Post-COVID headache is one of the most common neurologic symptoms reported in over 70% of active SARS-CoV-2 infection


Researchers discover that immunometabolic rewiring is responsible for chronic headaches in long COVID individuals

The study findings were published on a preprint server and is currently being peer reviewed.

Headache is among the most frequent symptoms persisting or newly developing after coronavirus disease 2019 (COVID-19) as part of the so-called long COVID syndrome.

The knowledge on long COVID headache is still limited, however growing evidence is defining the features of this novel condition, in particular regarding clinical characteristics, some pathophysiological mechanisms and first treatment recommendations.

Long COVID headache can present in the form of worsening of a preexisting primary headache, or, more specifically, in the form of a new (intermittent or daily) headache starting during the acute infection or after a delay. It often presents together with other long COVID symptoms, most frequently with hyposmia.

It can manifest with a migrainous or, more frequently, with a tension-type-like phenotype. Persistent activation of the immune system and trigeminovascular activation are thought to play a role. As there are virtually no treatment studies, treatment currently is largely guided by the existing guidelines for primary headaches with the corresponding phenotype.

The present report, a collaborative work of the international group of the Junior Editorial Board of The Journal of Headache and Pain aims to summarize the most recent evidence about long COVID headache and suggests approaches to the diagnosis and treatment of this disorder.

Trigeminovascular system activation in patients with genetic predisposition to migraine or pre-existing headache

It has been hypothesized that long COVID headache could emerge as a result of the “activation” of a pre-existing headache or in patients with a genetic predisposition to migraine by activating the trigeminovascular system. In the previously mentioned study, some migraine-like features of the headache during the acute phase were associated with long COVID headache.

The phenotypic headache variables during an infection from SARS-CoV-2 were associated with a higher frequency of persistence of headache at 9 months, included higher frequency of throbbing quality (reported in 40.6% during the acute phase in patients with persistent headache at 9 months vs. 17.3%), lower frequency of pressing quality (40.6% vs. 63.4%), higher frequency of photophobia / phonophobia (45.7% vs. 34%) and higher frequency of worsening by physical activity (45.7% vs. 34%) [18].

In a multicentric study including 615 patients of which 205 having headache during the acute phase of COVID-19, followed for a mean of 7.3 months, the presence of headache during COVID-19 was associated with a higher frequency of long COVID symptoms (2.4 vs. 2.0 symptoms), higher frequency of fatigue during long COVID (OR: 1.55; 95% CI: 1.07–2.24) and a higher frequency of tension-type-like headache phenotype (2.65; 95% CI: 1.66–4.24).

In that sample, prior history of migraine was also associated with post-COVID headache (OR: 2.90; 95% CI: 1.41–5.98) [25, 26]. These data have been previously explored in a smaller sample from the same cohort, that evaluated 57 patients with confirmed diagnosis of migraine prior to the COVID infection and 144 age-and-sex matched controls, where no significant differences were observed regarding anxiety or depression during long COVID evaluated with the Hospital Anxiety and Depression Scale (HADS), but with a higher frequency of post-COVID symptoms (OR: 1.50; 95% CI: 1.09–2.09) [27]. Another case–control study observed that patients with prior history of migraine had 40% more frequent long-lasting headache, as defined by continuous headache present for more than 1 day [28].

Immune system activation

Acute headache attributed to a systemic viral infection may be related with a significant systemic immune response [11]. The presence of headache during the acute phase has been associated with a better prognosis, including lower mortality, lower duration of the acute phase and a lower need for intensive care unit admission [29–31]. This has been associated with a more efficient immune response. Indeed, patients with headache had lower blood levels of D-dimer, C-reactive protein, lactate dehydrogenase, ferritine, and higher levels of lympocythes [29–31].

It has been hypothesized instead that patients with long COVID headache can manifest a persistent immune system activation with biohumoral response, as demonstrated by the evidence of altered blood levels of cytokines and interleukins. Two studies observed lower levels of interleukin-6 [30, 31], while another study observed higher mean levels of IL-6, albeit differences were not statistically significant. In that study, the subgroup of patients with bilateral headache (77 out of 83 patients with headache), had higher levels of IL-6 than patients with unilateral headache [32].

The same group published another case–control study including 88 patients, where serum levels of HMGB1, NLRP 3, IL-6, angiotensin II and ACE 2 were higher in patients with headache during COVID-19 [33]. Another group found a significant alteration of IL-10 blood levels, after an analysis of 45 different cytokines and interleukins in 104 patients at the time of their emergency department visit [34].

Although the hypothesis of a persistent activation of the immune system in patients with predisposing headache biology could be supported by some data, the direct evidence about the immune response over time in terms of years in patients with long COVID headache is limited. A multivariate analysis of 576 hospitalized patients that were subsequently followed for one year, observed that immune-compromised patients had a more prolonged duration of the headache over time (HR: 2.9; 95% CI: 1.02–8.22) [35].

Hypoxia and/or hypercapnia

The first theories that were considered regarding COVID-19 headache pathophysiology were hypoxia and/or hypercapnia [36]. This hypothesis was evaluated in a cohort of 70 patients and followed 3 months after the acute phase. There were no differences regarding cardio-pulmonary function, assessed by laboratory parameters, echocardiography, pulmonary function tests or cardio-pulmonary exercise test [37].

