Association of New-Onset Seizures With SARS-CoV-2 Vaccines: A Systematic Review and Meta-Analysis of Randomized Clinical Trials | Vaccination | JAMA Neurology | JAMA Network
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Figure 1.  PRISMA Flow Diagram of the Systematic Search
PRISMA Flow Diagram of the Systematic Search
Figure 2.  Forest Plot of the Randomized Clinical Trials Reporting New-Onset Seizure Events in SARS-CoV-2 Vaccine Recipients vs Placebo Recipients (28-Day Follow-Up Period)
Forest Plot of the Randomized Clinical Trials Reporting New-Onset Seizure Events in SARS-CoV-2 Vaccine Recipients vs Placebo Recipients (28-Day Follow-Up Period)

mRNA indicates messenger RNA; OR, odds ratio.

Figure 3.  Forest Plot of the Randomized Clinical Trials Reporting New-Onset Seizure Events in SARS-CoV-2 Vaccine Recipients vs Placebo Recipients (Entire Blinded Phase)
Forest Plot of the Randomized Clinical Trials Reporting New-Onset Seizure Events in SARS-CoV-2 Vaccine Recipients vs Placebo Recipients (Entire Blinded Phase)

mRNA indicates messenger RNA; OR, odds ratio.

Table.  Summary of the Included Studiesa
Summary of the Included Studiesa
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Kaur  RJ, Dutta  S, Bhardwaj  P,  et al.  Adverse events reported from COVID-19 vaccine trials: a systematic review.   Indian J Clin Biochem. 2021;36(4):427-439. doi:10.1007/s12291-021-00968-zPubMedGoogle ScholarCrossref
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Fazlollahi  A, Zahmatyar  M, Noori  M,  et al.  Cardiac complications following mRNA COVID-19 vaccines: a systematic review of case reports and case series.   Rev Med Virol. 2022;32(4):e2318. doi:10.1002/rmv.2318PubMedGoogle ScholarCrossref
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Shiravi  AA, Ardekani  A, Sheikhbahaei  E, Heshmat-Ghahdarijani  K.  Cardiovascular complications of SARS-CoV-2 vaccines: an overview.   Cardiol Ther. 2022;11(1):13-21. doi:10.1007/s40119-021-00248-0PubMedGoogle ScholarCrossref
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Assiri  SA, Althaqafi  RMM, Alswat  K,  et al.  Post COVID-19 vaccination-associated neurological complications.   Neuropsychiatr Dis Treat. 2022;18:137-154. doi:10.2147/NDT.S343438PubMedGoogle ScholarCrossref
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Finsterer  J.  Neurological side effects of SARS-CoV-2 vaccinations.   Acta Neurol Scand. 2022;145(1):5-9. doi:10.1111/ane.13550PubMedGoogle ScholarCrossref
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Goss  AL, Samudralwar  RD, Das  RR, Nath  A; ANA Investigates.  ANA investigates: neurological complications of COVID-19 vaccines.   Ann Neurol. 2021;89(5):856-857. doi:10.1002/ana.26065PubMedGoogle ScholarCrossref
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Patone  M, Handunnetthi  L, Saatci  D,  et al.  Neurological complications after first dose of COVID-19 vaccines and SARS-CoV-2 infection.   Nat Med. 2021;27(12):2144-2153. doi:10.1038/s41591-021-01556-7PubMedGoogle ScholarCrossref
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Ghosh  R, Dubey  S, Roy  D, Mandal  A, Naga  D, Benito-León  J.  Focal onset non-motor seizure following COVID-19 vaccination: a mere coincidence?   Diabetes Metab Syndr. 2021;15(3):1023-1024. doi:10.1016/j.dsx.2021.05.003PubMedGoogle ScholarCrossref
16.
Makhlouf  AT, Van Alphen  MU, Manzano  GS, Freudenreich  O.  A seizure after COVID-19 vaccination in a patient on clozapine.   J Clin Psychopharmacol. 2021;41(6):689-690. doi:10.1097/JCP.0000000000001488PubMedGoogle ScholarCrossref
17.
Liu  BD, Ugolini  C, Jha  P.  Two cases of post-Moderna COVID-19 vaccine encephalopathy associated with nonconvulsive status epilepticus.   Cureus. 2021;13(7):e16172. doi:10.7759/cureus.16172PubMedGoogle ScholarCrossref
18.
Barlow  WE, Davis  RL, Glasser  JW,  et al; Centers for Disease Control and Prevention Vaccine Safety Datalink Working Group.  The risk of seizures after receipt of whole-cell pertussis or measles, mumps, and rubella vaccine.   N Engl J Med. 2001;345(9):656-661. doi:10.1056/NEJMoa003077PubMedGoogle ScholarCrossref
19.
Ma  SJ, Xiong  YQ, Jiang  LN, Chen  Q.  Risk of febrile seizure after measles-mumps-rubella-varicella vaccine: a systematic review and meta-analysis.   Vaccine. 2015;33(31):3636-3649. doi:10.1016/j.vaccine.2015.06.009PubMedGoogle ScholarCrossref
