Possible mechanisms for the occurrence of headache in COVID-19 include direct viral injury, the inflammatory process, hypoxemia, coagulopathy, and endothelial involvement. None of these mechanisms fully explain the occurrence of the headache. In this section, evidence on possible mechanisms will be discussed.
Direct Viral Injury, Vascular Injury, and Local Inflammatory Process
There is an association between headache and anosmia and ageusia. These symptoms most often occur in clusters, usually early in the symptomatic phase of COVID-19.[6,15] Those with anosmia/ageusia are more likely to present with headache.[6,12,14,15,41] It is possible that these symptoms partly share the same pathophysiological mechanisms.
A case series that assessed patients with persistent headache and anosmia with MRI reported microbleeds in the olfactory bulb. This study suggested that these changes were a consequence of direct viral injury or vascular injury.
Those with symptoms of rhinosinusitis are more likely to present with headache. Thus, the local inflammatory process may also be an important factor for the occurrence of headache.
In principle, both damage to the olfactory pathway and inflammation of the nasal cavity are capable of activating the trigeminal system and causing headache. However, not everyone who has anosmia has headache, and not everyone who has headache has anosmia.[6,12,14,15,41] Likewise, not everyone who has rhinosinusitis has headaches and vice versa. Thus, neither injury to the olfactory pathway nor local inflammation completely explains the genesis of headache.
Hypoxemia and Dehydration
A study that compared hospitalized individuals with and without headache reported that those with headache presented with a greater need for high oxygen flow, showing that hypoxia may be involved in the occurrence of the headache. Another study reported that the presence of dehydration was also associated with headache.
We recently observed that headache occurs in clusters with flu-like symptoms such as chills, fever, sore throat, fatigue, and myalgia. Others have reported that 46% to 62% of individuals who had previously presented headache associated with systemic viral infection had assessed the COVID-19 acute-phase headache as being similar to that headache.[12,16] The systemic inflammatory response to infection is considered important for the occurrence of headache associated with systemic viral infection.[28,40]
Bolay et al. compared patients with severe headache to those without headache among those who had been hospitalized with moderate COVID-19. Those with headache presented statistically significantly higher levels of pro-inflammatory serum high mobility group box-1, nod-like receptor pyrin domain-containing 3 and interleukin (IL) 6, and angiotensin-converting enzyme 2. There was no difference in serum IL-10 and calcitonin gene-related peptide levels in the two groups.
There is controversy about the role of interleukins in the occurrence of headache. The mean level of IL-6 was higher in the 13 patients with headache than in the 15 patients without headache in a Turkish study. However, a Spanish study that compared 36 patients with headache and 24 patients without headache found the opposite result; IL-6 levels remained more stable over time in the headache group.
Karadaş et al. assessed 287 patients with moderate COVID-19 disease, 83 of whom presented with headache. There was no difference in the level of serum IL-6 between those with or without headache. However, there was a positive correlation between the levels of this interleukin and the intensity of headache.
Trigo et al. compared 45 serum interleukins and cytokines between 29 patients with headache and 75 without who were hospitalized for COVID-19. The amount of only IL-10, which is anti-inflammatory, was higher in those with headache. Levels of IL-23 (p = 0.08) and the placental growth factor (p = 0.07), which are pro-inflammatory, were higher in those with headache but were not statistically significant. There was no difference for IL-6. The authors hypothesized that those with headache would have had a greater inflammatory response, and that a greater level of IL-10 would be caused by a better homeostatic response.
One of the difficulties in interpreting these studies is the lack of standardization for collecting samples of the levels of these substances.
Headache. 2022;62(6):650-656. © 2022 Blackwell Publishing