Headache as a Cardinal Symptom of Coronavirus Disease 2019

A Cross-Sectional Study

Javier A. Membrilla, MD; Íñigo de Lorenzo, MD; María Sastre, MD; Javier Díaz de Terán, MD


Headache. 2020;60(10):2176-2191. 

In This Article

Abstract and Introduction


Objective: To describe the semiology of pain and its associated features in patients with coronavirus disease 2019 (COVID-19) and headache presenting to the emergency department who do not require urgent services.

Background: Headache is one of the most frequent neurological symptoms reported in case series, epidemiological studies, and meta-analyses of COVID-19, with a prevalence ranging from 8 to 71.1%. Studies addressing the semiology of these headaches are lacking.

Methods: We conducted a cross-sectional study in the emergency department of a tertiary hospital. Patients classified according to the Manchester Triage System as standard and non-urgent and those fulfilling the criteria for probable or confirmed COVID-19 according to World Health Organization guidelines who presented with headache were included. A standardized questionnaire was used for data collection.

Results: Of the 145 confirmed and probable COVID-19 patients, 99 (68.3%) reported headache. A total of 54/99 (54.5%) were classified with probable COVID-19 and 45/99 (45.5%) with confirmed COVID-19. The mean age (44.7 ± 11.8 vs 40.4 ± 10.7, P = .061), sex distribution (35/54 [64.8%] vs 28/45 [62.2%] female, P = .768), and headache comorbidity (19/54 [35.2%] vs 17/45 [37.8%], P = .789) were similar between the probable and confirmed COVID-19 groups, along with other medical comorbidities and laboratory data. Patients with confirmed COVID-19 showed a higher incidence of anosmia (21/54 [38.9%] vs 28/45 [62.2%], P = .021) and pneumonia (10/54 [18.5%] vs 18/45 [40%], P = .018), headache at onset (32/54 [59.3%] vs 39/45 [86.7%], P = .002), and hospital admission (0/54 [0%] vs 2/45 [11.1%], P = .017). In most cases, the headache appeared simultaneously with other COVID-19 symptoms (57/99, 57.6%). It was bilateral (86/99, 86.9%), frontal or holocranial (34/99, 34.3% each) in location and intense (60/99, 60.6%, reported a visual analog scale [VAS] score ≥7). A total of 39/99 (39.4%) identified triggers, most commonly fever. The most frequent aggravating factors were physical activity (45/99, 45.5%) and coughing (43/99, 43.4%). Patients showed a propensity toward prostration (41/99, 41.4%), photophobia (29/99, 29.3%), and phonophobia (27/99, 27.3%). Partial (53/99, 53.5%) or total (26/99, 26.3%) responses to first-step analgesics were reported. A total of 25/99 (25.3%) patients had a prior history of migraine, presenting with headache different from the usual in 23/25 (92.0%) patients. Individuals with migraine were more likely to have earlier (headache at onset of the respiratory symptoms in 24/25 [96.0%] vs 57/74 [77.0%], P = .023 [95% CI: 0.067, 0.313]), longer (>24 hours of pain in 20/25 [80%] vs 25/74 [33.8%], P < .001 [95% CI: 0.272, 0.652]), and more intense (VAS score ≥5 in 25/25 [100%] vs 63/74 [85.1%], P = .043 [95% CI: 0.057, 0.213]) headaches than patients without migraine.

Conclusions: Headache is a very prevalent COVID-19 symptom among patients presenting to the emergency room, most frequently presenting as holocranial or bifrontal moderate to severe, and pressing quality headache. Individuals with migraine tend to present with earlier, longer, and more intense headaches.


Coronaviruses (CoVs) are pathogens that mainly affect the respiratory tract, causing outbreaks of epidemic potential. The novel CoV (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) was first described in December 2019 and was declared a pandemic by the World Health Organization (WHO) on March 11, 2020.[1] This pandemic has particularly hit Spain, which together with the United States and Italy, led the ranking of countries with the highest number of cases and deaths at the time this study was conducted.[2]

SARS-CoV-2 can cause a highly diverse spectrum of diseases (coronavirus disease 2019 [COVID-19]) ranging from asymptomatic infection to acute respiratory distress syndrome. The most common symptoms at onset are fever, cough, arthromyalgia, dyspnea, and fatigue. Other symptoms such as sputum production, headache, hemoptysis, and diarrhea have also been reported.[3]

The neurotropism of human CoVs has been addressed in several studies. The main potential mechanisms of neurological damage are parainfectious demyelination, encephalopathy in the context of sepsis,[4] and direct central nervous system (CNS) infection. It has been hypothesized that CNS invasion occurs either by neuron-neuron transmission or blood-barrier disruption (due to cytokine storm syndrome leading to a hematogenic pathway). Other CoVs have been isolated in the CNS, both in animal models and clinical scenarios.[5–8]

Neurological manifestations are common among COVID-19 patients. Anosmia and ageusia (present in up to 85.6 and 88.0% of the patients), headache (6.4–32.0%), and myalgia (11–52%) are frequently reported neurological symptoms, followed by confusion (9.0%), dizziness (9.0%), seizures (7.0%), and stroke.[9–14] Unusual cases of acute parainfectious myelitis,[15] acute necrotizing encephalitis,[16] acute disseminated encephalomyelitis,[17] and axonal or demyelinating polyradiculoneuropathies,[18–20] have been reported without microbiological confirmation in cerebrospinal fluid (CSF). Currently, case of meningoencephalitis with positive SARS-CoV-2 reactive polymerase chain reaction (PCR) is the only evidence of the presence of this virus in the CNS.[21] In a meta-analysis of 3062 cases, 15.4% of COVID-19 patients presented with headache.[22] Since most of the patients did not undergo specific neurologic assessments, some neurological syndromes might have been underdiagnosed.

The International Classification of Headache Disorders, 3rd edition (ICHD-III) includes acute headache attributed to systemic viral infection (code,[23] whose criteria can be applied to define headache caused by influenza and common cold viruses (mainly rhinoviruses and other CoVs). These viral infections can cause headaches in over 60% of cases.[24] Regarding COVID-19, in a large cohort of symptomatic healthcare workers tested for SARS-CoV-2, headache was present in 71.1% of SARS-CoV-2 positive individuals and was associated with test positivity (OR 3.5, P < .001).[25] However, the description of COVID-19-related headache features in clinical practice is lacking and the effects of COVID-19 on patients with a previously diagnosed headache are still unknown. Recently, a headache specialist neurologist reported his own experience as a COVID-19 patient, describing a multiphasic course starting with a diffuse pain related to fever, followed by headache associated with a cough, bilateral pain with pressing quality, and a moderate expansive headache associated with neck stiffness, photophobia, and worsening with postural changes and physical activity.[26] In addition, a study using a survey to investigate the characteristics of COVID-19-related headache in healthcare workers has been published, in which throbbing pain appeared most frequently in individuals with migraine.[27]

We hypothesized that COVID-19-related headache might be one of the most frequent symptoms of the infection and can have a more severe presentation in patients with migraine. We aimed to describe the semiology of pain and associated symptoms in patients with COVID-19-related headache in a clinical setting who visit the emergency department but do not require urgent services. Our second aim was to determine the effect of headache attributed to COVID-19 on patients with a previous history of migraine in the same clinical setting.