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Original article
peer-reviewed

Analysis of Neurological Adverse Events Reported in VigiBase From COVID-19 Vaccines



Abstract

Background: Fifteen COVID-19 vaccines have been granted emergency approval before the completion of conventional phases of clinical trials. The present study aimed to analyze the neurological adverse events (AEs) post-COVID-19 vaccination and focuses on determining the association of AEs with the vaccine.

Methodology: The neurological AEs reported for COVID-19 vaccines in the WHO pharmacovigilance database (VigiBase) were extracted from the System Organ Classes - neurological disorders and investigations. Descriptive statistics are reported as percentage and frequency and the disproportionality analysis was also conducted.

Results: For the neurological system, 19,529 AEs were reported. Of these, 15,638 events were reported from BNT162b2 vaccine, 2,751 from AZD1222 vaccine, 1,075 from mRNA-1273 vaccine, eight from Vero vaccine, two from Covaxin, and for 55 AEs, vaccine name was not mentioned. The reason for more AEs reported with BNT162b2 can be maximum vaccination with BNT162b2 vaccine in the study period. According to the disproportionality analysis based on IC025 value, ageusia, anosmia, burning sensation, dizziness, facial paralysis, headache, hypoaesthesia, lethargy, migraine, neuralgia, paresis, parosmia, poor sleep quality, seizure, transient ischemic attack, and tremor are some of the AEs that can be associated with the administration of the vaccine.

Conclusion: The vaccines should be monitored for these AEs till the causality of these AEs with COVID-19 vaccines is established through further long-term follow-up studies. These neurological AEs reported in VigiBase should not be taken as conclusive and mass vaccination should be carried out to control the pandemic until a definite link of these adverse effects is established.

Introduction

COVID-19 is an acute respiratory illness caused by the SARS-CoV-2 virus. Since its initial report in December 2019 in Wuhan, China, COVID-19 has rattled the global research to combat this deadly virus. As of now on April 7, 2021, it has infected 270,791,973 individuals including 5,318,216 deaths [1]. The sudden spike in the number of cases led to a shortage of various medicines and personal protective equipment in many countries and imposed a lockdown to stop the spread of the virus further worsening the daily life of people across the globe [2-4]. The research related to the COVID-19 virus is exploring mainly four arenas- dissecting the virus itself, exploring the diagnostic tools, finding the prevention and the treatment modalities. Various modalities, repurposed drugs, complementary and alternative medicines, vitamins, nutraceuticals, and immune-boosters were being used to tackle the condition as there was no definitive treatment [5-9]. The drugs being explored for treatment include drugs like hydroxychloroquine, remdesivir, favipiravir, tocilizumab, ivermectin, baricitinib, etc. Numerous studies were conducted to observe the safety and efficacy of these drugs in COVID-19 [6,7,10-12]. As of May 19, 2021, 15 vaccines were approved for COVID-19 namely Comirnaty (BNT162b2), Moderna COVID‑19 vaccine (mRNA-1273), AstraZeneca COVID-19 vaccine (AZD1222); also known as Vaxzevria and Covishield, Sputnik V, Sputnik Light, COVID-19 vaccine Janssen (JNJ-78436735; Ad26.COV2.S), CoronaVac, BBIBP-CorV, EpiVacCorona, Convidicea (Ad5-nCoV), Covaxin, WIBP-CorV, CoviVac, ZF2001, and QazVac (QazCovid-in) [13]. In view of the initial pandemic scenario, all vaccines were granted emergency approval trials based on the data generated from the initial phases of clinical trials, before completion of all the phases of a clinical trial [14-16]. The remaining phases of clinical trials were continuing to confirm their safety and efficacy. Thus, it was imperative to monitor the adverse events reported post-COVID-19 vaccination. There were scattered reports of neurological adverse events following the COVID-19 vaccination [17-19]. Thus, the present study was planned by the authors in order to evaluate the neurological adverse events reported in the WHO pharmacovigilance database, VigiBase.

VigiBase is the global post-marketing pharmacovigilance database maintained by WHO, which contains the adverse events of approved drugs reported from all over the world [20]. VigiBase database had been used previously to analyze the safety profile of many drugs and vaccines including the therapies used for treatment and prevention of COVID-19 [6,7,10,11,21,22]. We evaluated all the neurological adverse events reported for COVID-19 vaccines in VigiBase. We also analyzed if there exists any relationship between the reported adverse events and the vaccines. This study was also planned to generate a safety signal for COVID-19 vaccines in the prime stage and provide a platform for other studies for generating or detecting the safety data of COVID-19 vaccines.

Materials & Methods

The authors used VigiBase for analysis of adverse events related to COVID-19 Vaccines reported between December 15, 2020, and January 24, 2021. VigiBase is a global pharmacovigilance database established in 1978 and consists of over 20 million reports of suspected adverse events reported since its origin by its 130 member countries which represent 90% of the world population [20,23,24].

VigiBase is linked with MedDRA, WHO-ART, WHO-ICD in order to facilitate uniform data entry, retrieval, and analysis. The adverse events are reported as Individual Case Safety Report (ICSR). ICSR is also termed as “spontaneous” or “voluntary” when the reports are generated in the post-marketing phase of the drug when it is available for general use [20,23-25].

The adverse events reported in VigiBase are in a structured form that consists of information regarding three domains: patient (age, gender, country, and continent of residence), drug (name, start and end date, dose, route of administration, and the indication for use), and adverse event (type of event, onset date, seriousness, causality, and the outcome). The drugs are coded in VigiBase in alliance with the WHO Drug Dictionary enhanced including the Anatomical Therapeutic Classification. The adverse events are also reported and coded in accordance with the Medical Dictionary for Regulatory Authorities (MedDRA) and the WHO adverse reaction Terminology [25,26]. The information in the MedDRA is contained as highly standardized medical terminology to allow the global sharing of consistent regulatory information for drugs used by humans [27,28]. In the VigiBase, the information related to adverse events is recorded in accordance with MedDRA in a highly specific hierarchical order containing five levels: lowest level terms (LTTs), preferred terms (PTs), high-level terms (HLTs), high-level group terms (HLGTs), and system organ classes (SOCs) [28,29].

In the present study, the SOC and PT were used for analysis. The PT contains the specific disease, symptom, therapeutic indication, and surgical or medical procedures. The PT is arranged into SOC according to the etiology (infections and infestations), manifestation site (e.g., neurological disorder, musculoskeletal disorder), or purpose (medical or surgical procedure) [30].

The present study incorporated all suspected neurological adverse events reported in VigiBase after administration of COVID-19 vaccines - BNT162b2, AZD1222, mRNA-1273, Covaxin, and unknown vaccines (vaccine for which no name is mentioned in the ICSR form) between December 15, 2020, and January 24, 2021. The authors extracted SOC - neurological disorders and investigations from the database. The SOC investigation was cleaned further to remove all adverse events except for those related to the neurological system. The individual neurological adverse events are reported as frequency and percentage. The authors also used disproportionality analysis, the method of signal detection for the adverse events that are spontaneously reported in the database. In disproportionality analysis, the Frequentist and the Bayesian information component (IC) methods are applied to compare the drug adverse event pair with the other drug adverse events pairs of the database to evaluate if the observed frequency of the events for a drug is more than expected [31-35].

The IC was used by the authors to evaluate the relationship between the specific adverse events to COVID-19 vaccine administration. IC is a Bayesian method of signal generation, and it can avoid false-positive results when events are low [31,35]. In order to link a particular adverse event to a specific drug (COVID-19 vaccine in the current study), the lower limit of IC025 should have a positive value. Since in the present study, the frequency of many adverse events was less than four, thus the authors used only IC025 values and not the ROR or PRR values. Although, in this study, the reporting odds ratios (ROR) and proportional odds ratios (POR) were not used to link the events with the vaccines, but for the events with positive IC025, the ROR and POR with 95% credibility Interval were also mentioned. The event was not considered to be linked to the vaccine if its IC025 value was negative and the ROR or PRR was more than 1. The IC025 values were calculated separately for the different age groups and genders. Descriptive statistics were reported in the form of frequency and percentage. Statistical Package for Social Science version 17 (SPSS Inc., Chicago, IL, USA) was used for analysis. Institutional Ethics Committee exempted this project from the ethics review as this study is based on secondary data analysis which involves no direct contact with any human subject.

Results

This study is based on adverse events reported in the VigiBase database from December 15, 2020 to January 24, 2021. In this period, 103,954 adverse events were reported from 30,532 subjects who were administered the COVID-19 vaccine. Out of 103,954, 19,529 AEs were related to clinical events and investigations related to the neurological system. Total 15,638 events were reported from the BNT162b2 vaccine, 2,751 from AZD1222 vaccine, 1,075 from mRNA-1273 vaccine, eight from Vero vaccine, two from Covaxin, and for 55 AEs vaccine name was not mentioned. Neurological AEs reported from the abovementioned vaccines are summarized in Supplementary Tables 1-6.