20.
Sun  Y, Christensen  J, Hviid  A,  et al.  Risk of febrile seizures and epilepsy after vaccination with diphtheria, tetanus, acellular pertussis, inactivated poliovirus, and Haemophilus influenzae type B.   JAMA. 2012;307(8):823-831. doi:10.1001/jama.2012.165PubMedGoogle ScholarCrossref
21.
Rafati  A, Jameie  M, Amanollahi  M,  et al.  Association of seizure with COVID-19 vaccines in persons with epilepsy: a systematic review and meta-analysis.   J Med Virol. 2023;95(9):e29118. doi:10.1002/jmv.29118PubMedGoogle ScholarCrossref
22.
Page  MJ, McKenzie  JE, Bossuyt  PM,  et al.  The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.   BMJ. 2021;372(71):n71. doi:10.1136/bmj.n71PubMedGoogle ScholarCrossref
23.
Sterne  JAC, Savović  J, Page  MJ,  et al.  RoB 2: a revised tool for assessing risk of bias in randomised trials.   BMJ. 2019;366:l4898. doi:10.1136/bmj.l4898PubMedGoogle ScholarCrossref
24.
Balduzzi  S, Rücker  G, Schwarzer  G.  How to perform a meta-analysis with R: a practical tutorial.   Evid Based Ment Health. 2019;22(4):153-160. doi:10.1136/ebmental-2019-300117PubMedGoogle ScholarCrossref
25.
Higgins  JP, Thompson  SG.  Quantifying heterogeneity in a meta-analysis.   Stat Med. 2002;21(11):1539-1558. doi:10.1002/sim.1186PubMedGoogle ScholarCrossref
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Viechtbauer  W.  Bias and efficiency of meta-analytic variance estimators in the random-effects model.   J Educ Behav Stat. 2005;30(3):261-293. doi:10.3102/10769986030003261Google ScholarCrossref
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Greenland  S, Robins  JM.  Estimation of a common effect parameter from sparse follow-up data.   Biometrics. 1985;41(1):55-68. doi:10.2307/2530643PubMedGoogle ScholarCrossref
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Robins  J, Breslow  N, Greenland  S.  Estimators of the Mantel-Haenszel variance consistent in both sparse data and large-strata limiting models.   Biometrics. 1986;42(2):311-323. doi:10.2307/2531052PubMedGoogle ScholarCrossref
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Peters  JL, Sutton  AJ, Jones  DR, Abrams  KR, Rushton  L.  Comparison of two methods to detect publication bias in meta-analysis.   JAMA. 2006;295(6):676-680. doi:10.1001/jama.295.6.676PubMedGoogle ScholarCrossref
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Egger  M, Davey Smith  G, Schneider  M, Minder  C.  Bias in meta-analysis detected by a simple, graphical test.   BMJ. 1997;315(7109):629-634. doi:10.1136/bmj.315.7109.629PubMedGoogle ScholarCrossref
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Sadoff  J, Gray  G, Vandebosch  A,  et al; ENSEMBLE Study Group.  Final analysis of efficacy and safety of single-dose Ad26.COV2.S.   N Engl J Med. 2022;386(9):847-860. doi:10.1056/NEJMoa2117608PubMedGoogle ScholarCrossref
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El Sahly  HM, Baden  LR, Essink  B,  et al; COVE Study Group.  Efficacy of the mRNA-1273 SARS-CoV-2 vaccine at completion of blinded phase.   N Engl J Med. 2021;385(19):1774-1785. doi:10.1056/NEJMoa2113017PubMedGoogle ScholarCrossref
33.
Voysey  M, Clemens  SAC, Madhi  SA,  et al; Oxford COVID Vaccine Trial Group.  Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.   Lancet. 2021;397(10269):99-111. doi:10.1016/S0140-6736(20)32661-1PubMedGoogle ScholarCrossref
34.
Tanriover  MD, Doğanay  HL, Akova  M,  et al; CoronaVac Study Group.  Efficacy and safety of an inactivated whole-virion SARS-CoV-2 vaccine (CoronaVac): interim results of a double-blind, randomised, placebo-controlled, phase 3 trial in Turkey.   Lancet. 2021;398(10296):213-222. doi:10.1016/S0140-6736(21)01429-XPubMedGoogle ScholarCrossref
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Anderson  EJ, Creech  CB, Berthaud  V,  et al; KidCOVE Study Group.  Evaluation of mRNA-1273 vaccine in children 6 months to 5 years of age.   N Engl J Med. 2022;387(18):1673-1687. doi:10.1056/NEJMoa2209367PubMedGoogle ScholarCrossref
36.
Creech  CB, Anderson  E, Berthaud  V,  et al; KidCOVE Study Group.  Evaluation of mRNA-1273 Covid-19 vaccine in children 6 to 11 years of age.   N Engl J Med. 2022;386(21):2011-2023. doi:10.1056/NEJMoa2203315PubMedGoogle ScholarCrossref
37.
Baden  LR, El Sahly  HM, Essink  B,  et al; COVE Study Group.  Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.   N Engl J Med. 2021;384(5):403-416. doi:10.1056/NEJMoa2035389PubMedGoogle ScholarCrossref
