August 23, 2023 | by Kara McGaughey, PennNeuroKnow and IAES Collaboration

A message from IAES Blog Staff:

The staff at IAES is proud to present to all of you another wonderful article/blog from the amazing team at PennNeuroKnow. Since 2019 IAES has been extremely lucky to be in partnership with the PennNeuroKnow(PNK) team to help us all better understand complex medical issues related to AE and neurology in general. The talented PNK team continues to keep us up-to-date and help clarify the complexities we face each day along our AE journey, and we are eternally grateful! You can find out much more about this stellar group at: https://pennneuroknow.com/

——-

Introduction

The Covid 19 pandemic spread its insidious tentacles all over the world. Scientific papers, chapters of books and entire university courses can be counted on to outline and delve deep into the wide spread effects on all levels of society that Covid has caused. For the AE community we are not only affected by the general Covid effects but possibly, also, in relation to our own ongoing AE journeys. How does the Covid virus affect AE? Is there a link between Covid 19 and AE? Kara McGaughey from the PNK team has done a wonderful job helping us all better understand what can be understood about this possible relationship at this time and what it may mean for the future of AE research.

Coronavirus Disease (COVID-19) is an ongoing global health crisis with more than 760 million confirmed cases and nearly 7 million deaths reported by the World Health Organization as of June 2023.¹ However, as we enter into the fourth year of the pandemic, we’re beginning to understand that knowing the number of active cases of COVID-19 isn’t the whole story.

In this post, we will dive into the long-term consequences of COVID-19, with a focus on the potential link between COVID-19 and autoimmune encephalitis (AE). We will explore why scientists think these diseases might be connected as well as what implications these new, post-COVID cases can have for AE research.

What is the connection between COVID-19 and AE?

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a newly-emerged virus that causes Coronavirus Disease 2019 (COVID-19). SARS-CoV-2 infection results in various systemic and respiratory symptoms such as fever, fatigue, cough, and difficulty breathing. In cases of severe disease, these symptoms can cause heart and lung failure, requiring hospitalization. However, the struggle isn’t always over once infection has subsided. Around 15% of patients have persistent symptoms for months after testing positive.^2-3 These symptoms, often including fatigue and brain fog, can be debilitating. In many cases, a patient’s ability to carry out normal, everyday activities is profoundly affected. In a much, much smaller percentage of cases, the SARS-CoV-2 virus can also function as a trigger for some autoimmune diseases, like Guillain-Barré Syndrome (GBS), rheumatoid arthritis, and even autoimmune encephalitis (AE).^4-5

AE refers to a group of conditions that occur when the body’s immune system mistakenly attacks healthy brain tissue.⁵ The cause of AE is often unknown. However, experts say that, in some cases, exposure to certain bacteria or viruses may increase someone’s risk of AE. For example, infection with herpes simplex virus 1 (HSV-1) has been linked to later development of AE, particularly the anti-NMDA AE subtype.⁷

We are seeing something similar happening now with SARS-CoV-2 viral infections (and re-infections) leading to an uptick in the number of AE diagnoses. Case reports of this so-called “post-COVID AE” have come from all over the world — Iran, Canada, France, Italy, the United Kingdom, China, Sweden, India, Mexico, and the United States — and describe patients across a wide range of ages from 2 to 88.^4,8-9  A majority of these post-COVID AE diagnoses are for either limbic or anti-NMDA AE subtypes with patients experiencing headache, cognitive impairment, and seizures.⁴ Fortunately, a majority of patients respond well to treatment.⁴

How can SARS-CoV-2 infection lead to AE?

How exactly AE develops from SARS-CoV-2 infections is not yet fully understood. However, scientists do have some theories.

The “cytokine storm” and inflammatory cytokines:

Cytokines are small proteins that are crucial for controlling the immune system’s activity.¹⁰ Inflammatory cytokinesact as signals that tell the immune system to turn on, enabling the body to recognize and destroy foreign invaders (like the SARS-CoV-2 virus). Anti-inflammatory cytokines are responsible for dialing immune system activity back down once the threat has been neutralized. During the pandemic, you may have heard about COVID-19 causing the overproduction of inflammatory cytokines, known as a “cytokine storm.” With too many of these cytokines released in the body, immune system activity and inflammation can spiral out of control, leading to, in the worst cases, multi-organ failure.^4-6,11

Scientists think that one link between COVID-19 and AE is a particular inflammatory cytokine, IL-6, released during this storm.^5,12 Elevated levels of IL-6 are often found in patients with anti-NMDA AE.^11,13-14 In fact, they are considered a characteristic feature of this AE subtype.¹³ Given that many post-COVID AE cases are anti-NMDA, it is possible that high levels of IL-6 as a result of SARS-CoV-2 viral infection could be one reason for the increased risk of developing AE after COVID-19.