As per the disproportionality analysis based on IC025 value, ageusia, allodynia, anesthesia, anosmia, aura, balance disorders, burning sensation, cervicobrachial syndrome, cluster headache, dizziness, postural dizziness, dysgeusia, exertional headache, facial paralysis, facial paresis, facial spasm, febrile convulsion, head discomfort, headache, hemiparaesthesia, hemiparesis, hyperaesthesis, hypersomnia, hypoaesthesia, hypogeusia, hyperresponsive to stimuli, hyposomnia, ischemic stroke, lethargy, loss of consciousness, migraine, migraine with aura, monoparesis, neuralgia, paraesthesia, paresis, parosmia, petit mal epilepsy, poor sleep quality, presyncope, seizure, sensory disturbance, sensory loss, sinus headache, syncope, taste disorder, tension headache, transient global amnesia, transient ischemic attack, tremor, tunnel vision, and unresponsive to stimuli are the AEs, which can be considered to be associated with the administration of the vaccine (Table 1).

TermText Stratification  (Full database/ Age/Gender) Population OR   IC025 POR
Ageusia Age group 18 - 44 years 6.3 (5.0-7.9) 2.223 6.2(5.0-7.8)
Ageusia Age group Age group 45 - 64 years 4.1(3.1-5.3) 1.567 4.0(3.1-5.3)
Ageusia Age group Age Group unknown 4.9(2.9-8.3) 1.245 4.9(2.9-8.2)
Ageusia Gender Gender Male 5.8(4.3-7.9) 1.968 5.8 (4.3-7.8)
Ageusia Gender Gender Female 4.0(3.3-4.8) 1.668 3.9(3.3-4.8)
Ageusia Full database All subjects 4.4(3.7-5.1) 1.864 4.4(3.7-5.1)
Allodynia Age group Age group 18 - 44 years 14.1(6.2-31.9) 1.404 14.1(6.2-31.9)
Allodynia Gender Gender Female 8.6(3.6-20.8) 0.808 8.6(3.6-20.8)
Allodynia Full database All subjects 11.2(5.3-23.6) 1.466 11.2(5.3-23.6)
Anesthesia Age group Age group 45 - 64 years 80.2(38.1-168.8) 2.621 80.2(38.1-168.5)
Anesthesia Gender Gender Female 34.6(17.7-68.0) 2.520 34.6(17.7-68.0)
Anesthesia Full database All subjects 32.1(17.0-60.5) 2.640 32.1(17.0-60.4)
Anosmia Age group Age group 18 - 44 years 10.3(7.9-13.3) 2.808 10.2(7.9-13.3)
Anosmia Age group Age group 45 - 64 years 5.9(4.3-8.1) 1.976 5.9(4.3-8.1)
Anosmia Age group Age group 65 - 74 years 11.3(4.2-30.3) 0.658 11.3(4.2-30.0)
Anosmia Age group Age Group unknown 12.2(7.7-19.9) 2.508 12.1(7.7-18.9)
Anosmia Gender Gender Male 12.8(9.3-17.6) 2.959 12.7(9.3-17.5)
Anosmia Gender Gender Female 6.3(5.1-7.9) 2.271 6.3(5.1-7.8)
Anosmia Full database All subjects 7.7(6.5-9.3) 2.630 7.7(6.5-9.2)
Aura Age group Age group 18 - 44 years 5.0(2.2-11.2) 0.548 5.0(2.2-11.2)
Aura Gender Gender Female 3.7(1.6-8.2) 0.224 3.7(1.6-8.2)
Aura Gender Gender Male 11.2(3.6-34.8) 0.133 11.2(3.6-34.7)
Aura Full database All subjects 4.9(2.6-9.5) 0.935 4.9(2.6-9.5)
Balance disorder Age group Age group ≥ 75 years 2.2(1.4-3.4) 0.422 2.2(1.4-3.4)
Balance disorder Gender Gender Male 1.7(1.1-2.4) 0.128 1.7(1.1-2.4)
Burning sensation Age group Age group 18 - 44 years 1.5(1.2-1.8) 0.186 1.5 (1.2-1.8)
Burning sensation Age group Age group 45 - 64 years 1.6(1.2-2.1) 0.283 1.6(1.2-2.1)
Burning sensation Gender Gender Female 1.4(1.1-1.6) 0.185 1.4(1.1-1.6)
Burning sensation Full database All subjects 1.5(1.3-1.8) 0.356 1.5(1.3-1.8 )
Cervicobrachial syndrome Gender Gender Female 7.0(2.9-17.0) 0.645 7.0(2.9-17.0)
Cervicobrachial syndrome Full database All subjects 7.4(3.3-16.6) 0.929 7.4(3.3-16.6)
Cluster headache Age group Age group 18 - 44 years 15.2(9.2-25.1) 2.566 15.1(9.2-25.0)
Cluster headache Age group Age group 45 - 64 years 18.7(10.5-33.2) 2.493 18.6(10.5-33.1)
Cluster headache Gender Gender Female 24.0(16.4-35.0) 3.468 24.0(16.4-35.0)
Cluster headache Full database All subjects 19.5(13.6-27.9) 3.333 19.5(13.6-27.8)
Dizziness Age group Age group 0 - 27 days 15.3(5.4-43.6) 0.761 13.6(5.4-34.4)
Dizziness Age group Age group 28 days to 23 months 81.3(46.6-141.8) 3.530 73.3(44.4-121.2)
Dizziness Age group Age group 2 - 11 years 4.7(2.3-9.7) 0.723 4.5(2.3-8.7)
Dizziness Age group Age group 18 - 44 years 2.6(2.5-2.7) 1.206 2.4(2.3-2.5)
Dizziness Age group Age group 45 - 64 years 2.2(2.1-2.4) 0.973 2.1(2.0-2.2)
Dizziness Age group Age group 65 - 74 years 2.2(1.7-2.8) 0.679 2.1(1.7-2.6)
Dizziness Age group Age group ≥ 75 years 1.4(1.2-1.6) 0.191 1.4(1.2-1.6)
Dizziness Age group Age Group unknown 3.1(2.7-3.6) 1.334 3.0(2.6-3.4)
Dizziness Gender Gender Male 2.2(2.0-2.5) 0.971 2.2(2.0-2.4)
Dizziness Gender Gender Female 2.7(2.6-2.8) 1.279 2.5(2.4-2.6)
Dizziness Gender Gender not known 4.4(3.4-5.7) 1.630 4.2(3.3-5.3)
Dizziness Full database All subjects 2.8(2.7-2.9) 1.356 2.7(2.6-2.7)
Dizziness postural Age group Age group 18 - 44 years 21.1(16.7-26.6) 3.790 21.0(16.7-26.4)
Dizziness postural Age group Age group 45 - 64 years 13.7(10.2-18.5) 3.095 13.7(10.2-18.5)
Dizziness postural Age group Age group 65 - 74 years 16.4(6.8-39.6) 1.239 16.3(6.8-39.1)
Dizziness postural Age group Age group ≥ 75 years 6.8(3.2-14.4) 1.030 6.8(3.2-14.3)
Dizziness postural Age group Age Group unknown 13.8(6.9-27.7) 1.802 13.7(6.9-27.5)
Dizziness postural Gender Gender Male 8.5(5.3-13.5) 2.065 8.4(5.3-13.4)
Dizziness postural Gender Gender Female 17.4(14.5-20.9) 3.711 17.3(14.5-20.8)
Dizziness postural Gender Gender not known 48.6(19.9-118.5) 1.654 48.3(19.9-117.2)
Dizziness postural Full database All Subjects 15.5(13.1-18.3) 3.605 15.4(13.1-18.2)
Dysgeusia Age group Age group 18 - 44 years 3.7(3.3-4.3) 1.665 3.7(3.2-4.2)
Dysgeusia Age group Age group 45 - 64 years 3.7(3.2-4.3) 1.642 3.7(3.2-4.2)
Dysgeusia Age group Age group 65 - 74 years 3.1(1.7-5.8) 0.458 3.1(1.7-5.7)
Dysgeusia Age group Age Group unknown 3.1(2.2-4.5) 0.998 3.1(2.1-4.5)
Dysgeusia Gender Gender Male 2.6(2.0-3.4) 0.950 2.6(2.0-3.4)
Dysgeusia Gender Gender Female 3.6(3.3-4.0) 1.683 3.6(3.2-4.0)
Dysgeusia Gender Gender not known 7.6(4.9-11.9) 1.982 7.5(4.8-11.5)
Dysgeusia Full database All Subjects 3.7(3.4-4.1) 1.733 3.7(3.4-4.0)
Dysstasia Age group Age group 18 - 44 years 2.5(1.6-4.0) 0.557 2.5(1.6-4.0)
Exertional headache Gender Gender Female 57.8(20.6-162.3) 1.228 57.8(20.6-162.2)
Exertional headache Full database All Subjects 50.7(18.4-139.6) 1.208 50.7(18.4-139.6)
Facial paralysis Age group Age group 18 - 44 years 5.7(4.4-7.3) 2.057 5.7(4.4-7.2)
Facial paralysis Age group Age group 45 - 64 years 6.8(5.1-9.1) 2.218 6.8(5.1-9.0)
Facial paralysis Age group Age group ≥ 75 years 11.7(6.8-20.3) 2.161 11.6(6.7-20.1)
