Autoimmune encephalitis in COVID-19 patients: a systematic review of case reports and case series

Background There is mounting evidence suggesting that autoimmune encephalitis (AE) can be observed as a neurological complication in patients with COVID-19. This review aimed to summarize the clinical manifestations, types, and outcomes of COVID-19-associated AE. Methods A systematic search was conducted in the PubMed, Embase, and Web of Science databases to identify case reports and case series related to COVID-19-associated AE from 1 January 2020 to 31 March 2023. After a thorough screening and evaluation, irrelevant articles were excluded. Relevant information concerning types, clinical manifestations, and outcomes was extracted and synthesized. Results A total of 37 studies, comprising 34 case reports and 3 case series, were included in this review. Among the 42 COVID-19-associated AE patients, 21 (50%) cases were classified as an unknown antibodies (Ab) type of COVID-19-associated AE, 10 (23.80%) cases as anti-N-methyl-D-aspartate (NMDA) encephalitis, 4 (9.5%) cases as limbic encephalitis, and 3 (7.1%) cases as anti-myelin-oligodendrocyte-glycoprotein encephalitis, along with other rare types of AE. Disturbance of consciousness, seizures, and psychiatric symptoms were identified as the main clinical manifestations of COVID-19-associated AE. While the symptoms of AE displayed variation, most patients achieved full recovery although a few experienced residual symptoms of neurological damage. Conclusion This systematic review comprehensively describes the characteristics of COVID-19-associated AE. The main type of COVID-19-associated AE identified in this study is an unknown Ab type of COVID-19-associated AE. Despite the potentially life-threatening risks of COVID-19-associated AE, the majority of patients survived, with some patients reporting residual neurological symptoms.


. Introduction
Coronavirus disease 2019 (COVID-19) is an emerging infectious disease caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (1).It has placed an unprecedented burden on economies and healthcare systems worldwide since the beginning of the COVID-19 pandemic (2).Recent studies have demonstrated that both COVID-19 patients and those with autoimmune diseases exhibit similar immune responses affecting multiple organs and systems,

. . Search strategy
We conducted an extensive and exhaustive search of case reports and series between 1 January 2020 and 31 March 2023 from PubMed, Embase, and Web of Science.The search terms included "Autoimmune Encephalitis, " "Antibody-Mediated Encephalitis, " "Antibody Mediated Encephalitis, " "limbic encephalitis, " "Anti NMDA, " "Anti MOG, " "Anti LGI1, " "Anti GABA, " "coronavirus disease-19, " "SARS-CoV-2, " "COVID 19, " and "COVID-19."All English publications describing case reports and case series of confirmed COVID-19 infections with AE were included.Two independent reviewers comprehensively searched and filtered the eligible studies.We excluded all review articles, other types of encephalitis, and unconfirmed cases of AE.

. . Inclusion criteria
This case report and case series met the following inclusion criteria: (1) patients tested positive for SARS-CoV-2 in the reverse transcription-polymerase chain reaction (RT-PCR) or had a positive title for SARS-CoV-2 serum antibody and (2) raw data on clinical symptoms, diagnosis, treatment, and outcome of COVID-19-associated AE were provided.

. . Study selection and data extraction
Two reviewers independently selected studies by reading the full articles and then extracting data from the eligible articles.The following data were extracted from the included studies: the first author's last name, year of publication, number of patients, participant's age, participant gender, SARS-CoV-2 diagnosis method, neurological manifestations, imaging analysis, cerebrospinal fluid (CSF), types, AE diagnosis method, treatment details, and outcomes.

. . Searching published literature
A total of 443 articles were yielded after a comprehensive search in our literature.After removing 223 duplicate articles, 153 irrelevant title and abstract articles and 66 full-text articles were further evaluated.Finally, 37 studies were included in our systematic review after excluding 6 review articles, 4 modeling studies, 4 commentary, 3 editorials, and 13 other encephalitides (including herpes simplex virus encephalitis, cytomegalovirus encephalitis, and varicella-zoster virus encephalitis) (Figure 1) (20-56). .

