García-Azorín et al. The Journal of Headache and Pain (2021) 22:108 https://doi.org/10.1186/s10194-021-01324-5 The Journal of Headache and Pain S H O R T R E P O R T Open Access Delayed headache after COVID-19 vaccination: a red flag for vaccine induced cerebral venous thrombosis David García-Azorín1, Thien Phu Do2, Andreas R. Gantenbein3,4, Jakob Møller Hansen5, Marcio Nattan P. Souza6, Mark Obermann7,8, Heiko Pohl9, Christoph J. Schankin10, Henrik Winther Schytz5, Alexandra Sinclair11,12, Guus G. Schoonman13† and Espen Saxhaug Kristoffersen14,15*† Abstract Background: 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. Findings: We reviewed all vaccine related CVT published cases by April 30, 2021. We assessed demographic, clinical variables and the interval between the vaccination and onset of headache. We assessed whether the presence of headache was associated with higher probability of death or intracranial hemorrhage. We identified 77 cases of CVT after COVID-19 vaccination. Patients’ age was below 60 years in 74/77 (95.8%) cases and 61/68 (89.7%) were women. Headache was described in 38/77 (49.4%) cases, and in 35/38 (92.1%) was associated with other symptoms. Multiple organ thrombosis was reported in 19/77 (24.7%) cases, intracranial hemorrhage in 33/77 (42.9%) cases and 19/77 (24.7%) patients died. The median time between vaccination and CVT-related headache onset was 8 (interquartile range 7.0–9.7) days. The presence of headache was associated with a higher odd of intracranial hemorrhage (OR 7.4; 95% CI: 2.7–20.8, p < 0.001), but not with death (OR: 0.51, 95% CI: 0.18–1.47, p = 0.213). Conclusion: 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. Keywords: Headache disorders, Secondary; sinus thrombosis, Vaccine-induced immune thrombotic thrombocytopenia, Cerebrovascular disorders; Stroke * Correspondence: e.s.kristoffersen@medisin.uio.no †Guus G. Schoonman and Espen Saxhaug Kristoffersen shared last authorship. 14Department of Neurology, Akershus University Hospital, Lørenskog, Norway 15Department of General Practice, HELSAM, University of Oslo, Oslo, Norway Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. García-Azorín et al. The Journal of Headache and Pain (2021) 22:108 Page 2 of 5 disease coronavirus Introduction Headache is within the most frequent adverse effects following (COVID-19) immunization. It is reported by approximately half of the vaccine recipients, both in clinical trials and real- world data [1, 2]. Headache typically presents within the first 72 h post-vaccination and may be associated with fever, myalgia, additional symptoms, such as fatigue, arthralgia, or diarrhea [1, 2]. 2019 Several cases of cerebral venous thrombosis (CVT) have been reported in non-replicant adenovirus vector- based COVID-19 vaccine recipients (Oxford-AstraZe- neca ChAdOx1-S and Johnson & Johnson (J&J) Janssen Ad26.COV2S) [3–7]. The association was based on the presence of thrombocytopenia [3–8], anti-platelet factor 4 antibodies [6, 7], and multiple organ thrombosis (vac- thrombocytopenia cine-induced immune (VITT)) [3–8]. There was a higher mortality rate [3–8] than in other CVT series reported in the literature and an increased standardized morbidity ratio (SMR) in pa- tients aged between 30 and 49 [3]. SMR is also known as observed-to-expected analysis, which analyses the ratio between the observed number of cases in the population over the number of cases that would be expected based on the baseline incidence according to databases and prior studies [9, 10]. thrombotic Headache is the most frequent symptom in CVT, and it may occur isolated or accompanied by other symptoms [9–11]. As in other secondary headache disorders, CVT may be recognized by the presence of red flags [11, 12]. Herein 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 adenovirus vector-based COVID-19 vaccines. Methods This is an observational study with case-control design. The study population were vaccinated with non- replicant adenovirus vector-based vaccines. The case definition was CVT following COVID-19 non-replicant adenovirus vector-based vaccines. We screened PubMed for all published cases and case series between March 01 and April 30, 2021, and assessed specific reports from the United States Centers for Disease Control and Pre- vention and the European Medicines Agency providing patient-level data. The search term is available in the supplementary appendix. We assessed and extracted the following variables, which