. Our results are similar to that of Bolay et al. [
10] who found that approximately 6%–10% of symptomatic COVID-19 patients reported new-onset, moderate-severe, bilateral headache with pulsating or pressing quality in the temporo-parietal, forehead, or periorbital, of sudden to gradual onset, poorly responsive to common analgesics, with high relapse rate, that was limited to the active phase of the COVID-19. The headache was worse among males compared to females in our cohort. This result is in agreement with Uygun et al. study [
20].
Headache can be the prodromal symptom of COVID-19 which could be predictive of a shorter COVID-19 clinical course [
25]. On the other hand, disabling headache can persist after COVID-19 resolution. Late-onset headache ascribed to high cytokine levels.
In a follow-up study by Caronna et al. 37.8% (28/74) had ongoing headache after 6 weeks, of those, 50% (14/28) had de novo post-COVID-19 headache [
25]. Headache was the prodromal symptom of COVID-19 in 21.9% (7/32) of patients. A total of 62.5% of patients (30/32) had daily constant and poorly responsive to headache treatment. The recent study by Magdy et al. [
14] has found that most of the patients had headache onset during COVID-19 (57%) with diffuse headache (52.9%), pressing character (40.7%) with a median intensity of 7, a median duration of 6 h, and median frequency of 7 days/week [
19]. In another study by Caronna et al., of 130 patients, 74.6% (97/130) had headache with COVID-19 infection [
25].
The neurological symptoms post-COVID-19 may be explained by different pathophysiological bases as direct neuro-invasion with a damage on the neuronal pathway, indirect effects mediated by hypoxia, hypertension, coagulopathy and cytokine storm on the CNS, up to the worsening of pre-existing brain diseases or new disorder [
26]. Previous reports showed that COVID-19 has neuroinvasive potential via various pathways [
27]. The angiotensin-converting enzyme 2 (ACE-2) receptor, through which COVID-19 appears to cause infection, is primarily present in epithelium of the lungs; however it is also found in the brain, particularly the brainstem [
28]. It has been hypothesized that SARS-CoV-2 can invade peripheral trigeminal nerve terminals and enter the central nervous system via transsynaptic pathways [
27,
29] and/ or invade meningeal endothelial cells, which are characterized by high angiotensin-converting enzyme 2 receptor expression [
30]. Another mechanism of COVID-19 viral entry into the brain may be through the olfactory bulb via trans-synaptic route [
28].
In addition, headaches attributed to systemic infection might be caused by the production of pro-inflammatory and nociceptive mediators such as interlukin -1beta, interliukin-6, tumour necrosis factor-alpha, nitric oxide and prostaglandins [
31]. Activation of the trigeminovascular system by inflammation or direct involvement of SARS-CoV-2 could explain the migraine like nature of COVID-19 related headache.
Considering these facts, when seeing patients presenting with these characters of headache, physicians should consider SARS-CoV-2 infection as a differential diagnosis to avoid delayed diagnosis or misdiagnosis and prevention of transmission. Physicians should pay more attention to neurological symptoms of COVID-19 in order to avoid chronicization.
Physicians should consider headache during the course of COVID-19 as a possible prognostic factor for the severity of symptoms and for the possible development or worsening of neurological symptomsor headache as sequelae of COVID-19. Headache should be taken into consideration as a possible chronic sequela of the COVID-19, despite it does not be proved as a prognostic factor of COVID-19 severity [
26]. Headache also could be considered a prognostic factor for COVID-19 positive evolution and its severity [
32]. A recent concept is raised that the international scientific community should use headache as prognostic factor of COVID-19 duration or severity in a COVID-19 clinical setting. Such concept is expressed in two studies, Caronna and Magdy [
19,
25].
Conclusion
The COVID-19 pandemic has a characteristic effect on the course of headaches in individuals with and without pre-existing primary headache disorders. We concluded that post-COVID-19 headaches are significantly more intense and frequent with the migraine-type being the most common. For an accurate diagnosis and disease spread prevention.
Worsening of COVID-19 related headache was higher in patients with primary headache group disorders. Meanwhile, high pain intensity was associated with male gender, younger age and moderate COVID-19 infection. Headache post COVID-19 improved within 3 months. We can reassure our patients that headache will get back to normal after few months post COVID-19.
Recommendation
Long-COVID headache is a new entity to be closely flooded in these patients. Further studies are needed for better better understanding impact of COVID-19 on headache in order to provide better care and optimal management plan for those patients. Larger studies evaluating the experience of COVID-19 in patients with a history of a primary headache disorder and to assess the time of improvement of their headache post COVID-19 infection.
Limitations of the study
The limitation of our study are short follow-up period and relatively small size of cohort. Despite we used headache diary, still there is recall biased.
Strength of the study
Our strength is that the headache-specialist neurologists were directly involved in data collection, which made detailed headache history and characteristics more reliable. To our knowledge, we report the first experience with COVID-19 related headache in Arabian Gulf. This study represents comprehensive description of COVID-19 related headache.
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