. . Neurological manifestations
Neurological manifestations in this study were reported in seven categories: (A) disturbance of consciousness; (B) seizures; (C) psychiatric symptoms; (D) neuromuscular symptoms such as myalgia, weakness, and myoclonus; (E) extrapyramidal movements; (F) cerebellar syndrome; and (G) other clinical symptoms.The frequency of various neurological manifestations is presented in Figure 2.
In this review, disturbances of consciousness were observed in 13 patients, primarily characterized by symptoms such as drowsiness, delirium, confusion, and unconsciousness.Additionally, 19 patients exhibited seizures, with 5 experiencing generalized tonic-clonic seizures and 2 experiencing refractory status epilepticus.In all, 18 patients in the study exhibited .
In this study, the main type of COVID-19-associated AE is an unknown antibody (Ab) type of COVID-19-associated AE, where despite no detection of AE-related Ab in the CSF, a diagnosis of possible AE was made according to Graus criteria: first, they had an acute (<2 weeks) or subacute (≤3 months) onset, accompanied by neurological and psychiatric symptoms or clinical syndrome signs.Second, they showed one or more of the following auxiliary examinations: CSF abnormalities, neuroimaging abnormalities, or electrophysiological abnormalities.Third, other potential causes were reasonably excluded (57).Notably, 21 patients were diagnosed with an unknown Ab type of COVID-19-associated AE; these patients exhibited consciousness disturbance, generalized tonicclonic seizures, persecution delusion, autonomic instability, and dysarthria (Table 1) (24-27, 29-31, 39, 41, 45, 46, 48, 51, 52, 55, 56).The ages of these patients ranged from 1 to 88 years, with a mean age of 45.3 years.Among this group, 10 cases reported symptom onset ranging from 2 to 12 days (with an average of 8 days) from the positive SARS-CoV-2 RT-PCR.
There were four cases of limbic encephalitis, with the main symptoms being generalized seizures and disturbances of consciousness (26,35,44,50).Three cases reported anti-MOG encephalitis, and prominent clinical manifestations were vertigo, non-specific blurry vision, and assaultive behavior.Notably, the magnetic resonance imaging findings of anti-MOG encephalitis were usually diffuse and multifocal (36,38,42).

. . Cerebrospinal fluid
Among 42 patients, 19 (45.23%) had elevated CSF protein levels, ranging from 49.0 to 838.0 mg/dl.Most of these cases showed mild elevation.The average glucose level in CSF was 81.7 mg/dl (range: 59.0-130.0mg/dl), indicating raised levels.CSF glucose was found to be elevated in 9 (21.42%)patients, with a maximum value of 78 mg/dl.Additionally, four cases reported elevated levels of IgG in the CSF, and four cases reported the presence of oligoclonal bands.

. . MRI results
Among the 42 patients, 36 patients conducted ordinary MRI and 2 conducted enhanced MRI.Of these, 12 (33.33%)patients exhibited no significant abnormalities on ordinary MRI, while 24 (66.66%)patients displayed varying degrees of abnormalities.In the reviewed cases, hyperintensity has been observed in different regions, such as white matter, temporal lobe, parietal lobe, insular cortex, brainstem, cerebellum, and corpus callosum, and in some cases, it has been observed in multiple disseminated regions.Among 21 unknown types of COVID-19-associated AE patients, 12 (57.14%)patients exhibited abnormalities on ordinary MRI, which mainly manifested as hyperintensity in the frontal lobe, corpus callosum, and temporal lobe, and in severe cases, brainstem and multiple diffuse hyperintensities.

. . Outcome
Among the 42 patients, 29 (69.04%)achieved complete recovery, 8 (19.04%) showed partial recovery, and 1 experienced multiorgan damage, and in 2 cases the outcome was not reported.Two (4.76%) patients died due to sepsis and intracranial hemorrhage, respectively.Despite the varied symptoms of AE, most .

