COVID-19-Associated Encephalitis:  Systematic Review of Case ReportsFindings on Cytokine-Immune-Mediated Inflammation as an Underlying Mechanism

Abstract

Background : Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily attacks the respiratory system resulting to a disease called coronavirus disease 19 (COVID-19), several studies also reported the involvement of the central nervous system along the course of the disease, one of which manifest as encephalitis. This study aims to determine the clinical profile, laboratory, and imaging results of encephalitis associated with COVID-19.Methods : Three databases namely, PubMed / Medline, Embase, and Scopus were systematically used in the search for this literature, in order to gather case reports and case series related to COVID-19-associated encephalitis published from January 1, 2019 to July 20, 2020.Result: There were 24 studies with 33 cases included in this review. The most reported neurological symptoms were disorientation / confusion (72.72%), decreased consciousness (54.54%), and seizures (27.27%). The laboratory examination showed an increase in the levels of C-reactive protein (48.48%), lactate dehydrogenase (30.3%), and lymphophenia (27.27%). The brain imaging examination did not show any pathological findings in half of the cases (51.51%). EEG (electroencephalography) showed a generalized decrease in 45.45% of the cases. The CSF analysis showed an increase in the levels of protein (42.42%) and lymphocytosis (24.24%). Positive cerebrospinal fluid polymerase chain reaction (PCR) was only found in 3 cases, while the most widely used pharmacological agent was hyroxychloroquine (48.48%). Intravenous steroids were given in 8 cases, while immunotherapy such as plasmapheresis and intravenous immunoglobulin were given in 10 cases. Fifteen patients were reported to be discharged from the hospital in stable conditions, while four mortality cases were recorded. Conclusion: The clinical, laboratory, and imaging findings in this review supported the hypothesis that the process of cytokine-immune mediated inflammation was the cause of cerebral damage in COVID-19-associated encephalitis, rather than direct invasion. However, due to the limited availabile facilities in this study, further research and examination are needed to confirm the hypothesis

Encephalitis as a neurological complication of COVID‐19: A systematic review and meta‐analysis of incidence, outcomes, and predictors

“…This could be due to milder encephalitis or imaging conducted prematurely before brain changes developed. Neuroimaging findings in patients with encephalitis as a complication of COVID‐19 resemble those in the previous severe acute respiratory syndrome coronavirus 1 (SARS‐CoV‐1) and Middle East respiratory syndrome outbreaks, suggesting possible similarities in pathophysiology of central nervous system (CNS) involvement across these three coronaviruses [13]. Electroencephalography (EEG) in some patients showed patterns of general slowing [24].…”

“…CoV-2 virus into the CNS may be less likely to be the main mechanism causing encephalitis in COVID-19 [12,13], as most patients with encephalitis in COVID-19 have had negative CSF polymerase chain reaction against SARS-CoV-2, and symptoms of direct CNS involvement such as anosmia and ageusia have been very uncommon [30,[32][33][34].…”

“…Once infected in blood vessels, these leukocytes cross the BBB, entering the CNS and taking the SARS‐CoV‐2 virus with them, where they can infect other cell types within the CNS to cause encephalitis [46]. However, it has been suggested that direct invasion of SARS‐CoV‐2 virus into the CNS may be less likely to be the main mechanism causing encephalitis in COVID‐19 [12,13], as most patients with encephalitis in COVID‐19 have had negative CSF polymerase chain reaction against SARS‐CoV‐2, and symptoms of direct CNS involvement such as anosmia and ageusia have been very uncommon [30,32–34].…”

“…Supportive evidence for this theory includes CSF analysis and serology, which show a proinflammatory state [24,28,30]. Additionally, EEG results reveal diffuse patterns indicative of extensive inflammation [13]. Further studies reporting CSF and/or serum levels of such inflammatory cytokines may be useful for elucidating underlying pathophysiological mechanisms.…”

“…The association of encephalitis with severe patient outcomes suggests that systematic studies are required to determine the risk factors predisposing to its development. Currently, systematic reviews that consolidate findings on encephalitis as a complication of COVID-19 are scarce, providing limited information on this condition [10][11][12][13]. To address this important gap in the literature, a systematic review was conducted to more comprehensively evaluate the epidemiology, clinical course, risk factors, and outcomes of patients who suffer from encephalitis as a complication of COVID-19.…”