The heart versus the brain, are they also different when it comes to post-vaccination complications, insights from a systematic review of post-COVID-19 vaccines ADEM cases

Background COVID-19 vaccines have been a game changer in the pandemic, their extensive use was favorable compared to the burden of COVID-19 complications. Despite the low incidence of complications, it was important to analyze them carefully to understand the underlying mechanisms and predisposing factors. For instance, myoperi-carditis especially from mRNA vaccines, and its relatively higher prevalence in young adults and adolescents has raised a public concern about the use of this vaccine in this group. We aimed through this review to compare the age likelihood of ADEM from COVID-19 vaccines, with that reported in myopericarditis cases; secondary outcome parameters included the gender and number of doses needed to induce COVID-19 vaccines related to ADEM. Methodology A literature search has been conducted on relevant databases to retrieve all case reports/series and systematic reviews describing ADEM with possible linkage to COVID-19. Exclusion criteria included any report not including the desired outcome parameters. Our results were then qualitatively compared with a similar systematic review reporting myopericarditis from COVID-19 vaccines. Results In 38 cases with ADEM, mean age was 49 ± 16 compared to 25 ± 14 in myopericarditis, females were more likely to be affected, and while most of myopericarditis cases develop after the second dose, most of ADEM cases develop after the first dose (76%). Moreover, age > 56 years was more predictive of negative outcome after ADEM in the form of death or permanent vegetative state. Short conclusion


Background
There has been a dilemma in the diversified sequelae of post-COVID-19 (coronavirus disease 2019) mRNA (messenger Ribonucleic acid) vaccinations.Although most of the outcomes are satisfactory, and vaccination benefits outweighs the risk, there have been some case reports that intrigued further analysis.A study conducted by Minghui Li et al. assessed the incidence rate of myocarditis and pericarditis following COVID-19 vaccination in the USA in perspective to age group and vaccine type (Li et al. 2021).It was found that the rates of myocardial affection are more prevalent in adolescents and young adults than in older age groups while using the mRNA vaccines.As the reporting odds ratio (ROR) of BNT162b2 (Pfizer-Biontech) and mRNA-1273 (Moderna) vaccine subtypes were higher than the ROR of viral vector vaccines of Ad26.COV2.S (Janssen), 5.3, 2.91 and 1.39, respectively.Another study supports the outcomes of mRNA vaccination post-COVID-19 in youths.A retrospective study was implemented by Dongngan T. Truong et al., and the results of the collected data on patients < 21 years old following mRNA vaccination were significant.(Truong et al. 2022) The incidence of suspected myocarditis in younger patients was noticeable.
The affection of young age by postvaccine myocarditis has not only be observed with mRNA vaccines; as myocardial and pericardial complications can also occur in young age groups following the smallpox vaccine, not only after the COVID-19 mRNA vaccine.This can be supported by an observational cohort study conducted by Engler et al., where the outcomes of smallpox vaccines were elaborated (Engler et al. 2015).Three hundred and forty-eight individuals out of over 5000 case reports that showed side effects post smallpox vaccination, manifested with cardiological adversities such as myocarditis and pericarditis: 276 and 72 cases, respectively.The median age of the myopericarditis cases was 24 years old, emphasizing the prevalence of myocarditis post-vaccination in the younger segment of the age spectrum, irrespective to vaccination subtype.
This young age trend for postvaccine myocarditis, regardless of the type of vaccine, is poorly understood.
In contrast, postvaccine acute disseminated encephalomyelitis (ADEM), tend to occur in a relatively older age.A report by Huynh and colleagues illustrated a case of 61-year-old male with ADEM following influenza vaccine, while Nakamura et al. documented two adult cases aged 62 and 70 with post-influenza vaccine ADEM (Huynh et al. 2008;NAKAMURA et al. 2003).The rest of systematic reviews were mainly focused on postvaccine neurologic sequelae overall and not specifically targeting the specific age of ADEM following different types of vaccines.In addition most of the studies assessing postvaccine ADEM, cannot be reliably cited as the involved vaccines are exclusive childhood compulsory vaccines, thus they cannot reflect the true age trend of postvaccine ADEM.(Sejvar 2005;Williams et al. 2011).
It seems, from the above that age likelihood of postvaccine tissue affection, might be related to the tissue characteristics rather than to the vaccine type.For this purpose, we dedicate this systematic review, to study the age likelihood of acute disseminated encephalomyelitis (ADEM), post-COVID-19 vaccination specifically post-mRNA COVID-19 vaccines.We hypothesize that we might find a discrepancy between the mean age of ADEM cases reported after COVID-19 vaccines compared to myocarditis seen after the same vaccines.The latter finding might consolidate our initial impression that tissue characteristics might be closely tied to the age predilection of post-vaccination immune sequelae in the respective tissue.