Facial paralysis Gender Gender Male 12.8(9.7-16.9) 3.069 12.7(9.6-16.7)
Facial paralysis Gender Gender Female 6.1(5.0-7.5) 2.258 6.1(5.0-7.5)
Facial paralysis Age group Age Group unknown 18.3(11.9-28.1) 3.008 18.1(11.8-27.8)
Facial paralysis Full database All Subjects 7.6(6.4-8.9) 2.631 7.6(6.4-8.9)
Facial paresis Age group Age group 18 - 44 years 5.2(3.1-8.8) 1.311 5.2(3.1-8.8)
Facial paresis Age group Age group 45 - 64 years 5.1(2.5-10.2) 0.861 5.1(2.5-10.2)
Facial paresis Age group Age group ≥ 75 years 10.4(3.3-32.4 ) 0.093 10.4(3.3-32.3)
Facial paresis Gender Gender Male 7.9(3.5-17.6) 0.984 7.9(3.5-17.6)
Facial paresis Gender Gender Female 4.7(3.0-7.4) 1.407 4.7(3.0-7.4)
Facial paresis Full database All Subjects 5.6(3.8-8.2) 1.750 5.6(3.8-8.2)
Facial spasm Age group Age group 18 - 44 years 7.2(3.4-15.2) 1.065 7.2(3.4-15.2)
Facial spasm Gender Gender Female 6.2(3.1-12.4) 1.068 6.2(3.1-12.4)
Facial spasm Full database All Subjects 6.1(3.2-11.8) 1.173 6.1(3.2-11.8)
Febrile convulsion Age group Age group 18 - 44 years 7.2(2.7-19.5) 0.343 7.2(2.7-19.5)
Head discomfort Age group Age group 18 - 44 years 2.2(1.5-3.2) 0.544 2.2(1.5-3.2)
Head discomfort Age group Age group 45 - 64 years 2.7(1.9-3.8) 0.853 2.7(1.9-3.7)
Head discomfort Gender Gender Female 2.1(1.6-2.7) 0.643 2.1(1.6-2.7)
Head discomfort Gender Gender Male 2.7(1.5-4.7) 0.393 2.7(1.5-4.7)
Head discomfort Full database All Subjects 2.4(1.9-3.0) 0.865 2.4(1.9-3.0)
Headache Age group Age group 0 - 27 days 43.9(18.9-101.7) 2.151 35.0(17.9-68.6)
Headache Age group Age group 28 days to 23 months 207.9(143.8-300.4) 5.244 147.7(113.4-192.4)
Headache Age group Age group 2 - 11 years 13.2(8.9-19.6) 2.560 9.4(7.1-12.3)
Headache Age group Age group 12 - 17 years 3.6(1.7-8.0) 0.291 3.1(1.7-5.7)
Headache Age group Age group 18 - 44 years 9.0(8.7-9.3) 2.650 6.6(6.4-6.8)
Headache Age group Age group 45 - 64 years 8.8(8.4-9.1) 2.645 6.6(6.4-6.8)
Headache Age group Age group 65 - 74 years 6.9(5.7-8.3) 2.261 5.8(5.0-6.7)
Headache Age group Age group ≥ 75 years 4.6(4.0-5.3) 1.882 4.3(3.8-4.8)
Headache Age group Age Group unknown 8.5(7.7-9.4) 2.660 7.0(6.4-7.5)
Headache Gender Gender Male 9.9(9.3-10.4) 2.890 7.9(7.5-8.2)
Headache Gender Gender Female 8.9(8.6-9.1) 2.680 6.6(6.5-6.8)
Headache Gender Gender not known 18.0(15.5-20.9) 3.505 13.4(12.0-14.9)
Headache Full database All Subjects 10.0(9.7-10.2) 2.871 7.5(7.4-7.7)
Hemiparaesthesia Age group Age group 18 - 44 years 17.1(6.2-46.8) 0.853 17.1(6.2-46.8)
Hemiparaesthesia Gender Gender Female 18.3(7.5-44.7) 1.287 18.3(7.5-44.7)
Hemiparaesthesia Full database All Subjects 21.1(9.4-47.5) 1.660 21.1(9.4-47.5)
Hemiparesis Age group Age group ≥ 75 years 4.9(2.7-8.9) 1.081 4.9(2.7-8.8)
Hyperaesthesia Age group Age group 18 - 44 years 2.8(1.9-4.2) 0.797 2.8(1.9-4.2)
Hyperaesthesia Gender Gender Female 2.7(1.9-3.8) 0.829 2.7(1.9-3.8)
Hyperaesthesia Full database All Subjects 2.7(1.9-3.7) 0.890 2.7(1.9-3.7)
Hypersomnia Age group Age group 45 - 64 years 3.0(2.0-4.3) 0.897 3.0(2.0-4.3)
Hypersomnia Gender Gender Female 1.7(1.3-2.3) 0.283 1.7(1.3-2.3)
Hypersomnia Full database All Subjects 1.6(1.2-2.2) 0.260 1.6(1.2-2.2)
Hypoaesthesia Age group Age group 18 - 44 years 2.7(2.4-2.9) 1.233 2.6(2.4-2.9)
Hypoaesthesia Age group Age group 45 - 64 years 2.8(2.5-3.1) 1.258 2.7(2.4-3.1)
Hypoaesthesia Age group Age group 65 - 74 years 2.7(1.6-4.7) 0.459 2.7(1.6-4.60
Hypoaesthesia Age group Age Group unknown 2.3(1.6-3.3) 0.601 2.3(1.6-3.2)
Hypoaesthesia Gender Gender Male 2.5(2.0-3.1) 0.985 2.5(2.0-3.0)
Hypoaesthesia Gender Gender Female 3.0(2.8-3.3) 1.459 3.0(2.8-3.2)
Hypoaesthesia Gender Gender not known 6.5(4.0-10.6) 1.704 6.4(4.0-10.3)
Hypoaesthesia Full database All Subjects 3.3(3.1-3.5) 1.586 3.2(3.0-3.5)
Hypogeusia Age group Age group 18 - 44 years 4.7(1.9-11.4) 0.278 4.7(1.9-11.4)
Hypogeusia Gender Gender Male 6.8(2.5-18.1) 0.305 6.8(2.5-18.1)
Hypogeusia Full database All Subjects 3.0(1.5-6.0) 0.252 3.0(1.5-6.0)
Hyporesponsive to stimuli Gender Gender Female 4.7(2.0-11.4) 0.285 4.7(2.0-11.4)
Hyposmia Age group Age group 18 - 44 years 6.0(2.2-16.0) 0.190 6.0(2.2-16.0)
Hyposmia Age group Age group 45 - 64 years 8.1(3.6-18.0) 0.996 8.0(3.6-18.0)
Hyposmia Gender Gender Male 9.9(3.2-30.7) 0.067 9.8(3.2-30.6)
Hyposmia Gender Gender Female 5.7(2.7-12.1) 0.856 5.7(2.7-12.1)
Hyposmia Full database All Subjects 6.6(3.5-12.3) 1.342 6.6(3.5-12.3)
Hypotonia Age group Age group ≥ 75 years 5.3(2.4-11.8) 0.605 5.3(2.4-11.7)
Ischaemic stroke Age group Age group ≥ 75 years 3.6(2.0-6.6) 0.726 3.6(2.0-6.6)
Lethargy Gender Not known 17.0(11.2-25.7) 2.976 16.5(11.0-24.8)
Lethargy Age group Age group 18 - 44 years 8.0(7.0-9.1) 2.734 7.9(6.9-8.9)
Lethargy Age group Age group unknown 9.0(6.6-12.2) 2.545 8.9(6.6-12.0)
Lethargy Full database All Subjects 5.9(5.4-6.5) 2.390 5.8(5.3-6.4)
Lethargy Gender Gender Female 5.7(5.1-6.4) 2.317 5.6(5.1-6.3)
Lethargy Age group Age group 45 - 64 years 5.8(4.9-6.8) 2.223 5.7(4.8-6.8)
Lethargy Gender Gender Male 5.9(4.9-7.2) 2.219 5.9(4.8-7.1)
Lethargy Age group Age group ≥ 75 years 6.6(4.8-9.1) 2.096 6.5(4.7-8.9)
Loss of consciousness Age group Age group ≥ 75 years 1.8(1.2-2.7) 0.113 1.7(1.2-2.6)
Migraine Age group Age group 2 - 11 years 32.6(10.3-102.9) 0.507 31.8(10.4-97.3)
Migraine Age group Age group 18 - 44 years 4.3(3.8-4.8) 1.887 4.2(3.8-4.7)
Migraine Age group Age group 45 - 64 years 4.1(3.5-4.8) 1.748 4.0(3.4-4.8)
Migraine Age group Age group 65 - 74 years 5.0(2.1-12.2.) 0.349 5.0(2.1-12.0)
Migraine Age group Age group ≥ 75 years 4.7(2.1-10.6) 0.500 4.7(2.1-10.6)
Migraine Age group Age Group unknown 3.5(2.5-5.0) 1.203 3.5(2.5-4.9)
Migraine Gender Gender Male 7.5(5.8-9.6) 2.420 7.4(5.8-9.5)
Migraine Gender Gender Female 4.0(3.7-4.4) 1.845 4.0(3.6-4.4)
Migraine Gender Gender not known 8.2(5.1-13.3) 1.976 8.1(5.0-12.9)
Migraine Full database All Subjects 5.2(4.8-5.7) 2.223 5.1(4.7-5.6)
Migraine with aura Age group Age group 18 - 44 years 7.3(4.6-11.7) 1.872 7.3(4.6-11.6)
Migraine with aura Age group Age group 45 - 64 years 6.7(3.2-14.1) 1.007 6.7(3.2-14.1)
Migraine with aura Gender Gender Female 6.7(4.5-10.1) 1.945 6.7(4.5-10.1)
Migraine with aura Full database All Subjects 8.4(5.7-12.3) 2.279 8.4(5.7-12.3)
Monoparesis Gender Gender Female 3.6(1.6-8.1) 0.209 3.6(1.6-8.1)
Neuralgia Age group Age group 18 - 44 years 2.9(2.1-4.1) 0.962 2.9(2.1-4.1)
