Encephalitis following COVID-19 Vaccination: A Systematic Review

Background: Since the advent of global COVID-19 vaccination, several studies reported cases of encephalitis with its various subtypes following COVID-19 vaccinations. In this regard, we conducted a systematic review to investigate and characterize the clinical settings of these reported cases to aid in physician awareness and proper care provision. Methods: We systematically searched PubMed, Web of Science, and Scopus and manually searched Google Scholar. Studies published until October 2022 were included. Demographic data, clinical features, vaccine data, treatment lines, and outcomes were extracted. Results: A total of 65 patients from 52 studies were included. The mean age of patients was 46.82 ± 19.25 years, 36 cases (55.4%) were males. AstraZeneca was the most-reported vaccine associated with encephalitis (38.5%) followed by Pfizer (33.8%), Moderna (16.9%), and others. Moat encephalitis cases occurred after the first dose of vaccination in 41/65 (66.1%). The mean time between vaccination and symptom onset was 9.97 ± 7.16 days. Corticosteroids (86.2 %) and immunosuppressants (81.5 %) were the most used lines of treatment. The majority of affected individuals experienced a full recovery. Conclusion: Our study summarizes the current evidence of reported post-vaccination encephalitis, regarding clinical presentation, symptoms onset, management, outcomes, and comorbid conditions; however, it fails to either acknowledge the incidence of occurrence or establish a causal relationship between various COVID-19 vaccines and encephalitis.


Introduction
Encephalitis is an inflammation of the brain tissues and is most usually caused by a viral infection (mainly herpes simplex virus), which represents about 75% of diagnosed cases; however, autoimmune causes such as N-methyl D-aspartate receptor (NMDAR) antibody encephalitis are also common [1]. Encephalitis is a neurological emergency that can cause severe cognitive impairment or death if not treated promptly. It can be diagnosed by at least two of the following criteria: fever, seizures, focal neurological findings by a cause of brain parenchymal damage, EEG findings indicative of encephalitis, lumbar puncture pleocytosis (more than four white cells per µL), or neuroimaging findings suggestive of encephalitis [2]. studies, we manually retrieved other studies from Google Scholar and performed backward citation analysis.

Screening and Inclusion Criteria
We included all published or pre-published papers presenting cases of any type of encephalitis in individuals who received any type of COVID-19 vaccination either as case reports, case series, or letters to editors. No language restrictions were applied. Secondary studies including reviews and meta-analyses, book chapters, and press releases were excluded from our study. Studies underwent title and abstract blind screening by two reviewers using Rayyan Artificial Intelligence [29]. After the removal of duplicates, the identified full-text articles were examined, and we manually assessed retrieved full-text records from Google Scholar and related references of further studies (Figure 1).
Our systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) checklist. It is registered in PROSPERO database with ID number: CRD42023389901. We performed a systematic literature search of PubMed, Scopus, and Web of Science databases, from inception until October 2022, following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) [28]. The following search strategy was used (COVID-19 vaccination OR SARS-CoV-2 vaccine OR COVID-19 vaccine) AND (encephalitis). To increase our chances of identifying all relevant studies, we manually retrieved other studies from Google Scholar and performed backward citation analysis.

Screening and Inclusion Criteria
We included all published or pre-published papers presenting cases of any type of encephalitis in individuals who received any type of COVID-19 vaccination either as case reports, case series, or letters to editors. No language restrictions were applied. Secondary studies including reviews and meta-analyses, book chapters, and press releases were excluded from our study. Studies underwent title and abstract blind screening by two reviewers using Rayyan Artificial Intelligence [29]. After the removal of duplicates, the identified full-text articles were examined, and we manually assessed retrieved full-text records from Google Scholar and related references of further studies (Figure 1).

Statistical Analysis
To provide a comprehensive understanding of the data included in those studies, we extracted patients' characteristics (i.e., age and gender), the type of encephalitis, the type and dose of the vaccine, and the latency period before the onset of symptoms. We extracted symptoms, either relating to the nervous system or any other systems, and whether these patients had any other comorbidities. Investigations, treatment, and treatment outcomes were likewise extracted (Table 1). Extracted data were pooled into mean and standard deviation for continuous variables or frequency and percentage for categorical variables ( Table 2).

