Cardiac and Neurological Complications Post COVID-19 Vaccination: A Systematic Review of Case Reports and Case Series

Following mass vaccinations for the control of the COVID-19 epidemic, a spectrum of cardiac and neurological disorders was reported among vaccinated individuals. This study examined the range of complications documented and factors related to their occurrence. Three electronic databases were searched for case reports and case series with descriptions of cardiac and/or neurological complications in COVID-19 vaccine recipients. A total of 698 vaccinees were included in this review, of which 259 (37.1%) had cardiac and 439 (62.9%) had neurological complications. Inflammatory conditions were the commonest among the cardiac complications; while polyneuropathy, demyelinating diseases and cerebrovascular disorders were the more common neurological complications. The mean age of those with cardiac complications (33.8 years) was much younger than those with neurological complications (49.7 years). There was no notable difference in the gender distribution between these two groups of vaccine recipients. mRNA vaccines (all brands) were associated with almost 90.0% of the cardiac complications, whereas viral vector vaccines were associated with slightly over half (52.6%) of the neurological complications. With regard to the dose, cardiac complications were more common after the second (69.1%), whereas neurological complications were more common after the first dose (63.6%). The majority of the cases had an uncomplicated clinical course. Nevertheless, 5.9% of cases with neurological complications and 2.5% of those with cardiac complications were fatal, underscoring the significance of the consistent surveillance and vigilant monitoring of vaccinated individuals to mitigate these occurrences.


Introduction
The COVID-19 pandemic caused catastrophic medical and public health problems worldwide.Urgent control measures were needed to stem its onslaught, the most effective of which was mass vaccination to prevent infection with the SARS-CoV2 virus.As a result, many vaccines of various designs were developed, and a universal mass vaccination program began in late 2021.
The application of mass vaccination includes the description and reporting of adverse side effects or complications associated with the use of the vaccines.As publicity on vaccinerelated complications can adversely affect vaccine uptake, it is essential that information on these complications be scientifically validated.
Early clinical data from various trials indicated that approved COVID-19 vaccines were safe for healthy adults.Nevertheless, complications following the administration of approved vaccines have been reported worldwide [1].These complications affected patient demographic characteristics (age and sex) and their vital signs (blood pressure, pulse rate, respiration rate, oxygen saturation at ambient temperature) at hospital admission.The following supplemental information was included and reviewed for the evaluation of their diagnoses: (i) medical history and comorbidities, (ii) clinical presentation, (iii) results of clinical examination and laboratory investigations (in vitro and in vivo) and (v) treatment given.Also examined were the in-hospital clinical outcomes and, where available, patient condition at follow-up.The other information extracted included vaccination profiles (vaccine types and the number of doses received) and the timing of the vaccination.Detailed descriptions of the included studies are summarized in Supplementary S3 for cardiac complications and Supplementary S4 for neurological complications.

Data Analyses
Statistical analyses were performed using IBM SPSS Statistics version 22.The data were presented as frequencies and percentages for categorical variables and as means ± standard deviations for continuous variables.No statistical significance tests were conducted, as the analyses were primarily descriptive in nature.

Search Results
Our initial search of the databases identified 906 articles (Figure 1); after removing duplicates (n = 96), 810 articles were retrieved for further assessment.After screening the titles and abstracts for suitability, 523 articles were selected for full-text assessment.Following a more detailed evaluation, 381 articles were included for systematic review.Of these, 134 articles (259 cases) reported cardiovascular complications [2,, 245 articles (439 cases) reported neurological complications [3,, and 2 articles described concurrent cardiac and neurological complications [384,385].

Geographical Distribution of Included Studies
The 134 articles related to cardiac complications were mostly from the USA (n = 40) and Japan (n = 20).Smaller numbers (1-10 each) were from 33 other countries in Europe, Africa, Asia, Australasia and S. America (Table 1).
The 245 reports on neurological complications were also mostly from the USA (n = 43), with 10-27 articles each from India, Italy, Japan, the UK, Iran and South Korea, and 1-9 each from another 37 countries in Europe, Africa, Asia, Australasia and S. America (Table 2).
There were two case reports from Bangladesh describing concurrent cardiac and neurological complications.

Characteristics of Patients
The 259 patients (139 male, 120 female; Table 1) with cardiovascular complications were aged between 12 and 96 years old.They were mostly from S. America (41.3%),Asia (38.6%) and Europe (18.9%), with just a small number from Australasia (0.8%) and Africa (0.4%).About a third (80; 30.9%) had pre-existing morbidities or a history of health problems that may or may not be risk factors for cardiac complications.The majority (233; 90%) received mRNA vaccines, 22 (8.5%) received viral vector vaccines, and the remaining 4 (1.5%) received inactivated vaccines.
Specific details on the vaccine doses and types related to complications are summarised in Supplementary S3 and S4.
Table 2 provides a summary of the cardiovascular complications categorized based on dose and brand information of the COVID-19 vaccines.The majority of cardiac complications occurred following the second dose of the COVID-19 vaccine (69.1%), followed by the first dose (25.1%), with the notable exception of acute myocardial infarction (AMI) where the majority of cases follow the first vaccine dose and mostly on the first day of vaccination.Regarding the brand of COVID-19 vaccine, Pfizer COVID-19 vaccines reported the highest prevalence (62.2%) in terms of cardiac complications, followed by the Moderna COVID-19 vaccine (25.5%), with other brands constituting a comparatively lower percentage.Thus, mRNA vaccines (Pfizer and Moderna) accounted for the majority (87.7%) of cardiac complications.However, it is interesting to note that this does not hold true for AMI, for which 60% of cases were associated with the vector-based vaccine AstraZeneca.