Neuralgia Age group Age group 45 - 64 years 1.9(1.2-2.9) 0.203 1.9(1.2-2.9)
Neuralgia Gender Gender Male 2.3(1.2-4.4) 0.008 2.3(1.2-4.4)
Neuralgia Gender Gender Female 2.1(1.6-2.7) 0.592 2.1(1.6-2.7)
Neuralgia Full database All Subjects 2.3(1.8-3.0) 0.799 2.3(1.8-3.0)
Paraesthesia Age group Age group 28 days to 23 months 70.1(22.1-222.2) 0.634 68.6(22.2-212.3)
Paraesthesia Age group Age group 18 - 44 years 3.6(3.3-3.9) 1.676 3.5(3.2-3.7)
Paraesthesia Age group Age group 45 - 64 years 3.9(3.5-4.2) 1.756 3.7(3.4-4.1)
Paraesthesia Age group Age group 65 - 74 years 2.4(1.4-4.0) 0.317 2.4(1.4-4.0)
Paraesthesia Age group Age group ≥ 75 years 1.7(1.1-2.6) 0.049 1.7(1.1-2.6)
Paraesthesia Age group Age group unknown 3.0(2.3-3.9) 1.138 3.0(2.3-3.8)
Paraesthesia Gender Gender Male 3.2(2.7-3.7) 1.380 3.1(2.6-3.6)
Paraesthesia Gender Gender Female 4.3(4.0-4.5) 1.949 4.1(3.9-4.4)
Paraesthesia Gender Gender not known 3.8(2.4-6.1) 1.065 3.8(2.4-6.0)
Paraesthesia Full database All Subjects 4.4(4.2-4.7) 2.021 4.3(4.1-4.6)
Paresis Age group Age Group unknown 14.2(4.6-44.3) 0.248 14.2(4.6-44.2)
Parosmia Age group Age group 18 - 44 years 2.8(1.7-4.7) 0.574 2.8(1.7-4.7)
Parosmia Age group Age group 45 - 64 years 2.4(1.4-4.1) 0.350 2.4(1.4-4.1)
Parosmia Gender Gender Female 2.5(1.7-3.7) 0.702 2.5(1.7-3.7)
Parosmia Full database All Subjects 2.5(1.8-3.6) 0.763 2.5(1.8-3.6)
Petit mal epilepsy Age group Age group ≥ 75 years 12.8(4.1-39.9) 0.195 12.7(4.1-39.8)
Poor quality sleep Age group Age group 18 - 44 years 2.4(1.5-3.7) 0.462 2.4(1.5-3.7)
Poor quality sleep Gender Gender Female 1.5(1.1-2.2) 0.019 1.5(1.1-2.2)
Poor quality sleep Full database All Subjects 1.6(1.1-2.2) 0.133 1.6(1.1-2.2)
Presyncope Age group Age group 18 - 44 years 9.1(7.8-10.7) 2.869 9.0(7.7-10.5)
Presyncope Age group Age group 45 - 64 years 8.3(6.7-10.4) 2.645 8.3(6.7-10.3)
Presyncope Age group Age group 65 - 74 years 4.8(1.8-12.9) 0.017 4.8(1.8-12.8)
Presyncope Age group Age group ≥ 75 years 2.9(1.6-5.3) 0.450 2.9(1.6-5.3)
Presyncope Age group Age group unknown 14.6(9.6-22.2) 2.805 14.4(9.5-21.9)
Presyncope Gender Gender Male 9.8(7.6-12.7) 2.788 9.8(7.6-12.6)
Presyncope Gender Gender Female 7.3(6.4-8.3) 2.620 7.2(6.3-8.3)
Presyncope Gender Gender not known 17.2(7.7-38.5) 1.551 17.1(7.7-38.0)
Presyncope Full database All Subjects 8.4(7.4-9.4) 2.846 8.3(7.4-9.3)
Seizure Age group Age group ≥ 75 years 1.9(1.2-3.0) 0.162 1.9(1.2-3.0)
Seizure like phenomena Full database All Subjects 3.3(1.6-6.9) 0.247 3.3(1.6-6.9)
Sensory disturbance Age group Age group 45 - 64 years 2.7(1.8-4.1) 0.708 2.7(1.8-4.1)
Sensory disturbance Gender Gender Female 1.7(1.2-2.4) 0.247 1.7(1.2-2.4)
Sensory disturbance Full database All Subjects 1.9(1.4-2.5) 0.433 1.9(1.4-2.5)
Sensory loss Age group Age group 18 - 44 years 3.5(2.2-5.5) 0.952 3.5(2.2-5.5)
Sensory loss Gender Gender Female 2.8(1.8-4.4) 0.683 2.8(1.8-4.4)
Sensory loss Full database All Subjects 2.6(1.7-3.9) 0.617 2.6(1.7-3.9)
Sinus headache Age group Age group 18 - 44 years 10.9(7.7-15.5) 2.673 10.9(7.7-15.5)
Sinus headache Age group Age group 45 - 64 years 6.8(4.4-10.6) 1.863 6.8(4.4-10.6)
Sinus headache Gender Gender Male 7.7(3.5-17.3) 0.969 7.7(3.5-17.3)
Sinus headache Gender Gender Female 8.1(6.2-10.7) 2.491 8.1(6.2-10.7)
Sinus headache Full database All Subjects 9.3(7.1-12.0) 2.708 9.3(7.2-12.0)
Syncope Age group Age group 18 - 44 years 1.8(1.5-2.1) 0.579 1.8(1.5-2.1)
Syncope Age group Age group 45 - 64 years 1.6(1.3-2.0) 0.345 1.6(1.3-2.0)
Syncope Age group Age group 65 - 74 years 2.6(1.4-4.7) 0.289 2.6(1.4-4.6)
Syncope Age group Age Group unknown 2.6(1.7-4.0) 0.627 2.6(1.7-3.9)
Syncope Gender Gender Male 1.5(1.2-2.0) 0.171 1.5(1.2-2.0)
Syncope Gender Gender Female 1.7(1.5-1.9) 0.526 1.6(1.5-1.9)
Syncope Full database All Subjects 1.7(1.5-1.9) 0.573 1.7(1.5-1.9)
Taste disorder Age group Age group 18 - 44 years 3.7(2.7-5.2) 1.303 3.7(2.7-5.2)
Taste disorder Age group Age group 45 - 64 years 3.5(2.4-5.0) 1.162 3.5(2.4-5.0)
Taste disorder Age group Age Group unknown 3.9(1.6-9.3) 0.087 3.9(1.6-9.3)
Taste disorder Gender Gender Male 3.3(1.9-5.8) 0.667 3.3(1.9-5.8)
Taste disorder Gender Gender Female 3.6(2.8-4.6) 1.419 3.6(2.8-4.6)
Taste disorder Full database All Subjects 3.8(3.0-4.7) 1.531 3.8(3.0-4.7)
Tension headache Age group Age group 18 - 44 years 18.6(14.2-24.3) 3.535 18.5(14.2-24.2)
Tension headache Age group Age group 45 - 64 years 13.0(8.6-19.6) 2.692 12.9(8.6-19.6)
Tension headache Age group Age group ≥ 75 years 23.3(9.6-56.6) 1.405 23.2(9.6-56.4)
Tension headache Age group Age Group Unknown 26.2(13.6-50.5) 2.392 26.1(13.5-50.2)
Tension headache Gender Gender Male 18.7(10.6-33.0) 2.510 18.6(10.6-32.9)
Tension headache Gender Gender Female 18.7(15.0-23.4) 3.705 18.7(15.0-23.3)
Tension headache Gender Gender not known 32.9(12.2-88.7) 1.113 32.8(12.2-87.9)
Tension headache Full database All Subjects 21.0(17.1-25.6) 3.912 20.9(17.1-25.5)
Transient global amnesia Age group Age group 45 - 64 years 12.7(4.7-34.3) 0.717 12.7(4.7-34.3)
Transient global amnesia Gender Gender Female 8.0(3.0-21.5) 0.425 8.0(3.0-21.5)
Transient global amnesia Full database All Subjects 5.9(2.2-15.8) 0.193 5.9(2.2-15.8)
Transient ischaemic attack Age group Age group ≥ 75 years 2.2(1.2-3.9) 0.130 2.2(1.2-3.8)
Tremor Age group Age group 18 - 44 years 1.7(1.5-1.9) 0.538 1.6(1.5-1.8)
Tremor Age group Age group 45 - 64 years 1.6(1.4-1.9) 0.447 1.6(1.4-1.9)
Tremor Age group Age group ≥ 75 years 1.5(1.1-2.0) 0.097 1.5(1.1-2.0)
Tremor Gender Gender Female 1.7(1.6-1.9) 0.656 1.7(1.6-1.9)
Tremor Full database All Subjects 1.7(1.6-1.9) 0.660 1.7(1.6-1.9)
Tunnel vision Age group Age group 18 - 44 years 8.8(5.1-15.3) 1.856 8.8(5.1-15.3)
Tunnel vision Gender Gender Male 13.6(5.6-32.7) 1.129 13.6(5.6-32.7)
Tunnel vision Gender Gender Female 9.0(5.1-15.8) 1.818 9.0(5.1-5.8)
Tunnel vision Full database All Subjects 9.9(6.1-15.9) 2.197 9.9(6.1-15.9)
Unresponsive to stimuli Age group Age group 65 - 74 years 20.1(10.7-37.6) 2.353 19.8(10.7-36.8)
Unresponsive to stimuli Age group Age group ≥ 75 years 14.1(10.0-19.9) 2.993 13.9(9.9-19.6)
Unresponsive to stimuli Gender Gender Male 4.4(3.1-6.3) 1.498 4.4(3.1-6.3)
Unresponsive to stimuli Gender Gender Female 2.2(1.6-3.0) 0.634 2.2(1.6-3.0)
Unresponsive to stimuli Full database All Subjects 2.6(2.1-3.3) 1.011 2.6(2.1-3.3)