are presented as descriptive statistics: age, sex, use of contraceptives or hormone- replacement therapy, presence of headache, presence of additional symptoms, the interval between the vaccin- ation and the first symptom, intracranial hemorrhage, and death. We compared the time elapsed between vaccination and the first clinical onset in patients with and without headache. As control group, we reviewed the United States Vaccine Adverse Event Reporting System (VAERS) [2] reports under the symptom “head- ache” following 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 prob- ability of death or with higher probability of intracranial hemorrhage by univariate logistic regression, presented as odds ratio (OR) and 95% confidence interval (CI). The statistical signification threshold was 0.05 and statis- tical tests were two-tailed. No statistical power calcula- tion was conducted prior to the study. Statistical analysis was done with SPSS version 26.0. Results We identified 77 cases of CVT included in eight publica- tions (supplementary appendix). Patients’ age was avail- able 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 majority of cases 61/68 (89.7%) were women. Five (5.2%) patients used contraceptives and one (1.3%) received estrogen therapy. (49.4%). The median time between the vaccination and the first symptom was 8 days (inter-quartile range (IQR) 7–12, range 1–19, n = 70). The presence of headache was described in 38/77 cases In 35/38 patients (92.1%), it was associated with other systemic or neurological symptoms. 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). Figure 1 shows the days elapsed between vaccination and headache onset. Intracranial hemorrhage was present in 33/77 (42.9%) cases, multiple location thrombosis was re- ported in 19/77 (24.7%) cases, and 19/77 (24.7%) died. In patients with CVT, the presence of headache was associated 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). presence with the of Discussion Although headache is a common symptom after vaccin- ation, it typically presents and resolves within the same day or a few days later [1, 2]. CVT, and other thrombotic complications in adenovirus-based vaccine recipients share a unique feature, the delayed presentation. In most of the reported cases symptoms started 1 week after immunization. Headache was not described in detail in it was reported as most cases, but in the few it was, García-Azorín et al. The Journal of Headache and Pain (2021) 22:108 Page 3 of 5 Fig. 1 Temporal distribution of vaccine-related headache in the general population and vaccine-related cerebral venous sinus thrombosis headache. Orange bars represent the proportion of patients that present headache during each day after vaccination according to VAERS data2. Blue bars represent the proportion of patients with headache attributed to vaccine-related cerebral venous sinus thrombosis severe, progressive and treatment-resistant, all of them well-known red flags [ 12]. Diagnostic delay is common in CVT [9]. Prompt treat- ment likely improves the clinical outcome, and therefore, every physician must be aware of the potential risk of vac- cine related thrombotic complications. Given this know- ledge 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. Non-contrast. computed tomography (CT) may detect indirect find- ings of CVT, including hyperdense vein or sinus (cord sign), venous infarcts, brain oedema and intracranial hemorrhages; however, the optimal imaging test in case of suspicion are contrast brain CT with CT venogram, magnetic resonance imaging (MRI) with contrast and/or venogram, showing a filling defect in a venous sinus (empty delta sign) [10, 13]. The pathophysiology of thrombosis with thrombocytopenia syndrome has been recently discussed [7, 14, 15]. The role of anti-platelet factor-4 antibodies seem causa- inducing platelet activation, aggregation, and tive, thrombosis, leading to a severe platelet consumption and thrombocytopenia. According to the existing evi- dence, an interim guideline published by the World Health Organization (WHO) states that the treatment should include the treatment of the immune-mediated phenomenon and adequate anticoagulation according to intravenous the existing evidence [14]. For the first, immunoglobulins seem to be the preferred option, while as anticoagulants, non-heparin-based anticoagulants must be used, while heparin-based anticoagulants and platelet infusion should be avoided [14]. Conclusion