Quality Assessment
For included case reports and case series, we used the Joanna Briggs Institute (JBI) quality assessment tools, based on the clinical features, history, diagnoses, interventions, and management plans. Fourteen letters to the editor were excluded from the assessment due to a lack of appropriate assessment tools. Two authors assessed the quality of included studies and resolved conflicts by consensus. For case reports, JBI domains included eight questions, and the case series checklist assessed ten domains. Grades were assigned such that; Low risk: 75-100%, Moderate: 50-74%, High risk < 50%. High-risk studies will be excluded.

Results
Out of 1395 studies identified from databases, 280 were excluded as duplicates. We screened 1079 records at a title and abstract level, through which we excluded 1030 records for irrelevancy. At this point, 15 studies retrieved from previous studies and 16 records identified manually through a Google Scholar search were compared with studies eligible for full-text screening (n = 49), excluding duplicates. In total, 80 records were assessed through full-text screening, from which 11 studies were excluded for reporting CNS infections other than encephalitis and non-COVID-19 vaccination; 14 systematic reviews, literature reviews, and meta-analyses were excluded; 3 studies were excluded for being high risk on quality assessment. In total, 52 studies were included in the final qualitative synthesis, see Figure 1.

Investigations and Diagnostic Results
Diagnostic test results were primarily available for CSF and MRI findings; 61.5% (40/60) of MRI results were abnormal with the following findings: FLAIR, T2, and DWI hyperintensities in various regions, central focal hemorrhage, bilateral white matter lesions, minimal T2 sulcal hyperintensity without contrast enhancement, plaques in periventricular, juxtacortical and cortical areas, swelling and hyperintensities of the anterior part of the optic nerves, restricted diffusion through insular and mesial temporal cortices, swelling of the hippocampus, encephalomalacia in frontoparietal lobes, blurred gadolinium enhancement on T1-weighted images; for MRI spine: multiple enhanced lesions of the spinal cord were found in addition to longitudinal edema along the thoracic spinal cord with contrast enhancement and longitudinally extensive transverse myelitis. In CSF, the most common finding was pleocytosis (48.5 %). Seven patients (10.8%) had high protein in their CSF samples, and six had positive CSF antibodies, including ANA, Anti-LGI1, SARS-CoV-2 spike S1 RBD IgG, anti-NMDA, intrathecal IgA, and IgM.
The type of vaccine administered was not statistically associated with any specific outcome (p = 0.124), see Table 3; however, patients with autoimmune encephalitis and other subtypes were more likely to undergo full recovery (p < 0.001), see Table 4. Patients who did not receive plasmapheresis were more likely to make a full recovery (p = 0.002), see Table 5 and Figure 2.

Quality Assessment
Fifty-two case reports and three case series were assessed using the JBI checklist, see Table 6. Most case reports (n = 40) had a low risk of bias, nine had a moderate risk, and three had a high risk of bias. All three case series had a moderate risk of bias; data are shown in Table 7. Three high-risk studies were excluded.