38.
Sadoff  J, Gray  G, Vandebosch  A,  et al; ENSEMBLE Study Group.  Safety and efficacy of single-dose Ad26.COV2.S vaccine against Covid-19.   N Engl J Med. 2021;384(23):2187-2201. doi:10.1056/NEJMoa2101544PubMedGoogle ScholarCrossref
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Mozzicato  P.  MedDRA: an overview of the Medical Dictionary for Regulatory Activities.   Pharmaceut Med. 2009;23(2):65-75. doi:10.1007/BF03256752Google ScholarCrossref
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Hussaini  H, Rogers  S, Kataria  S,  et al.  COVID-19-induced seizures: a meta-analysis of case series and retrospective cohorts.   Cureus. 2022;14(8):e28633. doi:10.7759/cureus.28633PubMedGoogle ScholarCrossref
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Barker-Haliski  M, White  HS.  Glutamatergic mechanisms associated with seizures and epilepsy.   Cold Spring Harb Perspect Med. 2015;5(8):a022863. doi:10.1101/cshperspect.a022863PubMedGoogle ScholarCrossref
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Ho  TC, Teresi  GI, Segarra  JR,  et al.  Higher levels of pro-inflammatory cytokines are associated with higher levels of glutamate in the anterior cingulate cortex in depressed adolescents.   Front Psychiatry. 2021;12:642976. doi:10.3389/fpsyt.2021.642976PubMedGoogle ScholarCrossref
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Chen  B, Lopez Chiriboga  AS, Sirven  JI, Feyissa  AM.  Autoimmune encephalitis-related seizures and epilepsy: diagnostic and therapeutic approaches.   Mayo Clin Proc. 2021;96(8):2029-2039. doi:10.1016/j.mayocp.2021.02.019PubMedGoogle ScholarCrossref
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Picod  A, Rebibou  JM, Dossier  A,  et al.  Immune-mediated thrombotic thrombocytopenic purpura following COVID-19 vaccination.   Blood. 2022;139(16):2565-2569. doi:10.1182/blood.2021015149PubMedGoogle ScholarCrossref
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López-Mena  D, García-Grimshaw  M, Saldivar-Dávila  S,  et al.  Stroke among SARS-CoV-2 vaccine recipients in Mexico: a nationwide descriptive study.   Neurology. 2022;98(19):e1933-e1941. doi:10.1212/WNL.0000000000200388PubMedGoogle ScholarCrossref
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Kuroda  N, Gajera  PK, Yu  H, Kubota  T.  Seizure control in patients with epilepsy during the COVID-19 pandemic: a systematic review and meta-analysis.   Intern Med. 2022;61(15):2287-2293. doi:10.2169/internalmedicine.9321-22PubMedGoogle ScholarCrossref
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Rafati  A, Pasebani  Y, Jameie  M,  et al.  Association of SARS-CoV-2 vaccination or infection with Bell palsy: a systematic review and meta-analysis.   JAMA Otolaryngol Head Neck Surg. 2023;149(6):493-504. doi:10.1001/jamaoto.2023.0160PubMedGoogle ScholarCrossref
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1 Comment for this article
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Problems with the reported statistics
Sander Greenland | University of California, Los Angeles
I have been unable to reproduce the statistics in the Rafati et al. paper. For example, the reported odds-ratio [OR] for the entire blinded period was 2.31, p>.99 for OR=1 (no association), 95% CI of .86, 6.23 [the upper limit was misprinted in the abstract as 3.23]. P>.99 is however mathematically inconsistent with the estimates, for it implies the observed OR is about 1. When I placed the numbers from Fig. 3 in the formulas in reference 28 of the paper, I got instead OR of 2.54, p=0.07, CI .90, 7.16.
With or without these corrections, all the CIs (including
for 28 days) contain odds ratios above 6, which means that in all the analyses the observed OR is not significantly different from 6 at the 0.05 level. For example, in my calculations for the entire blinded period, OR=6 has p=0.10, larger than the P-value for OR=1. It thus seems imperative to note that the trial data remain far too imprecise to rule out considerable effects. I suggest that careful meta-analyses of the 40 observational studies found by the authors are needed to supplement the trial data.
CONFLICT OF INTEREST: None Reported
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Original Investigation
April 29, 2024