Inclusion and exclusion criteria for literature search
A literature search was implemented on PubMed, Scopus, Google scholar and Web of science to identify studies using the following key words ADEM and COVID-19 vaccination.The bibliography of any identified study was clearly inspected to find any report that could have been missed during the initial computer run.
Inclusion criteria included any age, developing ADEM after COVID-19 vaccination, accepted type of studies were systematic reviews, case reports, and case series.
Studies not fulfilling the outcome parameters targeted by the study were excluded.

Outcome parameters
Three of the authors examined each study for the following outcome parameters: age, gender, type, and dose of the vaccine incriminated, the time interval between the vaccination and the development of ADEM, the main neurologic presentation, the treatment lines used, and the outcome of the case.

Statistical analysis
Data collected were analyzed using Excel and MedCalc statistical software.Numerical data were represented using mean and standard deviation when normally distributed and using median, minimum, and maximum when non-normally distributed.Non-recovery was defined as persistence of neurologic abnormalities, vegetative state or death in our collected cases, this categorical division was essential to perform a Receiver Operating Characteristic analysis (ROC) to determine the cut-off age predicting non-recovery from ADEM developing from COVID-19 vaccines.The latter was represented using an interactive dot diagram.
Most of the cases were attributed to the adenoviral vector vaccines (63%) ADEM occurred following the first dose of vaccination (76%), with a median interval of 14 after vaccination.(Table 2).
The oldest age seen in ADEM cases following vaccination was seen in patients receiving mRNA vaccines (57 ± 19) compared to a mean of 48 ± 14 following adenoviral vector vaccines.
Complete recovery was observed in 37% of patients, while non-recovery (defined as residual motor deficit or the development of vegetative state) or death was observed in a total of 45% of cases.(Table 2).
Receiver operating characteristic analysis illustrated as an interactive dot diagram showed that an age > 56, predicts non-recovery in ADEM cases following post-COVID-19 vaccines.(Fig. 2).
Treatment received was mainly steroids (oral and pulse intravenous), intravenous immunoglobulins, and plasma exchange.While only three cases received rituximab (8%), and one received eculizumab and another one received cyclophosphamide (3%) (Table 1).Table 1 illustrates the details of each case in the included cases and case reports.