Quality Assessment
Fifty-two case reports and three case series were assessed using the JBI checklist, see Table 6. Most case reports (n = 40) had a low risk of bias, nine had a moderate risk, and three had a high risk of bias. All three case series had a moderate risk of bias; data are shown in Table 7. Three high-risk studies were excluded. and others. Unlike typical diagnostic criteria for encephalitis (major criteria of patients presenting with altered mental status lasting ≥24 h with no alternative cause identified), the most occurring symptoms in our study were abnormal movements, fever, headache, and seizures [30]. CSF encephalitic findings and MRI abnormalities were evident in almost two-thirds of included patients. Most patients received corticosteroids as a part of the immunosuppressive regimen and achieved full recovery. However, death was common in patients who received plasmapheresis, which, to our understanding, could be contributed to the already late presentation and severe symptoms, which prompted plasma exchange therapy in the first place.
Although the exact etiology of vaccine-induced encephalitis is still not fully understood, it could be attributed to different potential mechanisms of vaccine-induced autoimmune diseases. COVID-19 vaccine was shown to trigger proinflammatory cytokine expression and the response of T-cells as in other vaccines [31]. This is important because these cytokines may reach the brain and activate microglial cells resulting in neuroinflammation [32]. However, the possible molecular mimicry between the vaccine antigens and self-antigens, or the acceleration of an ongoing autoimmune process caused by vaccines are still considered potential mechanisms [33].
Myalgia and general weakness were considered the most reported symptoms in a previous clinical trial assessing the safety of the AstraZeneca vaccine; notably, only two cases presented with neurologic symptoms, such as demyelinating polyradiculoneuropathy and hypoesthesia. Nonetheless, no encephalitis-associated symptoms were reported [34]. To our knowledge, no other clinical trials reported encephalitis post-vaccination. As the vaccinated population increased, several SARS-CoV-2 vaccines have been associated with neurological side effects on follow-up observational studies [35]. Most reported cases in the literature were immunized by AstraZeneca and Pfizer. The incidence of encephalitis after vaccination with the AstraZeneca and Pfizer-Biontech mRNA vaccines was estimated to be 8 per 10 million and 2 per 10 million vaccination doses, respectively, which denotes an extremely rare incidence of adverse event occurrence in comparison to other well-established vaccines such as hepatitis vaccines [24]. A previous systematic review addressing 11 patients with autoimmune encephalitis also corresponds with a greater majority of AstraZeneca and Pfizer predominant case reporting (8/15) [31]. Consistent with our findings, in which AstraZeneca and Pfizer comprised almost two-thirds of available cases. However, no statistical correlation between vaccine subtype and encephalitis outcomes could be established in our study. Generally, performing a lumbar puncture can suggest the presence of encephalitic involvement [36]. Huang et al. presented 9/11 cases with lumbar puncture findings indicating encephalitic changes. In our study, CSF sample abnormalities were indeed reported in most cases followed by MRI abnormalities. Full recovery is indicated in a greater percentage of all the aforementioned studies and also in our study.

Strengths and Limitations
The main strength of this systematic review is the use of a thorough search strategy to locate studies for evaluation, minimizing selection bias. These studies were evaluated using established critical appraisal tools and individually assessed by two authors to estimate the risk of bias in each study. We were able to synthesize comprehensive descriptive statistics. On the other hand, however, only 65 patients were included, which was considered insufficient to reach a precise conclusion. For a clear association between encephalitis and COVID-19 vaccination, a larger sample size with consistent reporting of clinical phases is required. To reduce the reporting bias, more clinical trials with appropriate follow-up of the treatment protocol must be analyzed. This would give a better insight into the severity and prognosis of the condition. Other limitations inherent to the nature of our systematic review of case reports and series follow naturally and must be considered.

Conclusions
With the increasing population of vaccinated individuals, a growing body of literature introduced a variety of rare side effects including encephalitis with its various subtypes. Studies included in our report should prompt awareness of possible encephalitis cases with presenting symptoms of abnormal movements, fever, and seizures, particularly 2-3 weeks post-vaccination. Physicians must pay attention to such adverse effects as they can be easily managed if noticed promptly and with excellent recovery rates. Further studies are needed to understand the underlying pathophysiologic mechanism and investigate an association relationship. Due to rarity of reported cases and good overall recovery, we still recommend COVID-19 vaccination. Institutional Review Board Statement: Ethical review and approval were waived for this study as this is a secondary study incorporating data from previously published studies.
Informed Consent Statement: Patient consent was waived as no patient identification data were included for this is a secondary study incorporating data from previously published studies.

Data Availability Statement:
The data that support the findings of this systematic review are available from the original studies, but restrictions may apply. Some authors may not have provided open access to their data. All data are available upon reasonable request and with permission of the original authors.

Conflicts of Interest:
The authors declare no conflict of interest.