Delayed headache after COVID-19 vaccination: a red flag for vaccine induced cerebral venous thrombosis

DOI: https://doi.org/10.1186/s10194- 021- 01324- 5

Abstract-Summary Headache is a frequent symptom following COVID-19 immunization with a typical onset within days post-vaccination.

Cases of cerebral venous thrombosis (CVT) have been reported in adenovirus

vector-based COVID-19 vaccine recipients.

We assessed demographic, clinical variables and the interval between the vacci-

nation and onset of headache.

We identified 77 cases of CVT after COVID-19 vaccination. The median time between vaccination and CVT-related headache onset was 8

(interquartile range 7.0–9.7) days.

Delayed onset of headache following an adenovirus vector-based COVID-19

vaccine is associated with development of CVT.

Patients with new-onset headache, 1 week after vaccination with an adenovirus vector-based vaccine, should receive a thorough clinical evaluation and CVT must be ruled out.

Extended: The median time between the vaccination and the first symptom was

8 days (inter-quartile range (IQR) 7–12, range 1–19, n = 70).

Introduction Headache typically presents within the first 72 h post-vaccination and may be asso- ciated with additional symptoms, such as fatigue, fever, myalgia, arthralgia, or diar- rhea [333, 334].

Several cases of cerebral venous thrombosis (CVT) have been reported in non- replicant adenovirus vector-based COVID-19 vaccine recipients (Oxford- AstraZeneca ChAdOx1-S and Johnson & Johnson (J&J) Janssen Ad26.COV2S) [335–341].

Headache is the most frequent symptom in CVT, and it may occur isolated or

accompanied by other symptoms [339–341].

As in other secondary headache disorders, CVT may be recognized by the pres-

ence of red flags [65, 341].

We highlight a potential novel red flag based on the available scientific data that may help clinicians to properly identify cases of CVT following non-replicant ade- novirus vector-based COVID-19 vaccines.

Methods The case definition was CVT following COVID-19 non-replicant adenovirus vector- based vaccines.

We assessed and extracted the following variables, which are presented as descriptive statistics: age, sex, use of contraceptives or hormone-replacement

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therapy, presence of headache, presence of additional symptoms, the interval between the vaccination and the first symptom, intracranial hemorrhage, and death. As control group, we reviewed the United States Vaccine Adverse Event Reporting System (VAERS) [334] reports under the symptom “headache” follow- ing COVID-19 vaccination up to April 30, 2021, assessing the number of days between the immunization and the headache onset.

In the statistical analysis, we assessed whether the presence of headache in patients with CVT was associated with higher probability of death or with higher probability of intracranial hemorrhage by univariate logistic regression, presented as odds ratio (OR) and 95% confidence interval (CI).

Results Patients’ age was available in 71 cases, and was below 40 in 46.5%, below 60 in 95.8% and between 60 and 69 years in 4.2% cases.

The presence of headache was described in 38/77 cases (49.4%). The CVT-related clinical symptoms started earlier in patients with headache (median 8, IQR 7–9.7, range 2–15) than in patients without headache (median 10, IQR 7–12.2, range 1–19), (P = 0.037, Mann-Whitney test).

In patients with CVT, the presence of headache was associated with the presence of intracranial hemorrhage (odds ratio (OR) 7.45; 95% confidence interval (CI): 2.67–20.80, P  <  0.001), but not with a higher odd of death (OR: 0.51, 95% CI: 0.18–1.47, P = 0.213).

Discussion Although headache is a common symptom after vaccination, it typically presents and resolves within the same day or a few days later [333, 334].

CVT, and other thrombotic complications in adenovirus-based vaccine recipients

share a unique feature, the delayed presentation.

Headache was not described in detail in most cases, but in the few it was, it was reported as severe, progressive and treatment-resistant, all of them well-known red flags [65].

Given this knowledge and the possibility of vaccine-related CVT, patients with new-onset headache, 1 week after immunization, should receive a thorough clinical evaluation and be closely monitored.

Conclusion Delayed onset of headache following an adenovirus vector-based COVID-19 vac- cine is associated with CVT.

Patients with new-onset headache, 1 week after vaccination with an adenovirus vector-based vaccine, should receive a thorough clinical evaluation and CVT must be considered in the diagnostic work-up.

Acknowledgement A machine generated summary based on the work of García-Azorín, David; Do, Thien Phu; Gantenbein, Andreas R.; Hansen, Jakob Møller; Souza, Marcio Nattan P.; Obermann, Mark; Pohl, Heiko; Schankin, Christoph J.; Schytz, Henrik Winther; Sinclair, Alexandra; Schoonman, Guus G.; Kristoffersen, Espen Saxhaug 2021 in The Journal of Headache and Pain.

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