Encephalitis in Patients with COVID-19: A Systematic Evidence-Based Analysis

Abstract

Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) predominantly infects the respiratory system, several investigations have shown the involvement of the central nervous system (CNS) along the course of the illness, with encephalitis being one of the symptoms. The objective of this systematic review was to evaluate the characteristics (clinical, neuro-radiological aspects, and laboratory features) and outcomes of encephalitis in COVID-19 patients. PubMed, Scopus, and Google Scholar databases were searched from 1 December 2019 until 21 July 2022 to identify case reports and case series published on COVID-19 associated with encephalitis. The quality of the included studies was assessed by the Joanna Briggs Institute critical appraisal checklists. This systematic review included 79 studies, including 91 COVID-19 patients (52.7% male) experiencing encephalitis, where 85.6% were adults (49.3 ± 20.2 years), and 14.4% were children (11.2 ± 7.6 years). RT-PCR was used to confirm 92.2% of the COVID-19 patients. Encephalitis-related symptoms were present in 78.0% of COVID-19 patients at the time of diagnosis. In these encephalitis patients, seizure (29.5%), confusion (23.2%), headache (20.5%), disorientation (15.2%), and altered mental status (11.6%) were the most frequently reported neurologic manifestations. Looking at the MRI, EEG, and CSF findings, 77.6%, 75.5%, and 64.1% of the patients represented abnormal results. SARS-CoV-2-associated or -mediated encephalitis were the most common type observed (59.3%), followed by autoimmune encephalitis (18.7%). Among the included patients, 66.7% were discharged (37.8% improved and 28.9% fully recovered), whereas 20.0% of the reported COVID-19-positive encephalitis patients died. Based on the quality assessment, 87.4% of the studies were of high quality. Although in COVID-19, encephalitis is not a typical phenomenon, SARS-CoV-2 seems like a neuropathogen affecting the brain even when there are no signs of respiratory illness, causing a high rate of disability and fatality.

Increased neurovirulence of omicron BA.5 and XBB variants over BA.1 in K18-hACE2 mice and human brain organoids

“…3b,c,d). Multiple sclerosis-like features, myelitis, demyelination 94,95 and encephalitis 9,24-26 are also features described for COVID-19 patients. Apoptosis of neurons was reported in the NHP model 31 , with pyroptosis in the CNS of COVID-19 patients also proposed 96 .…”

“…3b,c,d). Multiple sclerosis-like features, myelitis, demyelination 94,95 and encephalitis 9,[24][25][26] are also features described for COVID-19 patients.…”

“…Long COVID is now well described for many variants of concern 5 , and also occurs after infection with BA.5 6 . Neurological and psychiatric manifestations represent a major component of COVID-19 and long COVID [7][8][9] and these remain for patients infected with omicron viruses [10][11][12][13] , although data specifically for BA.5 neurological manifestations has not yet emerged. The large number of changes in spike for omicron and omicron sub-lineages has rendered vaccination [14][15][16] , many monoclonal antibody treatments 17 , and prior exposure with other variants 18 less protective.…”

“…There is strong evidence for brain abnormalities in COVID-19 patients [20][21][22][23] . Encephalitis is well documented, usually in hospitalized COVID-19 patients with severe disease, with encephalitis predisposing to poor outcomes and a higher risk of mortality 9,[24][25][26] . The mechanism(s) whereby brain pathology/immunopathology and/or neuropathology might manifest in COVID-19 patients remains debatable, with the systemic cytokine storm and/or direct brain infection likely involved 22,[27][28][29][30][31][32] .…”

Neuroinflammatory syndromes in children

“…Specifically in children and adolescents, data are more limited, but reports exist detailing new-onset autoimmune antibody positivity in individuals with encephalitis including ANMDARE [37–40] and MOG Ig [41,42,43 ▪ ]. Other post-infectious neuroinflammatory presentations have been recently described, such as rhombencephalitis as well as features of COVID encephalitis itself [44,45 ▪ ]. The question of a potential paediatric post-acute SARS-CoV-2 syndrome due to inflammatory or other insults is being actively researched and is challenging given the high rate of overlapping symptoms identified in children who lacked a history of COVID infection [46 ▪▪ ].…”