Association of New-Onset Seizures With SARS-CoV-2 Vaccines: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Author Affiliations
  • 1School of Medicine, Iran University of Medical Sciences, Tehran, Iran
  • 2Neuroscience Research Center, Iran University of Medical Sciences, Tehran, Iran
  • 3Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
  • 4Cardiovascular Diseases Research Institute, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
  • 5Cardiac Primary Prevention Research Center, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
  • 6School of Medicine, Sari Branch, Islamic Azad University, Sari, Iran
  • 7School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  • 8Islamic Azad University East Tehran Branch, Tehran, Iran
  • 9Kermanshah University of Medical Sciences, Kermanshah, Iran
  • 10Center for Surgery and Public Health, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 11Department of Nutrition, School of Public Health, Zanjan University of Medical Sciences, Zanjan, Iran
  • 12Departments of Neurology, Epidemiology, Neurosurgery and the Gertrude H. Sergievsky Center, Columbia University, New York, New York
JAMA Neurol. Published online April 29, 2024. doi:10.1001/jamaneurol.2024.0967
Key Points

Question  Is incidence of new-onset seizures after SARS-CoV-2 vaccines statistically different from the incidence among individuals not receiving SARS-CoV-2 vaccines?

Findings  This systematic review and meta-analysis showed that the incidence proportion of new-onset seizures after SARS-CoV-2 vaccination was not statistically different between vaccine recipients and placebo recipients or unvaccinated participants in the pooled analyses of more than 118 000 participants in randomized clinical trials.

Meaning  The incidence of new-onset seizure was not significantly different between SARS-CoV-2 vaccine recipients and placebo recipients, and there was no evidence of increased new-onset seizure following SARS-CoV-2 vaccination in the general population.

Abstract

Importance  Seizures have been reported as an adverse effect of the SARS-CoV-2 vaccine. However, no study has answered the question of whether there is any association between seizures in the general population and COVID-19 vaccination.

Objective  To evaluate the seizure incidence among SARS-CoV-2 vaccine recipients compared with those who received a placebo.

Data Sources  A systematic search of MEDLINE (via PubMed), Web of Science, Scopus, Cochrane Library, Google Scholar, review publications, editorials, letters to editors, and conference papers, along with the references of the included studies from December 2019 to July 7, 2023.

Study Selection  Randomized clinical trials (RCTs) reporting seizure incidence with SARS-CoV-2 vaccination were included.

Data Extraction and Synthesis  This study is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses framework and used the Mantel-Haenszel method with random- and common-effect models. The risk of bias of the studies was assessed using the Cochrane assessment tool for RCTs.

Main Outcomes and Measures  The outcome of interest was new-onset seizure incidence proportion compared among (1) SARS-CoV-2 vaccine recipients and (2) placebo recipients.

Results  Six RCTs were included in the study. Results of the pooled analysis comparing the incidence of new-onset seizure between the 63 521 vaccine and 54 919 placebo recipients in the 28-day follow-up after vaccine/placebo injection showed no statistically significant difference between the 2 groups (9 events [0.014%] in vaccine and 1 event [0.002%] in placebo recipients; odds ratio [OR], 2.70; 95% CI, 0.76-9.57; P = .12; I2 = 0%, τ2 = 0, Cochran Q P = .74). Likewise, in the entire blinded-phase period after injection, with a median of more than 43 days, no significant difference was identified between the vaccine and placebo groups regarding incident new-onset seizure (13/43 724 events [0.03%] in vaccine and 5/40 612 [0.012%] in placebo recipients; OR, 2.31; 95% CI, 0.86-3.23, P > .99, I2 = 0%, τ2 = 0, Cochran Q P = .95).

Conclusions and Relevance  According to this systematic review and meta-analysis, there was no statistically significant difference in the risk of new-onset seizure incidence between vaccinated individuals and placebo recipients.

Introduction

Coronavirus disease 2019 (COVID-19) is a highly contagious respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),1 manifested by various symptoms with a broad spectrum of severity, ranging from asymptomatic infection or mild symptoms to hospitalization, severe illness, and death.2 As of April 14, 2022, a total of 500 186 525 individuals with COVID-19 and 6 190 349 deaths have been reported.3 Amid the COVID-19 pandemic, several vaccines have been developed worldwide, dramatically reducing COVID-19–related hospitalizations and deaths.4,5 By April 13, 2022, 11 294 502 059 doses of SARS-CoV-2 vaccines had been injected.3 Notably, several trials and systematic reviews confirmed the safety and efficacy of the SARS-CoV-2 vaccines.5-7 However, adverse effects were also reported, including systemic reactions,8 cardiovascular complications,9,10 and neurological adverse events.11

