Persistent Headache After COVID-19: Pathophysioloy, Clinic And ...

SARS-CoV-2 is a novel coronavirus that appeared in China in late 2019, and causes the disease COVID-19. COVID-19 is characterised by respiratory symptoms, including respiratory insufficiency requiring invasive ventilatory support. However, since the beginning of the pandemic in early 2020, other symptoms have been described during the acute stage of infection; these include neurological, gastrointestinal, kidney, and haematological manifestations, among others.1 Among neurological symptoms, headache is a common complaint.2–5

Since early in the pandemic, persistent symptoms and/or late-onset complications have been reported in some patients after the acute stage of COVID-19. The most frequent symptoms are headache, cognitive alterations, insomnia, fatigue, and dizziness6,7; this phenomenon has been referred to as “post-COVID syndrome.” Although we currently lack epidemiological data on post-COVID syndrome, its high prevalence and the significant degree of disability it seems to be able to cause suggest that it may become a global healthcare issue in the immediate future. Among the associated symptoms, persistent headache is becoming an increasingly common reason for consultation at headache units. The objective of this study is to review the pathophysiology and clinical manifestations of persistent headache after SARS-CoV-2 infection and to provide recommendations on the management of these patients.

Several hypotheses have been proposed on the pathophysiology of headache in the context of acute COVID-19. Some of these mechanisms, both non-specific and specific to SARS-CoV-2, may be involved in the persistence of headache after resolution of the acute stage of the disease. However, due to the current lack of conclusive data, many of these hypotheses remain controversial.

Non-specific mechanisms include systemic inflammation, which during acute COVID-19 can be so severe that it has been described as a “cytokine storm.”8 It has been suggested that, during the acute stage, headache may be caused by circulating inflammatory mediators activating the trigeminovascular system at the meninges. We cannot rule out the possibility that this inflammatory response may be sustained after infection in some patients, which may play a role in the persistence of such post-COVID symptoms as headache. A recent study reported higher levels of proinflammatory cytokines between 3 and 9 months after hospital discharge in patients presenting persistent symptoms after COVID-19 than in healthy controls.9 These findings have not been confirmed by other authors.10,11 Another possibility is that more severe inflammation during the acute stage may cause persistent activation of the trigeminovascular system. However, this hypothesis would not explain the fact that post-COVID headache frequently appears in patients who presented milder disease in the acute stage. Therefore, the role of systemic inflammation in post-COVID headache remains controversial; clarifying this aspect of the pathophysiology of post-COVID syndrome is particularly relevant as inflammation reflects the activation of specific immune mechanisms. In this context, some authors have suggested that the persistence of symptoms after the acute stage may be related to constant immune activation.12 We cannot rule out the hypothesis that this phenomenon may be promoted by the persistent presence of SARS-CoV-2 antigens in some tissues, despite no longer being detectable in nasopharyngeal exudate.13 Other authors suggest that autoimmune mechanisms targeting host epitopes are generated during acute infection.14 However, we currently have insufficient information on the relationship between immunity and these symptoms, including headache.

We must also consider the role of local inflammatory mechanisms in post-COVID headache. Specifically, a degree of localised inflammation in the nervous system may persist as a sequela of direct mechanisms of viral damage occurring during the acute stage. In the case of headache, trigeminovascular damage may occur through several mechanisms. SARS-CoV-2 appears to be neurotropic, invading the nervous system through the trans-synaptic pathway.15,16 Another possibility is that the virus reaches the meninges via the blood, which would facilitate local inflammation of the endothelium (endotheliitis) and blood-brain barrier disruption,17 with potential to activate the trigeminovascular system. Both mechanisms require prior viral invasion of the respiratory epithelium via angiotensin-converting enzyme 2 (ACE2), which acts as a receptor.18 This enzyme is expressed in the epithelial cells of the nasal mucosa, although it is not present in the nerve endings of the first cranial nerve.19 However, recent studies have detected SARS-CoV-2 RNA not only in the olfactory mucosa, but also in the olfactory bulb and trigeminal nerve (including nerve endings in the conjunctiva, cornea, and the mucosa of the uvula, as well as the gasserian ganglion).20 This finding supports the idea that this mechanism acts as an activation pathway of the trigeminovascular system due to direct involvement of branches of the trigeminal nerve. The presence of ACE2 in cerebral blood vessels21 and the immunoreactivity of the cells of the cerebral endothelium and leptomeninges to SARS-CoV-2 proteins20 also support the hypothesis of damage to the meningeal endothelium. Therefore, this damage during the acute stage would lead to the activation of local inflammatory mechanisms, particularly those involving the microglia; this would facilitate the continuous release in the brain of such mediators as glutamate, quinolinic acid, interleukins, complement proteins, and tumour necrosis factor α.22,23 These mediators may perpetuate activation of the trigeminovascular system, playing a role in headache persistence.

Finally, we should mention the possible role of calcitonin gene-related peptide (CGRP). This protein is released by pulmonary nerve endings during viral infection, and participates in regulating the immunoinflammatory response.24 CGRP levels are elevated in patients with migraine,25 and infusion of the molecule can cause migraine attacks in patients with the condition.26 Elevated circulating CGRP levels may cause headache in predisposed individuals in the context of acute COVID-19. Sustained activation of the trigeminovascular system during the acute stage may lead to central sensitisation of second-order neurons; this may play a role in the persistence of headache after infection, similarly to the mechanism by which episodic migraine transforms to the chronic form.27 However, to date, only one study has attempted to analyse CGRP levels in patients with and without headache in the acute stage of COVID-19, finding no significant differences between groups28; another study observed lower CGRP levels in patients with COVID-19 than in controls.29 Therefore, further research is needed to confirm these findings and to ascertain whether CGRP plays a role in headache associated with COVID-19.

These observations seem to indicate that persistent headache after COVID-19 may involve several complex processes.