Structural and functional brain changes

Some neurological manifestations of long COVID may be associated with structural and functional brain changes. A longitudinal project that was studying brain structure and cognitive function over time in 785 participants prior to the pandemic onset was used to assess COVID-19 effects.

The availability of neuropsychological and MRI information allowed the comparison between patients that tested positive for COVID-19 (n = 401) and participants that remained COVID-19 free (n = 384). A second comprehensive evaluation, including MRI, was done 38 months in mean after the first one. In that assessment, gray matter reduction was observed in patients with COVID-19, specifically in orbitofrontal cortex and parahippocampal gyrus [38].

Furthermore, a higher cortical surface area and gray matter volume in orbitofrontal cortex was observed in a sample of patients with long COVID headache, but no differences were documented regarding cortical thickness [39], which could suggest that some gray matter changes may be manifestation-specific. Indeed, most changes were observed in areas that were functionally connected with the primary olfactory cortex [36].

Resting-state functional connectivity has been compared between COVID-19 survivors and healthy controls, observing weakened functional connections between the cingulate, hippocampal gyri, parietal, temporal and frontal gyri and strengthened functional connectivity with occipital regions [39].

Besides gray matter and connectivity changes, white matter changes have been reported in COVID-19 survivors, compared with healthy controls, with higher axial diffusivity in corona radiata, and internal and external capsules [39, 40], suggesting some degree of white matter axonal alterations, which could be involved in the persistence of headache, however, the specificity of these changes in regards to headache is still to be ascertained.

Some of these changes could be related with COVID-19 and its comorbidities, or specifically with headache, so whether the observed brain changes are cause or consequence of headache is currently unknown. Concerning brain metabolism, there are no headache-specific studies, but the regions most frequently reported as hypometabolic include the right parahyppocampal gyrus [41], the brainstem, thalamus, amygdala [41], orbital gyrus, olfactory gyrus, and temporal lobe [42].

One study compared images from 18-fluor-deoxy-glucose PET and functional MRI imaging, showing an overlap between the areas where the connectivity was altered in the MRI and F-18 FDG PET changes [43]. Figure ​Figure1 summarizes the main mechanisms which could be involved in the long COVID headache pathophysiology.

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Patients who contracted COVID-19 have a wide spectrum of symptoms, from being asymptomatic to developing severe symptoms such as acute respiratory distress syndrome and multiple organ failures 4.

Although most COVID-19 patients recovered from the respiratory disease within a few weeks, there is mounting clinical evidence that these post-COVID patients continue to experience persistent symptoms including headache, fatigue, shortness of breath, loss of smell and taste, depression, anxiety, cardiovascular damage, memory loss as well as joint pain.

These patients are often called ‘long-haulers’ and diagnosed with a condition termed post-acute sequelae of SARS-CoV-2 infection (PASC). Among these lingering symptoms, post-COVID headache is one of the most common neurologic symptoms reported in over 70% of active SARS-CoV-2 infection 5,6, while approximately 40% of COVID-19 patients developed chronic headaches which persisted up to three months post-infection 7-9.

Patients with post-COVID headaches experienced severe debilitating migraine-like pressure pain that spreads throughout the skull and persists for several months, leading to high morbidity 10.

The association between primary headaches and inflammation has been well reported, yet the pathophysiology of COVID-19-related secondary headaches is still unclear 11. COVID-19 is considered a multi-organ disease that is attributed by systemic inflammation 12,13.

In fact, the contribution of immunometabolism to the regulation of immune response and inflammation during viral infections, such as human immunodeficiency virus (HIV) and Dabie bandavirus (DBV), has been widely reported 14-16.

Recently, a metabolomics sera analysis of COVID-19-positive patients showed alterations in metabolites involved in arginine and tryptophan metabolisms which correlated tightly with circulating inflammatory cytokines such as IL-6, IP-10 and M-CSF, highlighting the role of perturbed host metabolisms in response to SARS-CoV-2 infection 17,18.

The neuro-invasion of SARS-CoV-2 has been shown to result in brain vascular inflammation, but the long-term impact of COVID-19 neurological sequalae is still unknown 19,20.

Interestingly, longitudinal effects of COVID-19 showed significant reduction in brain size and cognitive decline, suggesting that neuro-inflammation triggered by SAR-CoV-2 infection interferes with neuronal functions and disrupts neurotransmitter pathways 21. Indeed, a dysregulation in the neurotransmitter systems such as serotonin, dopamine and glutamate has been implicated in migraine pathogenesis and pain regulation 22.

Although SARS-CoV-2 is expected to trigger inflammation, immune activation, and dysregulation of metabolites 23,24, the biological factors associated with persistent and disabling chronic headaches specifically in the context of long COVID remains to be fully characterized.

To address the immuno-metabolomics landscape of post-COVID headaches in ‘long haulers’, we performed a longitudinal multi-omics profiling of peripheral blood specimens of PASC patients over the course of chronic headache progression. (Fig. 1A). Ultimately, identifying key factors that drive post-COVID headaches could provide insights for potential immunotherapies.


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