Cardiac Complications
Cardiac complications have been associated with both COVID-19 infections and COVID-19 vaccinations.Zuin M et al. (2022) estimated the occurrence of myocarditis to be 0.21 per 1000 COVID-19 patients compared to 0.09 per 1000 control subjects who were not infected but developed myocarditis within the same time frame, thus giving a hazard ratio of 5.15 within one year of the index infection [386], highlighting the significantly increased risk of myocarditis with infection.
Voleti N et al. ( 2022) compared the occurrence of myocarditis between 55.5 million COVID-19-vaccinated individuals and 2.5 million COVID-19 patients and found the odds of developing myocarditis to be higher in patients with COVID-19 (relative risk = 14.8, 95% CI = 11.1, 19.8) compared to COVID-19-vaccinated individuals (relative risk = 2.0, 95% CI = 1.4,2.7) [387].Hence, the risk of myocarditis is much higher in individuals who are infected with SARS-CoV2 that in those who received the COVID-19 vaccine, underscoring the importance of vaccination against the virus.
Ling RR et al. ( 2022) found no significant difference in the incidence of myopericarditis between those who were vaccinated against SARS-CoV2 (18.2 cases [10.9-30.3]per million doses, high certainty) and the general population (56.0 [10.7-293.7],moderate certainty, p = 0.20) [388].These observations by Ling RR et al. suggest that COVID-19 vaccination does not increase a person's risk of myopericarditis specifically.
Based on the above, it would appear that the risk of cardiac complications following COVID-19 far outweighs that following COVID-19 vaccination, thereby supporting the importance of vaccination to reduce the risk of infection, particularly in high-risk people.

Mechanisms Underlying Cardiac Complications following COVID-19 Vaccination
Different hypotheses have been proposed for the occurrence of cardiac complications following COVID-19 vaccination.One of these is the molecular mimicry hypothesis, which states that antibodies mounted against the vaccine cross-react with cardiac antigens [389][390][391].This proposed mechanism has been both supported [12] and refuted [13] by research findings.An alternative theory is that the host response directed against the mRNA component of vaccines causes the activation and dysregulation of immunological responses, leading to the development of myocarditis as part of a systemic reaction [392,393].In both cases, these aberrant responses are more likely to involve individuals with underlying genetic predispositions.It is pertinent to note that different complications could have different underlying pathogeneses in relation to the vaccine, an area that requires further investigation.

