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

Disclosures

Headache. 2020;60(10):2176-2191. 

In This Article

Results

A flowchart describing the patient selection and exclusion process is shown in Figure 1. A total of 145 participants were identified with probable or confirmed COVID-19 during the recruiting period. A total of 99 (68.3%) of the 145 participants reported headache as a COVID-19-related symptom. Among the 99 patients, 45 (45.5%) were confirmed cases and 54 (54.5%) were probable cases. In the probable COVID-19 group, 10 patients had a negative PCR, but with highly suggestive SARS-CoV-2 findings (false-negative PCR) and 45 participants did not undergo microbiological testing. Anosmia was present in 49/99 (49.5%) participants. 63/99 (63.6%) were women. The mean age was 42.7 ± 11.5 years, ranging from 21 to 70 years. A personal history of headache comorbidity was found in 33/99 patients (33.3%), the most common being migraine in 25/99 (25.3%) patients. Epidemiological and clinical data of patients presenting with and without headache are displayed in Table 1. The same information together with headache-related data was compared between probable and confirmed COVID-19 patients presenting with headache, as shown in Table 2.

Figure 1.

Flowchart of patient selection and exclusion.

When Does COVID-19-related Headache Start, Where Does the Pain Localize, how Much Does it Hurt, how Does it Feel, and how Long Does it Last?

Headache was present before other COVID-19 symptoms in 24/99 (24.2%), at the same time in 57/99 (57.6%), and after respiratory syndrome onset in 18/99 (18.2%) patients. Comparative data between patients with a headache before other COVID-19 symptoms and headache at the same time or after other symptoms did not show statistically significant differences in comorbidity, incidence of pneumonia, laboratory data, outcome, or other headache-related variables (see Table 3 for further information). Regarding the laterality of pain, a clear predominance of bilateral headache was observed, presenting in 86/99 patients (86.9%). The pain was most frequently located as frontal or holocranial, each of them presenting in 34/99 (34.3%) patients. Other frequent pain sites were the parietal region in 12/99 patients (12.1%) and occipital region in 9/99 (9.1%) (Figure 2). Regarding pain intensity, 89/99 (89.9%) patients scored ≥5 points in the VAS and 60/99 (60.6%) ≥7. The lymphocyte count, LDH, and analyzed acute-phase reactants (C-reactive protein, fibrinogen, and D-dimer) did not show a statistically significant correlation with the VAS score (correlation of the VAS score with lymphocyte count ρ = −0.054 [P = .731], LDH ρ = −0.077 [P = .636], C-reactive protein ρ = 0.203 [P = .198], fibrinogen ρ = 0.74 [P = .644], and D-dimer ρ = 0.176 [P = .296]). Pain quality was described as pressing in 73/99 (73.7%), throbbing in 14/99 (14.1%), stabbing in 11/99 (11.1%), and burning in 1/99 (1.0%) patients. The headache persisted for a long duration, lasting more than 24 hours without remission in 45/99 (45.5%) patients. Laboratory parameters did not present a statistically significant difference between patients with longer headache episodes (>24 hours) and those with shorter episodes (median ± IR lymphocyte count 1606.3 ± 1106.9 vs 2160.0 ± 834.4 [95% CI: −1960.0–3067.4; P = .574], median ± IR LDH 240.3 ± 201.5 vs 223.0 ± 38.2 [95% CI −500.0–465.0; P = .916], median ± IR C-reactive protein 189.8 ± 202.9 vs 28.5 ± 33.2 [95% CI: −585.6–263.2; P = .351], median ± IR fibrinogen 900.7 ± 389.0 vs 277.5 ± 26.2 [95% CI: −1546.9–300.5; P = .121], and median ± IR D-dimer 475.8 ± 471.3 vs 755.0 ± 898.0 [95% CI: −1179.8–1738.3; P = .623]).

Figure 2.

Location of headache, classified as cranial regions.

Does COVID-19-related Headache Have Triggers or Time Preference?

In this study, 39/99 patients (39.4%) identified headache triggers, with fever being the most frequent (18/99 patients, 18.2%) (Figure 3). Time preference was reported in 50/99 patients (50.5%). Headache started in the afternoon in 24/99 (24.2%), at night in 16/99 (16.2%), and in the morning in 10/99 (10.1%) patients.

Figure 3.

Headache triggers.

Which Factors Aggravate COVID-19-related Headache and Which Features are Associated With it?

Physical activity (45/99, 45.5%) and coughing without the influence of other Valsalva maneuver (43/99, 43.4%) were frequent aggravating factors. A propensity to prostration (41/99, 41.4%) was commonly seen. Stimuli-phobia was not rare, with an aversion to light, sound, or smell in 29/99 (29.3%), 27/99 (27.3%), and 9/99 (9.1%) patients, respectively (Figure 4). A patient with a prior history of migraine without aura presented with visual aura. Another patient presented 2 trigeminal-autonomic features (eyelid edema and otic fullness) ipsilateral to a unilateral headache, interestingly not presented previously to COVID-19 symptoms and without meeting criteria for any primary headache.

Figure 4.

Aggravating factors and features associated with headache.

How did COVID-19-related Headache Impact on Usual Activity and how did it Respond to Medication?

The need for cessation of usual activity was fairly frequent, being reported by 23/99 subjects (23.2%). Most of the patients (91/99, 91.9%) used medication for symptomatic relief. The most commonly used drug was acetaminophen (74/99, 74.7%). The remaining patients used nonsteroidal anti-inflammatory drugs (NSAIDs), metamizole, triptans, or a combination of them. These drugs achieved complete pain relief in only 26/99 (26.3%) cases. Partial response was more frequent (53/99, 53.5%). Further data and comparisons are summarized in Table 4.

How Does COVID-19-related Headache Affect Patients With Prior History of Migraine?

As previously depicted in Table 1, only 3/46 (6.5%) patients without headache in the context of COVID-19 had a prior history of migraine, as opposed to 25/99 (25.3%) individuals with migraine in the headache group (P = .007). Status migrainosus occurred in 2/25 (8.0%) patients with migraine in the context of COVID-19. In our sample, the frequency of status migrainosus in all patients with headache in the context of COVID-19 is 2.0% (2/99). Most patients with previous headache disorder (28/33, 84.9%) suffered from a headache that was clearly different from previous episodes. A longer COVID-19-related headache was observed in patients with migraine compared to those without this condition (Figure 5), resulting in a statistically significant association (P < .001, 95% CI: 0.272, 0.652). Most notably, 80% of individuals with migraine (20/25) had pain episodes lasting more than 24 hours, while only 33.8% of patients without migraine (25/74) presented with headache longer than 1 day. Migraine patients scored higher on the VAS than individuals without migraine (median ± IR 8.0 ± 2.5 vs 7.0 ± 3.0, P = .444). The proportion of patients with moderate-severe headache was also higher in the migraine group (25/25 [100.0%] vs 63/74 [85.1%], P = .043 [95% CI: 0.057–0.213]). Interestingly, there was no difference between the prevalence of migraine-like features in patients with migraine vs patients without this condition. The prevalence of anosmia was significantly higher in patients with a previous history of migraine (17/25 [68.0%] vs 32/74 [43.2%], P = .042 [95% CI: 0.033, 0.462]). The comparisons are summarized in Table 5.

Figure 5.

Distribution of COVID-19-related headache episode duration in patients with and without migraine (P < .001).

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