Among the neurological complications, headaches, Guillain-Barré syndrome, cerebral venous sinus thrombosis, and transverse myelitis were the most frequently reported.12 Nevertheless, there are still contradictory findings considering the possible increased risk of neurological disorders in vaccinated people.13 A self-controlled case series involving 32 552 534 vaccinated people suggested that the chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19) was associated with an elevated risk of developing Guillain-Barré syndrome and Bell palsy.14 Additionally, according to the authors, the Pfizer BioNTech (BNT162b2) vaccine was correlated with an increased risk of hemorrhagic stroke.14 It should be noted that the risk of these adverse events following the SARS-CoV-2 vaccination is much lower than the disease itself.14

Seizures have also been reported after SARS-CoV-2 vaccination in a few studies.11,15-17 Similarly, several studies have previously mentioned the occurrence of seizures after non–SARS-CoV-2 vaccination.18,19 According to large-scale cohort studies, postvaccination seizures have occurred after diphtheria and tetanus toxoids and whole-cell pertussis (DTP) vaccines; measles, mumps, and rubella (MMR) vaccines; and combination diphtheria, tetanus toxoids, and acellular pertussis–inactivated poliovirus–Haemophilus influenzae type b (DTaP-IPV-Hib) vaccines.18,20 Of note, follow-up analyses suggested that children with postvaccination febrile seizures were not at elevated risk of subsequent seizures in the long term.18,20

Of note, in persons with epilepsy, an increase in seizure frequency after SARS-CoV-2 vaccination has been shown.21 However, studies regarding the association between SARS-CoV-2 vaccines and seizures in the general population are still inconclusive. In addition, there remains uncertainty about whether SARS-CoV-2 vaccination and seizures have a cause-and-effect or merely a coincidental relationship. Because of the vast scale of the global vaccination programs, it is of great importance to track down the adverse effects of SARS-CoV-2 vaccines in the short and long term. Hence, we aimed to conduct a systematic review of the related studies to provide insight into the possible contribution of SARS-CoV-2 vaccines to developing seizures among the general population.

Methods

We investigated seizure incidence by pooling effect estimates of all phase 3 randomized clinical trial (RCT)–derived data on SARS-CoV-2 vaccine vs placebo recipients. This study is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines.22 The study protocol was registered with PROSPERO (CRD42022312475). A systematic search was performed in MEDLINE (via PubMed), Web of Science, Scopus, Cochrane Library, and Google Scholar from the inception of COVID-19 (December 2019) to July 7, 2023. We also searched review publications, editorials, letters to editors, and conference papers, along with the references of the included studies. The keywords included “SARS-CoV-2 vaccine,” “COVID-19 vaccine,” “seizure,” and “convulsion” (eTable in Supplement 1). We did not restrict the search based on the study design, age of the participants, literature language, or any other restriction. Because previously published data were used, the study was exempt from ethical approval by the local institutional ethics board.

Eligibility Criteria

Only RCTs were included in the study. The participants of the study were individuals who had undergone SARS-CoV-2 vaccination with SARS-CoV-2 vaccine platforms, including messenger RNA (mRNA), viral vector, and inactivated virus. Of note, there were no limitations placed on the duration of time over which adverse events were observed in the original studies. We compared the vaccine recipients with individuals receiving placebo or other vaccines. The outcome of interest was the incidence of seizure as the adverse event following the vaccination or following the respective time period in the placebo recipients or unvaccinated participants. The studies were included only if the seizure diagnosis was confirmed by a neurologist or fulfilled the clinical criteria and/or codes from the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, as mentioned by each study.

Selection Process

The obtained records were first transferred to Endnote. After duplicate removal, 2 independent researchers (Me.J. and Y.P.) screened all articles. First, title and abstract screening was carried out. Second, the remaining records were further assessed using the full texts. Finally, the records not meeting the pre-established eligibility criteria were excluded. Conflicts were resolved by the consensus of the authors.

Data Extraction

The following data of interest were extracted: (1) study-specific variables (first author’s name, publication year, sample size, study design, and the presence of control group and its general description), (2) vaccine-related variables including vaccine type, number of doses received, (3) demographic and baseline variables including age, sex, medical history, prior SARS-CoV-2 infection, and drug history, and (4) number of persons presenting with seizure, concomitant signs, and symptoms; initial physical examination; duration from vaccination to the event; paraclinical assessments; and treatments, outcome, and recurrence if followed up. All authors participated in the independent data extraction process, with 2 authors assigned to each article. The discrepancy was resolved by consensus among all authors.

Risk-of-Bias Assessment

The risk of bias of the studies was assessed using the Cochrane Assessment tool for RCTs (RoB-2), categorizing studies as unclear, low risk, or high risk.23 Two independent researchers (D.S. and M.A.) conducted the quality assessment, and conflicts were resolved via consensus.