Discussion

In this study, we inspected the VigiBase, the global pharmacovigilance database for the neurological adverse events reported for the COVID-19 vaccine. There was a total of 15,638 adverse events reported from BNT162b2 vaccine, 2,751 from AZD1222 vaccine, 1,075 from mRNA-1273 vaccine, eight from Vero vaccine, two from Covaxin, and for 55 AEs vaccine name was not mentioned.

When the disproportionality analysis was done based on the IC025 value, it was found that ageusia, allodynia, anaesthesia, anosmia, aura, balance disorders, burning sensation, cervicobrachial syndrome, cluster headache, dizziness, postural dizziness, dysgeusia, exertional headache, facial paralysis, facial paresis, facial spasm, febrile convulsion, head discomfort, headache, hemiparaesthesia, hemiparesis, hyperaesthesis, hypersomnia, hypoaesthesia, hypogeusia, hyperresponsive to stimuli, hyposomnia, ischemic stroke, lethargy, loss of consciousness, migraine, migraine with aura, monoparesis, neuralgia, paraesthesia, paresis, parosmia, petit mal epilepsy, poor sleep quality, presyncope, seizure, sensory disturbance, sensory loss, sinus headache, syncope, taste disorder, tension headache, transient global amnesia, transient ischemic attack, tremor, tunnel vision, and unresponsive to stimuli are the AEs those could be considered to have an association with the vaccine administration.

Frequently observed adverse events following vaccinations were headache, dizziness, paresthesia, hypoesthesia, lethargy, and migraine. Even though the total number of adverse events were high among individuals receiving BNT162b2 mRNA vaccine yet higher number of events in BNT162b2 mRNA vaccine can be explained as this is the first vaccine to receive emergency use authorization from USFDA, large number doses administration during the analysis period and a shorter interval between the two doses [36].

Polack et al. observed that frequently observed systemic adverse events following BNT162b2 mRNA vaccine second dose administration were fatigue (59%), headache (52%) in the younger population as compared to 51% and 39% among the older population, respectively [16]. In our analysis, headache accounted for 45.46% of the total adverse events with the BNT162b2 vaccine.

The fact sheet for healthcare providers administering BNT162b2 vaccine as published by FDA reported incidence of headache as 55.1% in participants of 16 years of age and older after the first dose and (75.5%) in adolescents of 12 through 15 years of age. In patients of age group 18-55 years reported that the prevalence of headache was 41.9% after dose 1 and 51.7% after dose 2 and 25.2% dose 1 and 39.0 % after dose 2 in 56 years of age and older vaccine recipients [37].

Similar adverse events were reported in the mRNA-1273 vaccine group. In clinical studies, adverse events were not presented as neurological per se, however, this analysis primarily focused on neurological manifestations. Headache was observed in 32.7 % of the total patients after the first vaccination and 58.6% after second vaccination and in both the instances the probability of headache was more in the ≥18 to <65 years group (first vaccination [35.3%] and second vaccination [62.8%]) as compared to the ≥65 years group recipients (first vaccination [24.5%] and second vaccination [46.2%]), respectively [38,39]. Similar results were published by the UK Department of Health and Social Care and the Medicines & Healthcare products Regulatory Agency for the AZD1222 vaccine where reporting AEs related to the nervous system disorders they showed headache as a very common category (Frequencies of occurrence: ≥1/10) which was reported by 52.6% of the vaccine recipients and as followed by dizziness, which was categorized as uncommon (frequencies of occurrence ≥1/1,000 to <1/100) [40]. Bell’s palsy was reported by four participants administered the BNT162b2 and by three participants in the mRNA-1273 vaccine group [37,39]. However, due to insufficient evidence and information, the causal relationship with the vaccines could not be established. The AEs reported with these COVID-19 vaccines may not be a true representation because neurological AEs like headaches are a common occurrence with vaccinations. A study by Cocores et al. conducted on Vaccine Adverse Events Reporting System (VAERS) reported that headache was the fifth most commonly reported adverse event post-vaccination after administration of any vaccine [41].

The disproportionality analysis of this study shows that the reactogenicity of the vaccine among individuals between 18 and 65 years was higher than the individuals above 65 years. This finding was supported by a few previously published clinical studies where a similar type of difference was observed with mRNA-1273, BNT162b2, and AZD1222 vaccines [16,38,42].

Early analysis of all adverse events following vaccination as reported in the COVID-19 vaccine safety update Advisory Committee on Immunization Practices (ACIP) by March 1, 2021, shows that more than 90% were non-serious in nature and headache was the commonest reported AE in both the mRNA vaccines with 20% with BNT162b2 and 23.4 % with the mRNA-1273 vaccine [43]. In a later report as of June 23, 2021, the ACIP in their early safety data of Pfizer-BioNTech vaccination in persons aged 12-15 years and 16-25 years old reported headache as one of the commonest reported adverse events [44]. Similar reports of headache (22.4%) were also reported by the Morbidity and Mortality Weekly Report by CDC, as per the data collected in VAERS in the early phase of vaccination [45]. This difference may be because of the inclusion of local and systemic adverse events, whereas in this study we have included only systemic neurological manifestations. The serious adverse events reported in the VigiBase need to be scrutinized for their association with vaccine administration. In the earlier clinical trials, the majority of serious adverse events were either unrelated to the vaccine or were coincidental due to age-related risk factors. 

Immune reactogenicity to vaccines refers to a group of reactions that are observed immediately after vaccination and are a physical presentation of the inflammatory response to the vaccination. Reactogenicity is determined by either host factors such as age, gender, preexisting immunity or vaccine characteristics, or both [46]. Systemic manifestations of reactogenicity are either due to the vaccine or its adjuvants or both. Presentation of these manifestations varies from fever, headache, dizziness, to seizures and life-threatening anaphylaxis. The systemic pyrogens and other immune mediators cross-talk with the nervous system through the vagus nerve, at the blood-brain barrier, and circumventricular organs. All adjuvant systems induce transient systemic innate responses, which include an increase in the levels of IL-6 and C-reactive protein (CRP), usually peaking at 24 hours after vaccination and subsides to the baseline values within one to three days [47].

The vaccine adjunct can also have a role in reactogenicity. The mRNA vaccines enveloped with lipid nanoparticle (LNP) based delivery system mimics as virus and prevent them from enzymatic digestion along with enhancing immunogenicity without integrating with the genome. However, mRNA itself causes immunogenicity with activation of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), Interleukin (IL)-6 and IL-12 and other innate reactivity manifests as systemic reactions including neurological adverse events. LNP used as an adjuvant precipitates reactogenicity through B-cell amplification and antigen-specific CD4+ and CD8+ T cell responses [48].

Strength of study

This study is based on VigiBase, a large global database of spontaneous reports of AEs used by Uppsala Monitoring Centre, Sweden to generate AEs related signals and used in various published studies to link adverse events with drug use. To avoid any kind of false-positive association, the most conservative method of disproportionality analysis, i.e. IC025 values, was used.

Limitations of the study

The data in this study were taken from VigiBase which includes information from varied sources. The probability that the suspected adverse effect is caused by the drug cannot be ascertained for all the cases. The information provided does not represent the opinion of the UMC or the WHO. The data in the study are from a limited duration and to draw conclusive evidence, larger studies with long-term data need to be analyzed.

Conclusions

Future prospects and conclusion

With numerous molecules being experimented with for the therapy of COVID-19, vaccines have given a ray of hope to curb this pandemic. Almost 15 approved vaccines around the world were being administered in different countries after receiving emergency approval from their respective licensing authorities. These vaccines, in view of an emergency need across the globe, were developed in a short period of time and tried in the clinical trials for a brief period as compared to usual vaccine development. The adverse events with these vaccines are known on the basis of the clinical trials done but long-term and rare adverse events were unclear and are now being revealed with the wide administration drives of vaccination across the globe. All the adverse events associated with any drug or therapy are ultimately reported to the international database called VigiBase hence it is better to analyze their data to find out the common adverse events associated with any therapy across the world. The neurological adverse events associated with these vaccines were not frequent and a headache was one of the common adverse events reported. There were some reported rare serious neurological adverse events but their causal association with the vaccines was to be established. As there can be many predisposing conditions in the patients and interaction with them could also lead to a particular adverse event, hence it was too early to associate a particular adverse event with the vaccines. These reported adverse events can serve as a preliminary signal for potential ADRs associated with these vaccines but based on these results one must not conclude the safety of the above-analyzed vaccines. Moreover, these reported events are adverse events and do not have adverse drug reactions hence definitive causality of the reported events could not be assessed. Therefore long-term robust follow-up studies or cohort studies must be conducted with close monitoring of the adverse events reported establishing the safety of these vaccines.

