Association between COVID-19 and headache: What evidence and history tell us

Since the start of the pandemic of coronavirus disease of 2019 (COVID-19), a great number of studies have been conducted and published regarding COVID-19 worldwide. It has become clear that COVID-19 comprises diverse clinical presentations rather than pure airway symptoms. Associations between COVID-19 and neurological conditions have been reported including systemic thromboembolism (1), stroke (2), and even Miller-Fischer syndrome (3). When it comes to headache, the question arises whether there is a specific association between headache and COVID-19. On the first glimpse, it looks like it, given that headache as a symptom has been reported in several early case series of COVID-19. In China, among 2203 patients from six different case series of COVID-19, headache was present in 12% (range 6.5% ∼ 13.6%) (4–9). In Europe, among 1510 patients from two case series, 1062 (70.3%) reported headache (10,11). Next to the unexplained huge difference in reports, none of these early case series specifically looked into the headache symptomatology or etiology. In this issue of Cephalalgia, seven studies across four continents specifically investigated headache symptomatology and associated features in patients with COVID-19. The results from these studies may shed some light on this question.

Two well done Spanish studies nicely shed light on the situation: Caronna et al. investigated 130 COVID-19 patients prospectively. Nearly 75% (n = 97) developed headaches, of which 24.2% presented with migrainous features (12). Trigo López et al. investigated 580 COVID-19 patients, of which 130 (22.4%) developed headaches, half of whom showed tension-type headache (TTH)-like features (13). Another case series from Egypt reported 172 patients with COVID-19 and headache (without a control group), and most patients presented with TTH-like features (14). One case series from Brazil reported 73 consecutive patients with COVID-19, among which 64.4% developed headaches. Contrary to the other studies, most patients in this study presented with prominent migrainous features (15). On the whole, it is probably fair to say that headache is common in COVID-19 patients, and the headache features in these patients are not restricted to just one phenotype. It needs to be pointed out that Caronna et al. prospectively followed patients with COVID-19 for up to 6 weeks and found that one-third of the patients still had daily persistent headaches. In some of these patients, the daily persistent headache remained the only residual symptom 6 weeks after the acute COVID-19 infection (12).

Certain associated symptoms are common in COVID-19 patients with headache: The prevalence of anosmia/ageusia ranged from 33.9–68% in patients with COVID-19 in general (16). Two studies showed that COVID-19 patients with headache vs. those without headache are more likely to have anosmia/ageusia: 54.6% vs. 18.2% in the study by Caronna and colleagues (12) and 46.7% vs. 18.7% in the study by Trigo López and colleagues (17). The study from Brazil suggests that patients with anosmia/ageusia are more likely to develop headaches than those without (83% vs. 47%) (15). Imaging studies may provide some clues to such an association. Politi et al. reported a case of COVID-19 with anosmia and MRI showed a transient regional signal alternation in the olfactory bulb and the posterior gyrus rectus (18). How common the regional signal changes are in the adjacent gyrus to the olfactory bulb awaits further investigation. Aragão et al. investigated five COVID-19 patients with fever and headache and found evidence of olfactory bulb injury using MR imaging in all five (three with anosmia and two without anosmia) (19). The nasal cavity receives innervation from V1 and V2 branches of the trigeminal nerve, and infections in the nasal cavity are known to cause headaches. This provides a possible explanation for why certain patients developed both anosmia and headache simultaneously. Of note, the two independent studies from Spain paradoxically showed lower IL-6 levels in those with headache vs. those without headache (12,13), which seems to contradict a simple pro-inflammatory activity (20,21) leading to headaches in patients with COVID-19.

One case series investigated 56 consecutive COVID-19 patients with headache who underwent lumbar puncture and found that six (10.7%) of them had elevated CSF pressure (>250 mm H₂O), among which one third had papilledema. The clinical picture of these patients does not resemble those of idiopathic intracranial hypertension. Therefore, the authors suspected that a link with coagulopathy may underlie the elevated CSF pressure (22). However, this study is without a control group and warrants further validation. Of note, all 56 patients with headache had a negative CSF study using RT-PCR for virus RNA (22). Therefore, a direct CNS involvement is probably rare even in those with headaches. Aside from a COVID-19 infection, the impact of lockdown brought unexpected effects on headache in certain subgroups of headache patients. In Italy, Papetti et al. followed 707 pediatric patients with primary headache disorders and found that 38% of them had headache improvement (compared to 15% with headache worsening) during the lockdown. The main factor for improvement is the reduction of school effort and anxiety (23).

Is COVID-19 specifically associated with headaches? The answer is probably “no”. Headache is very common as a symptom in patients with acute respiratory illness: 68–100% of patients with influenza (24) and 83% of patients with adenovirus (25) report headaches, and for a rhinovirus infection – one of the most frequent pathogens for common colds – headache is, in fact, the leading cause for seeking treatment (26). Headache is simply an adequate physiological response to an acute infectious disease. This is very nicely pointed out by Dr. Rozen’s article in this issue of Cephalalgia, who reviewed historical documents about neurologic sequelae after the 1890 Russian or Asiatic Flu and found that 75–83% of sufferers complained of headaches during the acute stage of illness, and some even developed persistent headache that mimicked new daily persistent headache (NDPH) in weeks or months afterward (27). This NDPH-like headache echoes the findings by Carorra et al. that up to one-third of their patients had persistent daily headache up to 6 weeks after the initial COVID-19 infection (12). In sum, given the current evidence, it is fair to say that headache during a pandemic of acute respiratory illness is not a new phenomenon, and that it no surprise that headache is also a symptom of COVID-19 infection. According to the International Classification of Headache Disorders, 3rd edition (ICHD-3), headache in patients with COVID-19 may fit into the diagnostic criteria 9.2.2.1—Acute headache attributed to systemic viral infection (28). Alternatively, another consideration would be 11.5 — Headache attributed to disorder of the nose or paranasal sinuses if cumulating evidence surfaces suggesting a strong association between olfactory bulb injury and headache, which however at the moment seems not to be the case.

One of the main limitations seen in these case series is selection bias. Most cohorts recruited patients with moderate severity – those who need to be hospitalized. Younger patients with COVID-19 usually have milder symptoms and need only house quarantine instead of hospital admission. More severe patients are intubated and headache is no longer the main concern (and the headache features cannot be properly approached if a patient is intubated). Diagnostic accuracy of COVID-19 is another issue: False-negative rates of RT-PCR can be up to 29% for COVID-19 infection (29). Besides, the issue of whether the headache is a new-onset headache or a worsening of previous existing headache disorders has not been properly addressed in all studies. There is certainly still a lot to be learned; however, there is (yet) no evidence to support the claim that COVID-19-specific headache exists.