Data Synthesis

The quantitative synthesis was performed to analyze phase 3 RCTs of the major SARS-CoV-2 vaccines, ie, Pfizer/BioNTech, Moderna, Janssen, CoronaVac, and Oxford/AstraZeneca. We compared seizure incidence between vaccine and placebo recipients. A further subgrouping was also performed by vaccine platform and age group. To ensure the proper capture of adverse events in the included RCT studies, pooled analyses were performed for 3 neurological adverse events: ischemic stroke, severe headache, and syncope.

Statistical Analysis

All statistical analyses were performed with the R package meta version 5.2-0 and R version 4.2.1 (R Foundation).24 To pool the dichotomous data on seizure incidence, the metabin function was used. The odds ratio (OR) and 95% CI were calculated for the measure of effect.

The between-study heterogeneity was evaluated by Cochran Q statistic, τ2, using the restricted maximum-likelihood (REML) estimator and I2 index.25,26 The selection between common-effects or random-effects models was determined by assessing the I2 index. If I2 was found to be 50% or more, indicating substantial heterogeneity, the random-effects model was used. Otherwise, the common-effects model using the Mantel-Haenszel method27,28 was applied. Publication bias was assessed with funnel plots, and asymmetry was tested using the Egger and Peters tests.29,30 A 2-tailed P value less than .05 was considered significant.

Results

Of 3065 records identified through the systematic database search, after title, abstract, and full-text screening, 6 studies31-36 were included in the qualitative and quantitative (ie, meta-analysis) syntheses (Figure 1). The characteristics of the included studies are summarized in the Table.31-36

It is worth mentioning that 2 studies were also identified that overlapped the included studies: one37 was an interim analysis of results of the RCT on the Moderna vaccine (overlapping the study32 on the final results of Moderna), and the other38 was the interim results of the RCT on the Janssen vaccine (overlapping the study31 on the final results of Janssen). All the RCT studies were deemed low risk regarding RoB-2 score (eFigure 1 in Supplement 1).

Vaccine vs Placebo Recipients in the 28-Day Postinjection Period

Six RCTs31-36 were included in the meta-analysis. One RCT34 assessed new-onset seizure events according to the judgment of the trial investigators through an on-site assessment of adverse events. The other 5 RCTs31-33,35,36 defined new-onset seizures according to the MedDRA39 preferred terms for reporting adverse events. In all 6 RCTs,31-36 the trial investigators evaluated each seizure event and confirmed the seizure event was related to the vaccine or placebo injection. Those seizure events that could be attributed to causes other than the vaccine/placebo injection were not counted and not reported as seizure events. In 5 RCTs,32-36 the participants received 2 vaccine/placebo injections 28 days apart, and in 1 RCT,38 the participants received only 1 injection. The incidence of seizure is reported in the overall 28-day periods after the first and the second injection.

During the 28-day follow-up period after each vaccine/placebo, the pooled analysis of the RCTs31-36 comparing the incidence of new-onset seizure between the 63 521 vaccine and 54 919 placebo recipients demonstrated no statistically significant difference between the 2 groups (9/63 521 events [0.014%] in vaccine recipients and 1/54 919 [0.002%] in placebo recipients; OR, 2.70, 95% CI, 0.76-9.57, P = .12, I2 = 0%, τ2 = 0, Cochran Q P = .74) (Figure 2). The funnel plot of studies is presented in eFigure 2 in Supplement 1. The Egger test (P = .76) and Peters test (P = .28) demonstrated no funnel plot asymmetry. We also carried out a subgroup analysis based on the vaccine platform and age groups, according to which no significant difference was observed in terms of new-onset seizure incidence in either subgroup (adults receiving viral vector vaccines vs placebo: OR, 3.63; 95% CI, 0.60-22.00; I2 = 14%, τ2 = 0, Cochran Q P = .28; children receiving mRNA vaccines vs placebo: OR, 1.00; 95% CI, 0.10-9.61, I2 = 0%, τ2 = 0, Cochran Q P > .99). The χ2 test for subgroup differences showed no statistically significant difference among the subgroups (P = .61).