Discussion
Our review describes the demographic, and clinical characteristics of a rare complication of COVID-19 vaccines.It is the second systematic review of reported cases in this context, after Nabizadeh et al. study (Nabizadeh et al. 2023), however with a different aim.The aim of our systematic review was mainly to study the differences of age predisposition, type of vaccine and number of doses between myocarditis and ADEM following COVID-19 vaccines.Several major differences were observed, notably the number of literature reports, which points to a relatively higher incidence of myocarditis as our group could only find 28 reports with a total of 38 cases compared to thousands of cases of myopericarditis in the literature; this can make the comparison between the two complications flawful, as the scarcity of ADEM reports is not very helpful to draw solid conclusions.
However, we still decided to compare the aforementioned outcome parameters across the two complications.We took Goyal et al. study as a reference for myopericarditis cases as it shares the different outcome parameters intended in our study, and it is not a VAERS based study; thus, its results can be qualitatively compared to the results of our research.(Goyal et al. 2023).
Age of clustered ADEM cases was 49 ± 16 compared to 25 ± 14 in myopericarditis cases.The young age of myopericarditis especially from mRNA vaccines, lead to fears among parents, planning to vaccinate their children using these vaccines, and led to an overall impression that mRNA vaccines might be associated with increased complications' rate at the young age.Our study contradicts this false belief, as it clearly shows that ADEM occurring from mRNA vaccines is likely to occur in older age groups compared to myocarditis and to ADEM cases from other COVID-19 vaccines.Nevertheless, older age was also predictive of worst outcomes in our collected cases (Fig. 2), patients older than 56 were more prone to develop residual neurologic deficit, vegetative state, or death.This might also mean that age likelihood and other demographic characteristics of any vaccine complication are related to the type of the complication and tissue involved rather than the vaccine type.
One of the theories that can explain the young age of myocarditis from COVID-19 and other vaccines (such as vaccinia virus vaccine used for smallpox) is the mechanism of immune inhibition inside the myocardium.The heart muscle harbors a strict system for immune surveillance, that can prevent any immune-mediated damage, this immune surveillance is particularly important in the heart as the regenerative capacity of myocardial cells is absent.
Two main mechanisms of peripheral tolerance protect myocytes from T cell damage namely cytotoxic T-lymphocyte-associated protein-4 (CTLA4), and Programmed cell protein death-1 (PD1).CTLA4 and PD1 block T cell activation by binding to CD-28 receptors on the surface of T cells, thereby preventing any viral antigen from its activation.(Grabie et al. 2019) The myocardial protection from autoimmunity, offered by inhibitory immune checkpoints, such as PD1, is upregulated by aging, which might mean that the susceptibility of myocardium to immune-mediated inflammation, should decrease with aging.(Platt et al. 2017) On another note, antibodies implicated in CNS autoimmune inflammation, must gain access to the CNS via the blood brain barrier, olfactory route, or blood-cerebrospinal fluid barrier, or sometimes produced locally witing the CNS itself.The latter mechanism has been particularly of focus in multiple sclerosis, as Quintana and colleagues proved the present of myelin reactive antibodies that are locally produced in the brain.There also hypotheses that postinfectious ADEM, which is intriguingly common in the pediatric age group, involves the local production of antibodies in the CNS against viral antigen entering the CNS through the olfactory route.But, for antibodies, to gain access to the CNS, this implies a leakier BBB Blood brain barrier) or BCSFB (Blood cerebrospinal fluid barrier),  this can be understandable in post-infectious ADEM, where implicated micro-organisms weaken the tight junctions of the BBB, and this allows access of crossreactive antibodies to the brain (Spindler and Hsu 2012); but this cannot be the case in post-vaccination ADEM, as no offending organism is present to play this synergistic getaway role.An explanation for antibody access to the CNS in post-vaccination ADEM, is aging.If aging protects the myocardium against autoimmunity, it plays an inverse role in the CNS by rendering the BBB and BCSFB more permeable to antibodies and to external antigens.(Adesse et al. 2022).Back to the findings, of our study, which also showed that ADEM mainly occurs after the first dose of vaccination, this is different than the immune-priming pattern seen in myocarditis from COVID-19 vaccines, as they need two doses usually to produce this complication.
This pattern might be consistent with a cytokine rather than immune-mediated damage.Wu et al. described a subtype of ADEM known as acute necrotizing encephalitis which involves a personal susceptibility to CNS damage due to hypercytokinemia.(Wu et al. 2015).
Finally, yet importantly female patients were more likely to develop ADEM following COVID-19 vaccination compared to male patients.A study by Falahi et al., outcomes across both genders, and showed that female patients have a higher susceptibility to cytokine storm, and suggested that estrogen upregulates pro-inflammatory molecules, leading to an augmented inflammatory response in females.This might consolidate the impression taken from dose pattern of post-COVID-19 vaccination ADEM, that it is mainly mediated via hypercytokinemia rather than auto-antibodies.(Falahi and Kenarkoohi 2021).
It is worth highlighting again as mentioned in the first paragraph of the discussion, that one of the most important limitations of this study that can hinder the solidity of our results; is the discrepancy in the number of cases across the two complications (ADEM and myopericarditis); with only 38 ADEM cases compared to hundreds of myopericarditis patients.
Figure 3 summarizes the differences outlined above between ADEM and myopericarditis developing following COVID-19 vaccines in view of our findings compared to the findings of Goyal et study (2023).

Conclusions
This review compares the demographic, vaccine types and dose characteristics of post-COVID-19 vaccines ADEM and Post-COVID-19 vaccines myopericarditis.Older age, predominance of female gender, and first dose implication all characterize ADEM compared to myopericarditis.And despite the rarity of these complications, they open new horizons in understanding post-vaccination complications and their underlying mechanisms.They might signify that aging can be protective against autoimmunity in the myocardium, but the same aging can jeopardize the BBB, rendering it more susceptible to delivery of antibodies and cytokines to the CNS.More studies at the molecular

Table 1
Details of the included cases

Table 2
Summary statistics of ADEM developing following COVID-19 ADEM Acute disseminated encephalomyelitis, COVID-19 Coronavirus disease, mRNA Messenger Ribonucleic acid, n number, NR not reported, SD standard deviations