The current study tries to summarize various neurological manifestations reported in patients who received the vaccines by analyzing the VigiBase, which can help find the common neurological AEs, which can help the prescribers in better management of the public vaccination program and also help in building public awareness and alleviating existing public perceptions.


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Appendices

Broad heading Specific adverse event   Non-serious n (%) (n=11,625) Serious n (%) (n=3,991) Total n (%) (n=15,616)
Nervous System Disorder(N=15616) Acoustic neuritis 1(0.01) 0(0.00) 1(0.01)
Acute disseminated encephalomyelitis 0(0.00) 2(0.05) 1(0.01)
Ageusia 106(0.91) 32(0.80) 138(0.88)
Akathisia 1(0.01) 0(0.00) 1(0.01)
Allodynia 3(0.03) 1(0.03) 4(0.03)
Altered state of consciousness 1(0.01) 5(0.13) 6(0.04)
Amnesia 5(0.04) 3(0.08) 8(0.05)
Anaesthesia 8(0.07) 0(0.00) 8(0.05)
Anosmia 89(0.77) 25(0.63) 114(0.73)
Anticholinergic syndrome 0(0.00) 1(0.03) 1(0.01)
Aphasia 6(0.05) 8(0.20) 14(0.09)
Areflexia 0(0.00) 4(0.10) 4(0.03)
Ataxia 2(0.02) 2(0.05) 4(0.03)
Aura 6(0.05) 2(0.05) 890.05)
Balance disorder 42(0.36) 25(0.63) 67(0.43)
Band sensation 3(0.03) 0(0.00) 3(0.02)
Basal ganglia haemorrhage 0(0.00) 1(0.03) 1(0.01)
Basilar artery occlusion 0(0.00) 1(0.03) 1(0.01)
Bradykinesia 2(0.02) 0(0.00) 1(0.01)
Brain oedema 1(0.01) 0(0.00) 1(0.01)
Brain stem infarction 0(0.00) 1(0.03) 1(0.01)
Burning sensation 104(0.89) 30(0.75) 134(0.86)
Burning sensation mucosal 1(0.01) 0(0.00) 1(0.01)
Carpal tunnel syndrome 1(0.01) 0(0.00) 1(0.01)
Central nervous system lesion 0(0.00) 4(0.10) 4(0.03)
Cerebellar haemorrhage 0(0.00) 1(0.03) 1(0.01)
Cerebellar infarction 0(0.00) 1(0.03) 1(0.01)
Cerebellar stroke 0(0.00) 1(0.03) 1(0.01)
Cerebral artery occlusion 0(0.00) 1(0.03) 1(0.01)
Cerebral haemorrhage 0(0.00) 6(0.15) 6(0.04)
Cerebral infarction 0(0.00) 4(0.10) 4(0.03)
Cerebral venous sinus thrombosis 0(0.00) 1(0.03) 1(0.01)
Cerebrovascular accident 3(0.03) 22(0.55) 25(0.16)
Cervicobrachial syndrome 4(0.03) 1(0.03) 5(0.03)
Cervicogenic headache 1(0.01) 0(0.00) 1(0.01)
Cholinergic syndrome 1(0.01) 0(0.00) 1(0.01)
Clonic convulsion 1(0.01) 0(0.00) 1(0.01)
Clumsiness 1(0.01) 1(0.03) 1(0.01)
Cluster headache 12(0.10) 6(0.15) 18(0.12)
Cognitive disorder 1(0.01) 4(0.10) 5(0.03)
Cold-stimulus headache 1(0.01) 0(0.00) 1(0.01)
Coma 0(0.00) 2(0.05) 1(0.01)
Complex regional pain syndrome 1(0.01) 2(0.05) 3(0.02)
Consciousness fluctuating 0(0.00) 2(0.05) 1(0.01)
Coordination abnormal 6(0.05) 5(0.13) 11(0.07)
Cranial nerve disorder 2(0.02) 2(0.05) 4(0.03)
Dementia 1(0.01) 2(0.05) 3(0.02)
Dementia of the Alzheimer's type, with delirium 0(0.00) 1(0.03) 1(0.01)
Demyelination 0(0.00) 1(0.03) 1(0.01)
Depressed level of consciousness 10(0.09) 11(0.28) 21(0.13)
Disturbance in attention 52(0.45) 18(0.45) 70(0.45)
Dizziness 1954(16.81) 595(14.95) 2549
Dizziness exertional 1(0.01) 1(0.03) 1(0.01)
Dizziness postural 50(0.43) 29(0.73) 79(0.51)
Dreamy state 0(0.00) 1(0.03) 1(0.01)
Drooling 0(0.00) 1(0.03) 1(0.01)
Dysaesthesia 10(0.09) 1(0.03) 11(0.07)
Dysarthria 11(0.09) 14(0.35) 25(0.16)
Dysgeusia 348(2.99) 41(1.03) 389(2.49)
Dyskinesia 11(0.09) 4(0.10) 15(0.10)
Dysstasia 19(0.16) 6(0.15) 25(0.16)
Dystonia 0(0.00) 2(0.05) 1(0.01)
Encephalitis post immunisation 0(0.00) 1(0.03) 1(0.01)
Encephalopathy 0(0.00) 1(0.03) 1(0.01)
Epilepsy 2(0.02) 9(0.23) 11(0.07)
Essential tremor 1(0.01) 0(0.00) 1(0.01)
Exertional headache 2(0.02) 1(0.03) 3(0.02)
Extrapyramidal disorder 0(0.00) 2(0.05) 1(0.01)
Facial nerve disorder 4(0.03) 0(0.00) 4(0.03)
Facial neuralgia 2(0.02) 0(0.00) 1(0.01)
Facial paralysis 799).68) 51(1.28) 130(0.83)
Facial paresis 9(0.08) 13(0.33) 22(0.14)
Facial spasm 5(0.04) 2(0.05) 7(0.04)
Febrile convulsion 1(0.01) 3(0.08) 4(0.03)
Fine motor skill dysfunction 1(0.01) 1(0.03) 1(0.01)
Formication 7(0.06) 2(0.05) 9(0.06)
Generalised tonic-clonic seizure 2(0.02) 7(0.18) 9(0.06)
Guillain-Barre syndrome 1(0.01) 3(0.08) 4(0.03)
Haemorrhage intracranial 0(0.00) 5(0.13) 5(0.03)
Head discomfort 40(0.34) 12(0.30) 52(0.33)
Head titubation 1(0.01) 0(0.00) 1(0.01)
Headache 5285(45.46) 1582(39.64) 6867(43.97)
Hemianaesthesia 3(0.03) 0(0.00) 3(0.02)
Hemidysaesthesia 1(0.01) 0(0.00) 1(0.01)
Hemihyperaesthesia 1(0.01) 0(0.00) 1(0.01)
Hemiparaesthesia 3(0.03) 2(0.05) 6(0.04)
Hemiparesis 1(0.01) 16(0.40) 17(0.11)
Horner's syndrome 0(0.00) 1(0.03) 1(0.01)
Hyperaesthesia 16(0.14) 5(0.13) 21(0.13)
Hypersomnia 32(0.28) 6(0.15) 389(0.24)
Hypertonia 2(0.02) 0(0.00) 1(0.01)
Hypoaesthesia 572(4.92) 144(3.61) 716(4.59)
Hypogeusia 7(0.06) 0(0.00) 7(0.04)
Hypokinesia 3(0.03) 3(0.08) 6(0.04)
Hyporeflexia 1(0.01) 3(0.08) 4(0.03)
Hyporesponsive to stimuli 2(0.02) 3(0.08) 5(0.03)
Hyposmia 7(0.06) 2(0.05) 9(0.06)
Hypotonia 10(0.09) 3(0.08) 13(0.08)
Incoherent 1(0.01) 0(0.00) 1(0.01)
Intracranial aneurysm 0(0.00) 1(0.03) 1(0.01)
Ischaemic stroke 0(0.00) 16(0.40) 16(0.10)
IVth nerve paralysis 0(0.00) 1(0.03) 1(0.01)
Lacunar infarction 0(0.00) 2(0.05) 1(0.01)
Lacunar stroke 0(0.00) 2(0.05) 1(0.01)
Language disorder 2(0.02) 3(0.08) 5(0.03)
Lethargy 212(1.82) 139(3.48) 351(2.25)
Locked-in syndrome 0(0.00) 1(0.03) 1(0.01)
Loss of consciousness 46(0.40) 40(1.00) 86(0.55)
Loss of proprioception 0(0.00) 1(0.03) 1(0.01)
Memory impairment 14(0.12) 7(0.18) 21(0.13)
Mental impairment 7(0.06) 1(0.03) 8(0.05)
Migraine 255(2.19) 121(3.03) 376(2.41)
Migraine with aura 17(0.15) 5(0.13) 22(0.14)
Migraine without aura 1(0.01) 0(0.00) 1(0.01)
Mononeuropathy 0(0.00) 1(0.03) 1(0.01)
Monoparesis 2(0.02) 3(0.08) 5(0.03)
Monoplegia 3(0.03) 1(0.03) 4(0.03)
Motor dysfunction 2(0.02) 0(0.00) 1(0.01)
Movement disorder 13(0.11) 2(0.05) 15(0.10)
Multiple sclerosis 0(0.00) 1(0.03) 1(0.01)
Multiple sclerosis relapse 1(0.01) 1(0.03) 1(0.01)
Muscle contractions involuntary 7(0.06) 2(0.05) 9(0.06)
Muscle spasticity 0(0.00) 1(0.03) 1(0.01)
Muscle tone disorder 0(0.00) 1(0.03) 1(0.01)
Myasthenia gravis 0(0.00) 2(0.05) 1(0.01)
Myelitis transverse 0(0.00) 1(0.03) 1(0.01)
Myoclonus 2(0.02) 2(0.05) 4(0.03)
Narcolepsy 0(0.00) 1(0.03) 1(0.01)
Nerve compression 3(0.03) 0(0.00) 3(0.02)
Nervous system disorder 5(0.04) 0(0.00) 5(0.03)
Neuralgia 37(0.32) 12(0.30) 49(0.31)
Neuralgic amyotrophy 0(0.00) 3(0.08) 3(0.02)
Neuritis 2(0.02) 0(0.00) 1(0.01)
Neurological symptom 3(0.03) 3(0.08) 7(0.04)
Neuropathy peripheral 12(0.10) 5(0.13) 17(0.11)
New daily persistent headache 1(0.01) 0(0.00) 1(0.01)
Noninfective encephalitis 0(0.00) 1(0.03) 1(0.01)
Nystagmus 2(0.02) 3(0.08) 5(0.03)
Occipital neuralgia 1(0.01) 0(0.00) 1(0.01)
Optic neuritis 1(0.01) 1(0.03) 1(0.01)
Orthostatic intolerance 1(0.01) 0(0.00) 1(0.01)
Paraesthesia 901(7.75) 201(5.04) 1102(7.06)
Paralysis 8(0.07) 10(0.25) 18(0.12)
Paraparesis 0(0.00) 1(0.03) 1(0.01)
Paresis 5(0.04) 2(0.05) 7(0.04)
Paresis cranial nerve 1(0.01) 0(0.00) 1(0.01)
Parkinsonian gait 1(0.01) 0(0.00) 1(0.01)
Parkinsonism 0(0.00) 1(0.03) 1(0.01)
Parosmia 24(0.21) 4(0.10) 28(0.18)
Partial seizures 1(0.01) 0(0.00) 1(0.01)
Peripheral sensory neuropathy 0(0.00) 3(0.08) 3(0.02)
Peroneal nerve palsy 0(0.00) 1(0.03) 1(0.01)
Persistent postural-perceptual dizziness 1(0.01) 0(0.00) 1(0.01)
Petit mal epilepsy 3(0.03) 1(0.03) 4(0.03)
Polyneuropathy 1(0.01) 0(0.00) 1(0.01)
Poor quality sleep 22(0.19) 4(0.10) 26(0.17)
Posterior reversible encephalopathy syndrome 0(0.00) 1(0.03) 1(0.01)
Postictal state 2(0.02) 0(0.00) 1(0.01)
Presyncope 177(1.52) 79(1.98) 256(1.64)
Primary headache associated with sexual activity 1(0.01) 0(0.00) 1(0.01)
Psychogenic seizure 1(0.01) 1(0.03) 1(0.01)
Psychomotor hyperactivity 3(0.03) 1(0.03) 5(0.03)
Radial nerve palsy 0(0.00) 1(0.03) 1(0.01)
Radiculitis brachial 0(0.00) 1(0.03) 1(0.01)
Radiculopathy 2(0.02) 1(0.03) 3(0.02)
Reduced facial expression 0(0.00) 1(0.03) 1(0.01)
Restless legs syndrome 7(0.06) 3(0.08) 10(0.06)
Retinal migraine 0(0.00) 1(0.03) 1(0.01)
