Potential association between SARS-CoV-2 infection and secondary outbreak of anti-NMDAR encephalitis

Coronavirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has caused unprecedented scale of damage and distress worldwide. Respiratory pathology associated with COVID-19 is well established. However, there are reports of extrapulmonary symptoms of the disease, including thrombotic complications, myocardial dysfunction, acute kidney injury, gastrointestinal symptoms, and neurological abnormalities.

study: Molecular mimicry of NMDA receptors may contribute to neuropsychiatric symptoms in severe COVID-19 cases.. Image Credit: Kateryna Kon / Shutterstock.com

Background

Early studies have identified neurological and psychiatric abnormalities in patients with COVID-19. Previous reports have identified molecular mimicry as a potential mechanism for the development of neuropsychiatric symptoms in patients with COVID-19.

NS NSThe -methyl-d-aspartate receptor (NMDAR) GluN1 and GluN2a subunits are structurally similar to SARS-CoV-2 nonstructural proteins 8 (NSP8) and 9 (NSP9), respectively. This can lead to molecular mimicry, with immunoglobulin G (IgG) antibodies induced against the SARS-CoV-2 proteins NSP8 and NSP9 cross-reacting with the host NMDAR and disrupting these receptors. And can cause subsequent neurological abnormalities observed with COVID-. 19 patients.

Anti-NMDAR encephalitis is a commonly occurring autoimmune encephalitis that has been reported with viral infections such as herpes simplex type 1 and varicella-zoster. The neurological symptoms of COVID-19 may be due to a secondary outbreak of anti-NMDAR encephalitis.In a recently published study Journal of Neuroinflammation, Scientists explore the link between SARS-CoV-2 infection and anti-NMDAR encephalitis.

Main survey results

Scientists in this study conducted a systematic review of the literature in PubMed and Google Scholar databases. The search terms they used include “NMDA encephalitis,” “NMDAR encephalitis,” and “.NMDA receptor “Encephalitis” and “SARS-CoV-2” or “COVID-19”. They identified eight case reports of COVID-19 patients between the ages of 23 months and 53 years who developed anti-NMDAR encephalitis.

Of the eight patients identified, four were female and four were male.Patient developed anti-NMDAR encephalitis 3 days to 3 weeks after onset COVID19 Symptoms.. In particular, four patients developed encephalitis within a week.

All eight patients tested positive for antibodies to the NMDAR GluN1 subunit in cerebrospinal fluid (CSF).

From the confirmed case reports, 4 patients showed symptoms of severe dyspnea. All eight patients exhibited neuropsychiatric symptoms such as impaired consciousness, delirium, and psychiatric illness, while six patients had epileptic seizures. Movement disorders or articulation disorders were observed in 5 patients.

Interleukin-6 (IL-6) levels, an inflammatory marker, were found to be elevated in two patients. IL-6 levels were increased in both blood and cerebrospinal fluid (CSF) in one patient, and in only one CSF.

Elevated C-reactive protein (CRP) levels were observed in blood samples from two patients. Decreased lymphocyte levels were observed in blood samples from 3 patients. Interestingly, elevated lymphocyte levels were observed in the CSF of 6 patients, including those who showed decreased lymphocyte levels in blood samples. In addition, the CSF of the two patients was positive for SARS-CoV-2.

In particular, one patient had an associated condition of ovarian teratoma, a factor in anti-NMDAR encephalitis.

Electroencephalogram (EEG) records of four patients show slow-wave activity, thereby implying brain abnormalities. One of these patients showed an extreme delta brush-like pattern showing anti-NMDA receptor encephalitis. Case reports of 5 patients showed images of normal brain.

Fluid attenuation reversal recovery (FLAIR) images of one patient showed hyperintensity in the left amygdala and left anterior putamen, with mild effects on the right amygdala. The patient was initially negative for SARS-CoV-2, but was later tested positive, suggesting a possible nosocomial infection.

Patients were treated according to standard guidelines and all patients received steroid therapy with intravenous IgG. Two of the patients also underwent plasma exchange. Case reports of all eight patients showed that they improved after treatment.

Possible pathophysiology of SARS-CoV-2-induced anti-NMDAR encephalitis. Viral particles such as NSP8 and NSP9 are released during acute COVID-19 infection.The released protein is recognized by T cells, Becomes plasma cells and leads to activation of B cells that produce IgM and subsequent IgG antibodies against NSP8 and NSP9. IL-17 produced by I SARS-CoV-2-related endothelitis and activated T cells disrupts the blood-brain barrier and allows NMDAR antibodies to invade the CNS. IL-6 alters glial cell activity and initiates neutrophil granulocyte migration, further causing blood-brain barrier disruption and inflammation. By molecular mimicry II, antibodies produced by plasma cells of CNS can cross-react with the NMDAR subunit GluN1, causing receptor internal translocation and subsequent degradation.

how Does anti-NMDAR encephalitis develop with SARS-CoV-2 infection?

Anti-NMDAR encephalitis, caused by IgG antibodies that act on the GluN1 subunit of NMDAR, is a commonly occurring form of autoimmune encephalitis.

When infected with SARS-CoV-2, viral particles such as NSP8 and NSP9 are released. When recognized by T cells, these proteins result in B cell activation and transformation into plasma cells. This results in the production of IgM and IgG antibodies by these plasma cells, which act on NSP8 and NSP9.

The blood-brain barrier (BBB) ​​is COVID-due to several factors, including IL-17 produced by activated T cells, SARS-CoV-2-related dermatitis, which is an inflammation of blood vessels, and neutrophil granulocytes. It can be destroyed in 19 patients. Migration caused by changes in glial activity mediated by IL-6. BBB damage allows these antibodies to enter the central nervous system (CNS) and cross-react with the NMDAR subunit GluN1. It causes internalization and degradation of NMDARs, which can interfere with excitatory glutamatergic transmission and cause anti-NMDAR encephalitis.

Further investigation is needed to reach conclusive evidence of the mechanism by which SARS-CoV-2 infection causes a secondary outbreak of anti-NMDAR encephalitis.

Limitations

Scientists have identified only eight case reports of patients with SARS-CoV-2 associated autoimmune anti-NMDAR encephalitis. This is a small number that limits the possibility of definitive evidence. In one of the symptoms of patients with anti-NMDAR encephalitis, the symptoms preceded a positive SARS-CoV-2 test, while another patient had an existing ovarian teratoma that was also a factor in anti-NMDAR encephalitis.

Case reports of these two patients do not establish a clear association between SARS-CoV-2 infection and subsequent development of anti-NMDAR encephalitis. Further investigation is needed to confirm the role of SARS-CoV-2 in the development of anti-NMDAR encephalitis in COVID-19 patients.

Conclusion

The secondary outbreak of anti-NMDAR encephalitis with neuropsychiatric symptoms following COVID-19 was demonstrated for the first time in this systematic review. Although the studies in this review are preliminary, these findings highlight the importance of considering the presence of neurological abnormalities when treating patients with COVID-19.

The findings presented here indicate that COVID-19 patients need to be monitored for neurological symptoms of autoimmune encephalitis such as seizures, psychiatric symptoms, headache, dizziness, dyskinesia, memory changes, and catatonia. Suggests. Screening for neurological abnormalities in COVID-19 patients using brain imaging, EEG records, along with cell-based assays to detect the presence of anti-neuronal antibodies using serological and CSF tests. Is also important. Early immunotherapy for patients with COVID-19 diagnosed with autoimmune encephalitis may be an effective treatment strategy based on the observations from this review.