To conclude, delayed onset of headache following an adenovirus vector-based COVID-19 vaccine is associated with CVT. Patients with new-onset headache, 1 week after vaccination with an adenovirus vector-based vac- cine, should receive a thorough clinical evaluation and CVT must be considered in the diagnostic work-up. Supplementary Information The online version contains supplementary material available at https://doi. org/10.1186/s10194-021-01324-5. Additional file 1. Acknowledgements Not applicable. Authors’ contributions All authors contributed in the interpretation of data for the work, critical revision of the work for important intellectual content and all authors gave their final approval of the work to be published. All authors had full access to the full data used in the manuscript and accept responsibility to submit it for publication. Funding No funding sources were involved in the writing of this manuscript or the decision to submit it for publication. García-Azorín et al. The Journal of Headache and Pain (2021) 22:108 Page 4 of 5 Availability of data and materials Datasheets are fully available to other researchers upon request to the corresponding author. Declarations Ethics approval and consent to participate The study was conducted in accordance with Helsinki Declaration as revised in 2013. According to local IRB no ethical approval or informed patient consent was necessary because no new individually collected patient data were used in this study. For this type of study formal consent is not required. Consent for publication Not applicable. Competing interests David García-Azorín received scientific support and received honoraria from the Brain Health Unit of the World Health Organization as scientific advisor for the COVID-19 Global Forum. Thien Phu Do reports no conflicts of interest. Andreas R. Gantenbein reports no conflicts of interest. Jakob Møller Hansen reports no conflicts of interest. Marcio Nattan Souza received speaker fees from Novartis, TEVA, Lilly, Allergan, Sanofi, Libbs and Lundbeck. Mark Obermann received scientific support, travel support and/or honoraria from Biogen Idec, Novartis, Sanofi/Genzyme, Pfizer, Teva, Lilly, Schwarz and Heel. He received research grants from Allergan, Electrocore, Heel, and the German Ministry for Education and Research (BMBF). Heiko Pohl was funded by the Werner Dessauer Stiftung and received speaker fees from TEVA Pharmaceuticals and honoraria from Eli Lilly. Christoph J. Schankin received scientific support, travel support and/or honoraria from Novartis, Eli Lilly, TEVA Pharmaceuticals, Allergan, Almirall, Amgen, MindMed, Grünenthal. He received research grants from German Migraine and Headache Society, Eye on Vision Foundation, and Baasch Medicus Foundation. He is part-time employee at Zynnon. Henrik Winther Schytz has received honoraria from Novartis, TEVA, Lilly and has received a research grant from Novartis. Alexandra Sinclair has received speaker fees and Honoraria from Novartis and Allergan. Guus Schoonman reports no conflict of interest. Espen Saxhaug Kristoffersen reports no conflicts of interest. Author details 1Headache Unit, Department of Neurology, Hospital Clínico Universitario de Valladolid, Valladolid, Spain. 2The Danish Headache Center, Department of Neurology, Rigshospitalet-Glostrup, Faculty of Health Sciences, University of Copenhagen, Glostrup, Denmark. 3Department of Neurology and Neurorehabilitation, ZURZACH Care, Bad Zurzach, Switzerland. 4Department of Neurology, University Hospital Zurich, Zürich, Switzerland. 5Danish Headache Center, Rigshospitalet-Glostrup, Faculty of Health Sciences, University of Copenhagen, Glostrup, Denmark. 6Department of Neurology, Hospital das Clínicas, University of São Paulo, São Paulo, Brazil. 7Department of Neurology, Hospital Weser-Egge, Höxter, Germany. 8Department of Neurology, University of Duisburg-Essen, Essen, Germany. 9Department of Neurology, University Hospital Zurich, Zurich, Switzerland. 10Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. 11Metabolic Neurology, Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK. 12Department of Neurology, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK. 13Department of Neurology, Elisabeth-TweeSteden Hospital, Tilburg, The Netherlands. 14Department of Neurology, Akershus University Hospital, Lørenskog, Norway. 15Department of General Practice, HELSAM, University of Oslo, Oslo, Norway. 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