Reversible cerebral vasoconstriction syndrome 0(0.00) 1(0.03) 1(0.01)
Sciatica 7(0.06) 2(0.05) 9(0.06)
Sedation 1(0.01) 1(0.03) 1(0.01)
Seizure 16(0.14) 40(1.00) 56(0.36)
Seizure like phenomena 2(0.02) 3(0.08) 5(0.03)
Sensory disturbance 30(0.26) 7(0.18) 37(0.24)
Sensory loss 10(0.09) 9(0.23) 19(0.12)
Serotonin syndrome 1(0.01) 0(0.00) 1(0.01)
Sinus headache 33(0.28) 14(0.35) 47(0.30)
Slow response to stimuli 2(0.02) 0(0.00) 1(0.01)
Slow speech 3(0.03) 0(0.00) 3(0.02)
Small fibre neuropathy 0(0.00) 1(0.03) 1(0.01)
Somnolence 167(1.44) 49(1.23) 216(1.38)
Speech disorder 17(0.15) 18(0.45) 35(0.22)
Status epilepticus 0(0.00) 2(0.05) 1(0.01)
Stiff leg syndrome 0(0.00) 1(0.03) 1(0.01)
Stupor 1(0.01) 1(0.03) 1(0.01)
Subarachnoid haemorrhage 2(0.02) 1(0.03) 3(0.02)
Sudden onset of sleep 1(0.01) 0(0.00) 1(0.01)
Syncope 140(1.20) 99(2.48) 239(1.53)
Taste disorder 50(0.43) 11(0.28) 61(0.39)
Tension headache 45(0.39) 18(0.45) 63(0.40)
Thunderclap headache 0(0.00) 1(0.03) 1(0.01)
Tongue biting 1(0.01) 0(0.00) 1(0.01)
Tonic clonic movements 2(0.02) 0(0.00) 1(0.01)
Tonic convulsion 1(0.01) 1(0.03) 1(0.01)
Transient global amnesia 0(0.00) 3(0.08) 3(0.02)
Transient ischaemic attack 3(0.03) 9(0.23) 12(0.08)
Tremor 257(2.21) 128(3.21) 385(2.47)
Trigeminal neuralgia 5(0.04) 1(0.03) 6(0.04)
Trigeminal neuritis 1(0.01) 0(0.00) 1(0.01)
Tunnel vision 10(0.09) 3(0.08) 13(0.08)
Typical aura without headache 1(0.01) 0(0.00) 1(0.01)
Unresponsive to stimuli 10(0.09) 37(0.93) 47(0.30)
Vestibular migraine 0(0.00) 11(0.03) 1(0.01)
Visual field defect 3(0.03) 3(0.08) 6(0.04)
Writer's cramp 0(0.00) 1(0.03) 1(0.01)
Investigations (N=22) Angiogram cerebral abnormal 0(0.00) 1(5.88) 1(4.55)
Brain natriuretic peptide increased 0(0.00) 2(0.05) 2(9.09)
Carotid bruit 0(0.00) 1(5.88) 1(4.55)
Computerised tomogram head abnormal 2(40.00) 0(0.00) 2(9.09)
CSF protein increased 0(0.00) 2(11.76) 2(9.09)
Electroencephalogram abnormal 0(0.00) 1(5.88) 1(4.55)
Magnetic resonance imaging brain abnormal 1(20.00) 6(35.29) 7(31.82)
Magnetic resonance imaging spinal abnormal 0(0.00) 1(5.88) 1(4.55)
Neurological examination abnormal 1(20.00) 2(11.76) 3(13.64)
NIH stroke scale abnormal 0(0.00) 1(5.88) 1(4.55)
Sensory level abnormal 1(20.00) 0(0.00) 1(4.55)
Broad heading Specific adverse event   Non-serious n(%) (n=1,527) Serious n(%) (n=1,224) Total n(%) (n=2,751)
Nervous System Disorder(N=2751) Ageusia 5(0.33) 5(0.41) 10(0.36)
Allodynia 2(0.13) 1(0.08) 3(0.11)
Amnesia 1(0.07) 0(0.00) 1(0.04)
Anosmia 1(0.07) 4(0.330 5(0.18)
Aphasia 0(0.00) 2(0.16) 2(0.07)
Balance disorder 2(0.13) 7(0.57) 9(0.33)
Brain stem stroke 0(0.00) 1(0.08) 1(0.04)
Burning sensation 0(0.00) 2(0.16) 2(0.07)
Cerebrovascular accident 0(0.00) 3(0.25) 3(0.11)
Cervicobrachial syndrome 1(0.07) 0(0.00) 1(0.04)
Clumsiness 0(0.00) 1(0.08) 1(0.04)
Cluster headache 4(0.26) 5(0.41) 9(0.33)
Cognitive disorder 1(0.07) 1(0.08) 2(0.07)
Coordination abnormal 1(0.07) 0(0.00) 1(0.04)
Disturbance in attention 2(0.13) 4(0.33) 6(0.22)
Dizziness 180(11.79) 154(12.58) 334(12.14)
Dizziness postural 11(0.72) 1290.98) 23(0.84)
Dysarthria 0(0.00) 1(0.08) 1(0.04)
Dysgeusia 23(1.51) 11(0.90) 34(1.24)
Dysstasia 0(0.00) 2(0.16) 2(0.07)
Epilepsy 0(0.00) 2(0.16) 2(0.07)
Facial paralysis 2(0.13) 1(0.08) 3(0.11)
Broad heading Specific adverse event   Non-serious n(%) (n=803) Non-serious n(%) (n=269) Total n(%) (n=1,072)
Nervous System Disorder(N=1072) Ageusia 4(0.50) 0(0.00) 4(0.37)
Akathisia 1(0.12) 0(0.00) 1(0.09)
Anosmia 3(0.37) 0(0.00) 3(0.28)
Anterograde amnesia 0(0.00) 1(0.37) 11(0.09)
Aphasia 1(0.12) 4(1.49) 5(0.47)
Aura 1(0.12) 0(0.00) 1(0.09)
Balance disorder 6(0.75) 1(0.37) 7(0.65)
Burning sensation 6(0.75) 4(1.49) 10(0.93)
Cerebral haemorrhage 1(0.12) 0(0.00) 1(0.09)
Cerebral ischaemia 1(0.12) 0(0.00) 1(0.09)
Cerebrovascular accident 0(0.00) 4(1.49) 4(0.37)
Cognitive disorder 0(0.00) 1(0.37) 1(0.09)
Consciousness fluctuating 0(0.00) 1(0.37) 1(0.09)
Dementia 0(0.00) 1(0.37) 1(0.09)
Depressed level of consciousness 0(0.00) 2(0.74) 2(0.19)
Disturbance in attention 2(0.25) 0(0.00) 2(0.19)
Dizziness/Dizziness postural 179(22.29) 39(14.50) 218(20.34)
Drooling 0(0.00) 1(0.37) 1(0.09)
Dysarthria 4(0.50) 7(2.60) 11(1.03)
Dysgeusia 20(2.49) 0(0.00) 20(1.87)
Dysstasia 4(0.50) 1(0.37) 5(0.47)
Dystonic tremor 0(0.00) 1(0.37) 1(0.09)
Encephalomalacia 1(0.12) 0(0.00) 1(0.09)
Facial paralysis 4(0.50) 9(3.35) 13(1.21)
Facial paresis 0(0.00) 2(0.74) 2(0.19)
Generalised tonic-clonic seizure 0(0.00) 1(0.37) 1(0.09)
Guillain-Barre syndrome 0(0.00) 1(0.37) 1(0.09)
Haemorrhagic stroke 0(0.00) 1(0.37) 1(0.09)
Head discomfort 5(0.62) 0(0.00) 5(0.47)
Headache 299(37.34) 37(13.75) 336(31.34)
Hemianopia 0(0.00) 1(0.37) 1(0.09)
Hemiparesis 1(0.12) 3(1.12) 4(0.37)
Hemiplegia 0(0.00) 1(0.37) 1(0.09)
Hyperaesthesia 1(0.12) 0(0.00) 1(0.09)
Hypersomnia 7(0.87) 0(0.00) 7(0.65)
Hypertonia 0(0.00) 1(0.37) 1(0.09)
Hypoaesthesia 59(7.35) 22(8.18) 81(7.56)
Hypokinesia 0(0.00) 1(0.37) 1(0.09)
Hypotonia 0(0.00) 2(0.74) 2(0.19)
Incoherent/Incoherent Speech disorder 1(0.12) 3(1.12) 4(0.37)
Intracranial aneurysm 0(0.00) 1(0.37) 1(0.09)
Ischaemic stroke 0(0.00) 1(0.37) 1(0.09)
Lacunar infarction 1(0.12) 00(0.00) 1(0.09)
Lethargy 9(1.12) 3(1.12) 12(1.12)
Loss of consciousness 9(1.12) 7(2.60) 16(1.49)
Memory impairment 3(0.37) 6(2.23) 9(0.84)
Migraine 16(1.99) 3(1.12) 19(1.77)
Monoplegia 1(0.12) 00(0.00) 1(0.09)
Motor dysfunction 0(0.00) 1(0.37) 1(0.09)
Muscle contractions involuntary 1(0.12) 0(0.00) 1(0.09)
Neuralgia 1(0.12) 1(0.37) 2(0.19)
Neurologic neglect syndrome 0(0.00) 1(0.37) 1(0.09)
Neurological symptom 0(0.00) 1(0.37) 1(0.09)
Opisthotonus 0(0.00) 1(0.37) 1(0.09)
Paraesthesia 70(8.72) 15(5.58) 85(7.93)
Poor quality sleep 0(0.00) 1(0.37) 1(0.09)
Posterior reversible encephalopathy syndrome 0(0.00) 1(0.37) 11(0.09)
Presyncope 11(1.37) 2(0.74) 13(1.21)
Reflexes abnormal 0(0.00) 1(0.37) 1(0.09)
Repetitive speech 0(0.00) 1(0.37) 1(0.09)
Sedation 1(0.12) 0(0.00) 1(0.09)
Seizure 0(0.00) 6(2.23) 6(0.56)
Seizure like phenomena 0(0.00) 1(0.37) 1(0.09)
Sensory disturbance 3(0.37) 2(0.74) 5(0.47)
Sinus headache 1(0.12) 0(0.00) 1(0.09)
Somnolence 8(1.00) 4(1.49) 12(1.12)
Speech disorder 1(0.12) 11(4.09) 12(1.12)
Syncope 11(1.37) 11(4.09) 22(2.25)
Taste disorder 0(0.00) 2(0.74) 2(0.19)
Thrombotic stroke 0(0.00) 1(0.37) 1(0.09)
Transient ischaemic attack 0(0.00) 1(0.37) 1(0.09)
Tremor 38(4.73) 11(0.37) 49(4.57)
Tunnel vision 3(0.37) 0(0.00) 3(0.28)
Unresponsive to stimuli 3(0.37) 19(7.06) 22(2.05)
Visual field defect 1(0.12) 0(0.00) 1(0.09)
Investigations(N=3) Coma scale abnormal 0(0.00) 1(50.00) 1(33.33)
Computerised tomogram head abnormal 0(0.00) 1(50.00) 1(33.33)
Magnetic resonance imaging brain abnormal 1(0.12) 0(0.00) 1(33.33)
Broad heading Specific adverse event   Non-serious n(%) (n=4) Serious n(%) (n=2) Total n(%) (n=6)
Nervous System Disorder (N=6) Cerebral venous sinus thrombosis 0(0.00) 1(50.0) 1(16.77)
  Dizziness 4(100.0) 0(0.00) 4(66.67)
  Headache 0(0.00) 1(50.0) 1(16.67)
Broad heading Specific adverse event   Non-serious n(%) (n=2) Serious n(%) (n=0) Total n(%) (n=2)
Nervous System Disorder(N=2) Headache 2(100.0) 0(0.00) 2(100.0)
Broad heading Specific adverse event   Non-serious n (%) (n=39) Serious n (%) (n=16) Total n(%) (n=55)
Nervous System Disorder(n=55) Balance disorder 0(0.00) 1(6.25) 1(1.82)
Cerebrovascular accident 0(0.00) 1(6.25) 1(1.82)
Dizziness 5(12.82) 2(12.5) 7(12.73)
Dysgeusia 1(2.56) 1(6.25) 2(3.64)
Dysstasia 0(0.00) 1(6.25) 1(1.82)
Headache 22(56.41) 4(25.0) 26(47.27)
Hypoaesthesia 1(2.56) 0(0.00) 1(1.82)
Lethargy 1(2.56) 1(6.25) 2(3.64)
Migraine 1(2.56) 1(6.25) 2(3.64)
Paraesthesia 1(2.56) 0(0.00) 3(5.45)
Presyncope 1(2.56) 1(6.25) 2(3.64)
Sinus headache 1(2.56) 0(0.00) 1(1.82)
Syncope 1(2.56) 1(6.25) 2(3.64)
Taste disorder 1(2.56) 0(0.00) 1(1.82)
Transient ischaemic attack 0(0.00) 1(6.25) 1(1.82)
Tremor 1(2.56) 1(6.25) 2(3.64)

