# Impact of the COVID‐19 Outbreak on the Incidence of Autoimmune Encephalitis and Paraneoplastic Neurological Syndromes Associated Antibodies in Singapore

## TL;DR

This study found a spike in autoimmune encephalitis antibodies during Singapore's early COVID-19 pandemic, suggesting a possible link between the virus and autoimmune reactions.

## Contribution

The study provides population-level evidence of a potential biological link between the early stages of the COVID-19 pandemic and increased autoimmune encephalitis antibody incidence.

## Key findings

- AE-associated antibody incidence spiked in 2020 during the pandemic outbreak.
- The incidence of PNS-associated antibodies remained stable throughout the pandemic.
- Widespread vaccination and new viral variants may explain the decline in AE antibodies after 2020.

## Abstract

Emerging evidence suggests a potential association between COVID‐19 and autoimmune encephalitis (AE). We aimed to evaluate the positivity rate of AE‐ and paraneoplastic neurological syndromes (PNS)‐associated antibodies in relation to COVID‐19.

We investigated the frequency and incidence of AE‐ and PNS‐associated antibodies amongst clinical tests performed at the National Neuroscience Institute, Singapore, before and during the COVID‐19 pandemic. Antibodies against surface‐exposed antigens associated with AE were tested using cell‐based assays; antibodies against intracellular antigens in PNS were detected by immunoblot and tissue‐based assays.

A total of 87 of 4347 samples and 29 of 3393 samples tested for AE‐ and PNS‐associated antibodies, respectively, were positive. A spike in the incidence of AE‐associated antibodies was observed in 2020 at 4.92 (95% CI, 3.05–7.53) per 1,000,000 person‐years, coinciding with the first year of the COVID‐19 “pandemic outbreak.” The cumulative incidence in the “pre‐pandemic” period from 2017 to 2019 was 2.44 (95% CI, 1.66–3.46) per 1,000,000 person‐years (p = 0.034, vs. “pandemic outbreak”), and in the “mid to late pandemic” period from 2021 to 2023, this was 2.74 (95% CI, 1.91–3.82) per 1,000,000 person‐years (p = 0.086, vs. “pandemic outbreak”). The incidence of PNS‐associated antibodies was unaffected by the COVID‐19 pandemic.

The increased incidence of AE‐associated antibodies during the COVID‐19 “pandemic outbreak” suggests a potential biological link. The subsequent decline in incidence in the “mid to late pandemic” period may be attributable to widespread vaccination and the emergence of new viral variants with less potential to induce autoimmunity. The incidence of PNS‐associated antibodies was stable throughout, reinforcing its primary association with malignancy.

Emerging evidence suggests a potential association between COVID‐19 and autoimmune encephalitis (AE). We evaluated the positivity rate of AE‐ and paraneoplastic neurological syndromes (PNS)‐associated antibodies in relation to COVID‐19. A spike in the incidence of AE‐associated antibodies was observed during the COVID‐19 “pandemic outbreak” in 2020, compared to the “pre‐pandemic” period from 2017 to 2019 and to the “mid to late pandemic” period from 2021 to 2023. The incidence of PNS‐associated antibodies was unaffected by COVID‐19. The increased incidence of AE‐associated antibodies during the COVID‐19 “pandemic outbreak” suggests a potential biological link. The subsequent decline in incidence in the “mid to late pandemic” period may be attributable to widespread vaccination and the emergence of new viral variants with less potential to induce autoimmunity.