Vaccine vs Placebo Recipients in the Entire Blinded Phase

Three RCT studies31,32,34 reported the results of the entire double-blinded phase (until unmasking), the interim 28-day follow-up results of which were previously published for 2 of them.37,38 The first study,32 an RCT on the safety and efficacy of the Moderna vaccine, with a median (IQR) follow-up of 148 days (131-162), reported 3 new-onset seizures among 15 184 vaccine recipients (<0.1%) and 1 new-onset seizure among 15 162 placebo recipients (<0.1%). The second study,31 on the safety and efficacy of the Janssen vaccine, with a median follow-up of 121 days (range, 1-284 days), reported 9 new-onset seizures among 21 894 vaccine recipients (<0.1%) and 4 new-onset seizures among 21 882 placebo recipients (<0.1%). The last study,34 on the safety and efficacy of the CoronaVac vaccine, with a median (IQR) follow-up of 43 days (36-48), reported 1 new-onset seizure among 6646 individuals (<0.1%) in the vaccine group and no events in the placebo group. After pooling the 3 studies, no statistical difference was identified between the vaccine and placebo groups (13/43 724 events [0.03%] in vaccine recipients and 5/40 612 events [0.012%] in placebo recipients; OR, 2.31; 95% CI, 0.86-3.23; P > .99, I2 = 0%, τ2 = 0, Cochran Q P = .95) (Figure 3). The funnel plot is shown in eFigure 3 in Supplement 1, and no publication bias was found with the Egger and Peters tests (P values of .91 and .73, respectively).

Other Neurological Adverse Events

It is crucial to ensure that the absence of difference regarding new-onset seizures between the vaccine and the placebo groups is not due to poor and improper capturing of adverse events. To do so, an effort was made to perform pooled analyses on other neurological adverse events with the data derived from the included RCT studies. Three studies31-33 reported ischemic stroke and syncope, and 4 studies31,32,35,36 reported severe headaches in a 28-day follow-up period. The results showed no significant difference in the incidence of ischemic stroke between the vaccine and the placebo groups (4 events [0.008%] in the vaccine and 0 in the placebo; OR, 3.64; 95% CI, 0.60-22.11; P = .16; I2 = 0%, τ2 = 0, Cochran Q P = .96). Similarly, no statistically significant difference was identified between the groups regarding severe headache (15 events [0.034%] in the vaccine group and 11 [0.028%] in the placebo group; OR, 1.16; 95% CI, 0.54-2.50; P = .70, I2 = 0%, τ2 = 0, Cochran Q P = .75). Likewise, the pooled results for syncope did not show any significant difference between the groups (2 events [0.004%] in the vaccine group and 1 [0.002%] in the placebo group; OR, 1.16; 95% CI, 0.54-2.50; P = .69; I2 = 0%, τ2 = 0, Cochran Q P = .54). The forest plots are presented in eFigures 4-6 in Supplement 1.

Discussion

The present study pooled data on more than 118 000 vaccine recipients in the meta-analysis. The meta-analysis of 6 RCTs involving 63 521 vaccine recipients and 54 919 placebo recipients revealed an OR of 2.70 for seizure incidence; however, the difference between the 2 groups was not statistically significant. Similar results were observed by follow-up of the participants through the entire blinded phase. The findings suggest that there is no difference in risk of seizure incidence among vaccinated individuals vs placebo recipients, according to the RCTs.

Pathogenesis of Postvaccine New-Onset Seizure

The pathogenesis of postimmunization seizures occurrence is not clearly determined. Also, among the included studies, the majority did not suggest a suspected pathophysiology for postvaccination seizure occurrence. The SARS-CoV-2 vaccines set off a series of events that could result in the release of inflammatory and proinflammatory molecules, triggering neuronal hyperexcitability and seizures. Indeed, seizures could be caused by induction of glutamate release and inhibition of the release of inhibitory neurotransmitters, triggered by proinflammatory cytokines in the brain, as also happens in SARS-CoV-2 infection.40-42 Furthermore, SARS-CoV-2 vaccines could result in autoimmune encephalopathy,43 which is commonly associated with seizures.44

Of note, according to a case report, immune-mediated thrombotic thrombocytopenic purpura following SARS-CoV-2 vaccination could have caused seizure.45 On the other hand, according to several case reports, the postvaccination seizures were not directly related to SARS-CoV-2 vaccines. Indeed, there were other suspected reasons for seizure occurrence, such as concomitant viral infections35 and glial neoplasm.34 Also, according to another study, a new-onset postvaccination seizure occurred 24 hours after the first dose of ChAdOx1 nCov-19. The final diagnosis was cerebral vein thrombosis, possibly due to severe dehydration.46 Taken together, the exact pathophysiology behind the occurrence of seizures after SARS-CoV-2 vaccination seizures is yet to be fully uncovered.

SARS-CoV-2 Infection vs SARS-CoV-2 Vaccines

Our meta-analysis showed no significant association between new-onset seizure occurrence and SARS-CoV-2 vaccination. However, the risk of seizure occurrence after SARS-CoV-2 infection seems to be relatively high.40 This has been observed for many other complications and other populations as well. For instance, in persons with epilepsy, the risk of increased seizure frequency after vaccinations seems to be less than that of SARS-CoV-2 infection.21,47 Furthermore, some other adverse events were also more pronounced in SARS-CoV-2 infection vs vaccine, such as Bell palsy, Guillain-Barré syndrome, encephalomyelitis, meningitis, and transverse myelitis.14,48 The inflammation after infection or vaccination seems to be responsible for the development of many adverse events. Hence, since the inflammatory response induced by SARS-CoV-2 infection is probably more prolonged and severe than the SARS-CoV-2 vaccines, the adverse events would be more prevalent and critical; however, it has to be confirmed by future studies.