Original article
peer-reviewed

Analysis of Neurological Adverse Events Reported in VigiBase From COVID-19 Vaccines


Author Information

Siddhartha Dutta

Department of Pharmacology, All India Institute of Medical Sciences, Rajkot, Rajkot, IND

Rimplejeet Kaur

Department of Pharmacology, All India Institute of Medical Sciences, Jodhpur, Jodhpur, IND

Jaykaran Charan Corresponding Author

Department of Pharmacology, All India Institute of Medical Sciences, Jodhpur, Jodhpur, IND

Pankaj Bhardwaj

Department of Community Medicine & Family Medicine and School of Public Health, All India Institute of Medical Sciences, Jodhpur, Jodhpur, IND

Sneha R. Ambwani

Department of Pharmacology, All India Institute of Medical Sciences, Jodhpur, Jodhpur, IND

Shoban Babu

Department of Pharmacology, All India Institute of Medical Sciences, Jodhpur, Jodhpur, IND

Jagdish P. Goyal

Department of Pediatrics, All India Institute of Medical Sciences, Jodhpur, Jodhpur, IND

Mainul Haque

Department of Pharmacology and Therapeutics, National Defence University of Malaysia, Kuala Lumpur, MYS


Ethics Statement and Conflict of Interest Disclosures

Human subjects: All authors have confirmed that this study did not involve human participants or tissue. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.



Original article
peer-reviewed

Analysis of Neurological Adverse Events Reported in VigiBase From COVID-19 Vaccines


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