Discussion
AE is one of the neurological complications of COVID-19.This study conducted a review of case series and case reports to evaluate the neurological manifestations, types, and outcomes of COVID-19-associated AE.Previous studies have shown that in COVID-19-associated AE patients, the onset of symptoms can occur several weeks after or even during acute SARS-CoV-2 infection (55).In our review, we observed that the neurological manifestations of patients could be categorized into seven categories, including disturbance of consciousness, seizures, psychiatric symptoms, neuromuscular symptoms, extrapyramidal movements, cerebellar syndrome, and other clinical symptoms.The most common symptoms were seizures (19 cases), disturbance of consciousness (13 cases), and psychiatric symptoms (18 cases).COVID-19-associated AE patients who experienced epileptic seizures predominantly presented with generalized tonic-clonic seizures.COVID-19-associated AE can also manifest as psychiatric symptoms, such as cognitive decline, abnormal behavior, delusions of persecution, and hallucinations.Furthermore, some patients may initially experience neuromuscular symptoms or extrapyramidal movements, including myalgia, weakness, myoclonus, perioral dyskinesias, myoclonus-like movements, and limb tremors.COVID-19-associated AE patients also exhibited other clinical symptoms, including uroclepsia, palilalia, autonomic instability, headache, vertigo, and non-specific blurry vision.
The mechanism of COVID-19-associated AE is extremely complex and not yet fully understood.One theory suggested that the occurrence of COVID-19-associated AE may be attributed to molecular mimicking between viral proteins and neuronal self-antigens (58).Additionally, it has been observed that severe COVID-19 patients exhibit higher levels of inflammatory cytokines compared to non-severe patients (33,59).In the case of anti-NMDAR encephalitis, elevated levels of interleukin-6 (IL-6) are commonly found during the inflammatory phase of the disease, which further stimulates the production of autoantibodies (32,33).Moreover, SARS-CoV-2 infection triggers an inflammatory response in the central nervous system, similar to other pathogens.This immune response involves the activation of neutrophils, monocytes, macrophages, dendritic cells, and natural killer (NK) cells, leading to the release of numerous inflammatory factors (60).
The diagnosis of AE is usually based on a combination of clinical presentation, imaging analysis, CSF analysis, and electroencephalogram (61).In AE patients, MRI scans can detect abnormalities in approximately 60% of cases, while 40% of scans show no significant changes.Among patients with positive MRI findings, most exhibit T2 and Flair high signal shadows on one or both sides of the medial temporal lobe (including the hippocampus and sulcus gyrus), insular lobe, and amygdala (62).These abnormalities may appear progressively but often disappear after immunotherapy.CSF analysis typically lacks specificity, with approximately 30% of results being normal (60, 61).A retrospective multicenter study suggested that 72% of patients did not fulfill AE diagnostic criteria, resulting in a high proportion of mistaken for AE (62).It is worth considering that during the initial phase of the pandemic, the high viral circulation and incidence in the general population may have led to mistakenly associating AEs with COVID-19, resulting in a misinterpretation.The reasons for misdiagnosis may be related to overinterpretation of positive serum antibodies and misinterpretation of functional/psychiatric or non-specific cognitive dysfunction such as encephalopathy (62).
Furthermore, little emphasis has been placed on distinguishing between delirium and seizures caused by metabolic derangements in this review.Metabolic encephalopathy (ME) arises from local or global brain edema, neurotransmitter transmission disorders, and the accumulation of metabolic toxins due to damage to the bloodbrain barrier, free radical damage, and apoptosis.It can manifest as coma, hemiplegia, epilepsy, and other symptoms (63).When considering ME, medical history, relevant laboratory tests, and imaging analysis need to be fully integrated.Also, when considering AE, physicians need to differentiate it from ME.
Regarding treatment strategies and outcomes, almost all patients received methylprednisolone, intravenous immunoglobulin, plasmapheresis, and oral prednisone therapy.In our study, we found that despite the potentially life-threatening risks of COVID-19associated AE, most patients completely or partially recovered, with a few having residual symptoms of neurological damage.
This study has certain limitations.First, this systematic review includes only case reports and case series.In addition, many poorquality reports have been published during the first stage of the health emergency, and the data are frequently partial or biased in consideration of the high circulation of the virus.Therefore, publication bias is inevitable.Second, we must admit that there are flaws in the inclusion criteria for case and case series reports.Among 42 COVID-19-associated AE patients, 39 (92.85%) cases were RT-PCR positive, and 3 (7.14%)cases were positive for SARS-CoV-2 serum antibody.This discrepancy might introduce bias since not all COVID-19-associated AE patients demonstrated positive RT-PCR either at the onset of AE symptoms or after SARS-CoV-2 infection.Third, most case reports and case series lack detailed descriptions of COVID-19 vaccination.This may lead to detection bias as some diagnoses rely on serum antibodies.Fourth, since the search was limited to articles published in English, some relevant articles in other languages were omitted.Finally, most studies did not have sufficient data, such as the time from onset to recovery and vaccination against COVID-19.

. Conclusion
This systematic review provides a comprehensive summary of the neurological manifestations, types, and outcomes in patients who developed AE as a complication of COVID-19.The main type of COVID-19-associated AE identified in this study is an unknown Ab type of COVID-19-associated AE.Although COVID-19-associated AE can present potentially life-threatening risks, the majority of patients survived, with some patients reporting residual neurological symptoms.

FIGURE
FIGUREFlowchart of the trial selection process for this systematic review.
TABLE Characteristics of included studies for autoimmune encephalitis as a neurological complication in COVID-patients.