Accidental autoimmunity:

While we want an immune system that can recognize and react to foreign invaders (e.g., SARS-CoV-2, tumor cells, etc.), it is just as important that our own cells don’t get caught up in the crossfire. Fortunately, our immune system has evolved to both quickly and accurately distinguish outsiders from the body itself. However, sometimes in the face of viral infections that cause extreme inflammation, this protective, self-recognition feature goes awry and the body begins to produce antibodies that accidentally target its own tissue (“autoantibodies”). This autoantibody-induced self destruction is called autoimmunity.⁴ It is possible that SARS-CoV-2 viral infections induce AE through an autoimmune process that generates antibodies targeting brain cells.

What implications might this have for AE research?

AE is notoriously rare and frequently misdiagnosed.¹⁵ Evidence for a link between SARS-CoV-2 infections and the development of AE means more of the scientific spotlight is being given to AE. This increased awareness could make physicians more likely to explore AE as a possible diagnosis, decreasing the time patients spend in limbo waiting for answers and treatment. Perhaps more importantly, in scientific research, money and resources flow where attention goes. This could mean more funding for AE research and more AE clinical trials. Hopefully, this will lead to a better understanding not only of the relationship between COVID-19 and AE, but AE and autoimmunity more broadly.

A final note: It’s important to remember that getting infected or re-infected with COVID-19 doesn’t mean you will end up with AE. While there have been a fair number of case reports of post-COVID AE, it is still a rare outcome. Moreover, it is very difficult to establish any sort of causal link between SARS-CoV-2 infection and the later development of a disease. In most cases it is impossible to know whether some of these patients would have developed AE even without exposure to COVID-19. Nonetheless, the best path forward is to be aware of ongoing research and continue preventive measures, like wearing a mask in high-risk situations and making sure you stay up to date on COVID-19 vaccinations.

Work cited:

1. WHO Coronavirus (COVID-19) Dashboard. (n.d.). Retrieved May 1, 2023, from https://covid19.who.int
2. Nearly One in Five American Adults Who Have Had COVID-19 Still Have “Long COVID.” (2022, June 22).https://www.cdc.gov/nchs/pressroom/nchs_press_releases/2022/20220622.htm
3. Lledó, G. M., Sellares, J., Brotons, C., Sans, M., Antón, J. D., Blanco, J., Bassat, Q., Sarukhan, A., Miró, J. M., & de Sanjosé, S. (2022). Post-acute COVID-19 syndrome: A new tsunami requiring a universal case definition. Clinical Microbiology and Infection, 28(3), 315–318. https://doi.org/10.1016/j.cmi.2021.11.015
4. Stoian, A., Stoian, M., Bajko, Z., Maier, S., Andone, S., Cioflinc, R. A., Motataianu, A., Barcutean, L., & Balasa, R. (2022). Autoimmune Encephalitis in COVID-19 Infection: Our Experience and Systematic Review of the Literature. Biomedicines, 10(4), 774. https://doi.org/10.3390/biomedicines10040774
5. Nabizadeh, F., Balabandian, M., Sodeifian, F., Rezaei, N., Rostami, M. R., & Naser Moghadasi, A. (2022). Autoimmune encephalitis associated with COVID-19: A systematic review. Multiple Sclerosis and Related Disorders, 62, 103795.https://doi.org/10.1016/j.msard.2022.103795
6. Payus, A. O., Jeffree, M. S., Ohn, M. H., Tan, H. J., Ibrahim, A., Chia, Y. K., & Raymond, A. A. (2022). Immune-mediated neurological syndrome in SARS-CoV-2 infection: A review of literature on autoimmune encephalitis in COVID-19. Neurological Sciences, 43(3), 1533–1547. https://doi.org/10.1007/s10072-021-05785-z
7. Armangue, T., Spatola, M., Vlagea, A., Mattozzi, S., Cárceles-Cordon, M., Martinez-Heras, E., Llufriu, S., Muchart, J., Erro, M. E., Abraira, L., Moris, G., Monros-Giménez, L., Corral-Corral, Í., Montejo, C., Toledo, M., Bataller, L., Secondi, G., Ariño, H., Martínez-Hernández, E., … Zabalza, A. (2018). Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: A prospective observational study and retrospective analysis. The Lancet Neurology, 17(9), 760–772. https://doi.org/10.1016/S1474-4422(18)30244-8
8. Saffari, P., Aliakbar, R., Haritounian, A., Mughnetsyan, R., Do, C., Jacobs, J., Hoffer, J., Arieli, R., Liu, A. K., Saffari, P., Aliakbar, R., Haritounian, A., Mughnetsyan, R., Do, C., Jacobs, J., Hoffer, J., Arieli, R., & Liu, A. K. (2023). A Sharp Rise in Autoimmune Encephalitis in the COVID-19 Era: A Case Series. Cureus, 15(2). https://doi.org/10.7759/cureus.34658
9. Mekheal, E., Mekheal, M., Roman, S., Mikhael, D., Mekheal, N., Manickam, R., Mekheal, E., Mekheal, M., Roman, S., Mikhael, D., Mekheal, N., & Manickam, R. (2022). A Case Report of Autoimmune Encephalitis: Could Post-COVID-19 Autoimmunity Become a Lethal Health Issue? Cureus, 14(6). https://doi.org/10.7759/cureus.25910
10. Kim, E. Y., & Moudgil, K. D. (2008). Regulation of autoimmune inflammation by pro-inflammatory cytokines. Immunology Letters, 120(1), 1–5. https://doi.org/10.1016/j.imlet.2008.07.008
11. Byun, J.-I., Lee, S.-T., Moon, J., Jung, K.-H., Sunwoo, J.-S., Lim, J.-A., Kim, T.-J., Shin, Y.-W., Lee, K.-J., Jun, J.-S., Lee, H. S., Lee, W.-J., Kim, Y.-S., Kim, S., Jeon, D., Park, K.-I., Jung, K.-Y., Kim, M., Chu, K., & Lee, S. K. (2016). Distinct intrathecal interleukin-17/interleukin-6 activation in anti-N-methyl-d-aspartate receptor encephalitis. Journal of Neuroimmunology, 297, 141–147. https://doi.org/10.1016/j.jneuroim.2016.05.023
12. Liu, J., Li, S., Liu, J., Liang, B., Wang, X., Wang, H., Li, W., Tong, Q., Yi, J., Zhao, L., Xiong, L., Guo, C., Tian, J., Luo, J., Yao, J., Pang, R., Shen, H., Peng, C., Liu, T., … Zheng, X. (2020). Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients. EBioMedicine, 55, 102763.https://doi.org/10.1016/j.ebiom.2020.102763
13. Liu, J., Liu, L., Kang, W., Peng, G., Yu, D., Ma, Q., Li, Y., Zhao, Y., Li, L., Dai, F., & Wang, J. (2020). Cytokines/Chemokines: Potential Biomarkers for Non-paraneoplastic Anti-N-Methyl-D-Aspartate Receptor Encephalitis. Frontiers in Neurology, 11.https://www.frontiersin.org/articles/10.3389/fneur.2020.582296
14. Byun, J.-I., Lee, S.-T., Moon, J., Jung, K.-H., Sunwoo, J.-S., Lim, J.-A., Kim, T.-J., Shin, Y.-W., Lee, K.-J., Jun, J.-S., Lee, H. S., Lee, W.-J., Kim, Y.-S., Kim, S., Jeon, D., Park, K.-I., Jung, K.-Y., Kim, M., Chu, K., & Lee, S. K. (2016). Distinct intrathecal interleukin-17/interleukin-6 activation in anti-N-methyl-d-aspartate receptor encephalitis. Journal of Neuroimmunology, 297, 141–147. https://doi.org/10.1016/j.jneuroim.2016.05.023
15. Lancaster, E. (2016). The Diagnosis and Treatment of Autoimmune Encephalitis. Journal of Clinical Neurology (Seoul, Korea), 12(1), 1–13. https://doi.org/10.3988/jcn.2016.12.1.1

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