Non–SARS-CoV-2 Vaccines and Seizures

Similar to SARS-CoV-2, seizures can also occur following non–SARS-CoV-2 vaccination, such as diphtheria, measles, mumps, DTP, DTaP-IPV-Hib, and MMR,18,19 which might be due to the induced inflammation and fever.49,50 However, follow-up analyses revealed that these vaccines did not put the recipients at elevated risk for developing seizures in the long term.18,20 Overall, the pathological mechanisms for vaccine-induced seizures in SARS-CoV-2 and non–SARS-CoV-2 could share similarities, which could be an interesting area for future research.

mRNA vs Viral-Vector Vaccines

According to this meta-analysis, no statistically significant difference was found between mRNA and viral-vector vaccines regarding the risk of seizures. Previous studies showed a higher risk for systemic adverse effects in viral-vector vaccines.51 Literature has suggested several reasons for the higher rate of some specific adverse effects of viral-vector compared with the mRNA vaccines. For instance, viral-vector could result in a higher proinflammatory response than mRNA vaccines.52 Also, viral-vector vaccines seem to have a longer half-life,7,53 which might introduce a higher potential to trigger the immune system. However, it should be noted that some adverse effects are more pronounced in mRNA vaccines compared with the viral-vector vaccines.51

Limitations

The current study contains a number of limitations. First, we were unable to perform subgroup analyses based on such factors as sex, age, and vaccination dose because public data were applied rather than data at the individual level. Second, the majority of studies did not provide enough information on additional risk factors for the development of seizures, such as concomitant conditions like metabolic conditions, drug history, and sleep quality. Third, it should be highlighted that the observed seizures after vaccination may be partially attributed to a reporting bias resulting from an overfocus on finding vaccine adverse effects according to the importance of this issue. Fourth, the research that made up the meta-analysis was carried out in various populations and environments, which might have affected the findings. Lastly, the studies included in the meta-analysis were conducted at different times, and the vaccines used in the studies may have differed in their composition and efficacy. Taken together, the aforementioned limitations may have led to potential drawbacks in this study.

Conclusions

The global vaccination drive against SARS-CoV-2 has been a monumental effort in combating the pandemic. SARS-CoV-2 vaccinations that are now available appear safe and appropriate. However, as with any mass vaccination campaign, rare adverse events can occur. Regarding new-onset seizures in the general population, there was no statistically significant difference in risk of seizure incidence among vaccinated individuals vs placebo recipients, according to our meta-analysis.

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Article Information

Accepted for Publication: March 1, 2024.

Published Online: April 29, 2024. doi:10.1001/jamaneurol.2024.0967

Corresponding Author: Churl-Su Kwon, MD, MPH, Departments of Neurology, Epidemiology, Neurosurgery and the Gertrude H. Sergievsky Center, Columbia University, 622 W 168th St, PH19-106, New York, NY 10032 (ck3112@cumc.columbia.edu).

Author Contributions: Drs Rafati and Jameie had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Rafati and Jameie contributed equally as co–first authors.

Concept and design: Rafati, Melika Jameie, Amanollahi, Y. Pasebani, Mana Jameie, Montazeri Namin, Ilkhani, Rahimlou, Kwon.

Acquisition, analysis, or interpretation of data: Rafati, Y. Pasebani, Kabiri, Montazeri Namin, Sakhaei, Feizollahi, M. Pasebani, Mohebbi, Azadi, Kwon.

Drafting of the manuscript: Rafati, Melika Jameie, Amanollahi, Y. Pasebani, Mana Jameie, Kabiri, Montazeri Namin, Sakhaei, Feizollahi, M. Pasebani, Mohebbi, Ilkhani, Rahimlou, Kwon.

Critical review of the manuscript for important intellectual content: Rafati, Melika Jameie, Y. Pasebani, Kabiri, Montazeri Namin, M. Pasebani, Ilkhani, Azadi, Kwon.

Statistical analysis: Rafati, Amanollahi, Y. Pasebani, Montazeri Namin, Ilkhani, Rahimlou, Kwon.

Administrative, technical, or material support: Mana Jameie, Mana Jameie, Sakhaei, Sakhaei, Mohebbi, Mohebbi, Kwon, Kwon.

Supervision: Ilkhani, Kwon.

Conflict of Interest Disclosures: None reported.

Data Sharing Statement: See Supplement 2.

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