Neurological Complications
Neurological complications following COVID-19 vaccinations are mostly mild and transient.The more serious illnesses present as strokes, meningitis encephalitis, neuromyelitis optica (NMO), acute disseminated encephalomyelitis (ADEM), a relapse of multiple sclerosis (MS), transverse myelitis (TM) and peripheral neuropathy (GBS and CIDP).Similar complications also occur with COVID-19, but generally at a much higher frequency.In this review, the most frequently reported post-vaccination disorders were GBS (n = 139, 31.7%),ischemic stroke (n = 58, 13.2%) and a group of demyelinating disorders comprising multiple sclerosis, (n = 41, 9.3%), transverse myelitis (n = 35, 8.0%) and ADEM (n = 26, 5.9%).GBS, an uncommon immune-mediated acute polyneuropathy that is often triggered by preceding viral or bacterial infections, has a worldwide distribution with a pooled global incidence estimated to be 0.81 to 1.89 per 100,000 per year [394].COVID-19 is associated with an increased risk of GBS, with an adjusted odds ratio (AOR) of 3.27 (95% CI = 1.32, 8.09) compared to non-infected controls [395].The pooled incidence of GBS among COVID-19 vaccine recipients, estimated to be 8.1 per 1,000,000 vaccinations [396], is also noted to be significantly higher than the reported annual incidence in the general population.
The classic form of GBS, a demyelinating neuropathy with rapidly ascending weakness, is the most common subtype [397,398].An axonal form is also quite common, especially in Central and South America and the Far East [399][400][401].Other well-recognised forms are Miller Fisher syndrome (MFS) and the facial diplegia subtypes.In this review, classic GBS is indeed the most common form, constituting about 84% of all cases, mirroring the worldwide distribution.Other subtypes reported include the axonal form (8.2%), MFS (4.8%) and facial diplegia (2.7%).Their age and gender distributions also appear to be similar to those widely reported, with a mean age of 55 years and a male preponderance of 61.6%.In terms of vaccine association, most (61%) cases reported taking viral vector vaccines, a finding that is similar to that of many other reports [153,402].
In this review, ischaemic stroke is the second most prevalent complication following COVID-19 vaccination.It accounts for about 90% of all stroke cases and has a fatality rate of 27.6%.As reported by other studies [408,409], it is more common in females (60.7%) and mostly (78.1%) associated with viral vector vaccines.Its causes are cerebral arterial occlusion and venous occlusion or cerebral venous thrombosis (CVT).Contrary to expectations, arterial occlusion only accounted for 41.1% of cases, while CVT, generally considered to be very rare, accounted for 58.9%.The annual incidence of CVT has been reported by others to be 2-15.7/10,000,000[410].
The incidence of CVT in SARS-CoV-2 infections was found to be 8.8 per 10,000 with a male predominance and average age of 49 years [411].In the TriNetX COVID-19 Research Network platform (www.trinetx.com),which is used to compare the prevalence of CVT in the setting of COVID-19 patients versus the uninfected population [412], the odds ratio for CVT in COVID-19 patients was 40.99 [95% CI = 30.11-55.81].Further, a retrospective cohort study found the incidence of CVT in the two weeks after a COVID-19 diagnosis to be 42.8 per million people (95% CI 28.5-64.2),which was significantly higher than in a matched cohort of people who received an mRNA vaccine (RR = 6.33, 95% CI 1.87-21 [413].Thus, the risk of CVT appears to be increased by a COVID-19 infection compared to those uninfected, and moderately increased compared to the COVID-19-vaccinated.Therefore, on balance, it would be more advantageous to be vaccinated despite the known risk of CVT post vaccination, for the simple reason that the risk with the infection is much higher.The risk can further be mitigated by avoiding a specific vaccine type, considering that the great majority (n = 54 out of 65, 83.1%) of cases are associated with vector-based vaccines (Refer to Table 3).

Mechanisms Underlying Neurological Complications following COVID-19 Vac-cination
The mechanism by which a COVID-19 vaccination could trigger neurological complications is generally attributed to molecular mimicry in the background of genetic susceptibility and pre-existing comorbidities.In the case of strokes, traditional risk factors such as hypertension, diabetes and hyperlipidaemia are likely to act in concert with the hypercoagulability seen in COVID-19 and after COVID-19 vaccination.Further research is needed to elucidate the pathways involved.

Limitations
This systematic review utilizes case series and case reports as its data sources.Although case series and case reports generally provide lower-quality evidence compared to cross-sectional studies, they provide in-depth descriptions of individual cases, which are essential for the investigation of vaccination-complication associations.Another limitation of note is the tendency for only unusual or exceptional cases to be published.This selective reporting can lead to an underestimation of the true prevalence and distribution of post-vaccination complications in the population, as more common or less striking cases may go unreported.Language bias is another possible limitation, given that this review exclusively considered case reports published in English through specific databases, inevitably overlooking cases published in other languages or in less widely recognized journals.Regional bias is also a concern, as cases reported in specific regions or countries may be more accessible, resulting in a skewed geographical representation of the reported cases.Additionally, diagnostic bias is a potential source of concern, as cases with clear and easily identifiable complications may be more likely to be reported compared to cases with more complex complications, introducing a bias toward certain types of complications.Furthermore, it is acknowledged that adverse events are expected when a large population is vaccinated, as in the case of the COVID-19 pandemic, thereby precluding a meaningful statistical analysis.This is particularly so in the absence of control groups for comparisons.Lastly, this review is based on publications collected over a relatively short time period, and quite soon after the initiation of the vaccination program, which necessarily limits the observed complications to those which are more acute in nature.

Conclusions
This systematic review highlights the potential of cardiac and neurological complications following COVID-19 vaccination, as reported through case reports and case series.The most frequently reported complications were myocarditis, Guillain-Barré syndrome (GBS), ischemic stroke and exacerbations of multiple sclerosis.However, it is essential to interpret these findings within the broader context of the available evidence.
It is crucial to acknowledge that the true prevalence and distribution of post-vaccination complications in the general population may be underestimated due to potential biases in case reporting and publication.Additionally, the mechanisms underlying these complications are not fully elucidated, and further research is needed to understand the pathways involved.
Continuous surveillance, the close monitoring of vaccinated individuals and the prompt treatment of relevant complications are essential, especially for those with associated risk factors or pre-existing comorbidities.Healthcare providers should remain vigilant and provide appropriate counselling to patients regarding the potential risks and benefits of COVID-19 vaccination.

Figure 1 .
Figure 1.PRISMA flow diagram of the literature screening process.Figure 1. PRISMA flow diagram of the literature screening process.

Figure 1 .
Figure 1.PRISMA flow diagram of the literature screening process.Figure 1. PRISMA flow diagram of the literature screening process.

Table 4 .
Summary of cases with neurological complications, categorized by dose and brand information for COVID-19 vaccines (n = 439).