October 15, 2023 | by Catrina Hacker, 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/

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Introduction

The causes and risk factors for autoimmune encephalitis (AE) are as varied as its many symptoms and subtypes. Determining the cause of a case of AE is challenging because there are often several factors to consider. In most cases, doctors do not know the cause of AE, but in an increasing number of cases they do. Continued research toward understanding the causes of AE is important, because they can help doctors determine which patients are at risk and help researchers in their quest to develop better treatments. This post will discuss a few known causes and risk factors for AE with a special focus on the link between viral infections and AE.

What are the known causes and risk factors for AE?

When considering what may lead to a case of AE, it’s important to distinguish between causes and risk factors. Doctors consider something a cause of AE when they know that a particular change or process is responsible for triggering AE. Other factors that may put someone at higher risk of developing AE but don’t actually cause AE are considered risk factors¹. For example, infection with SARS-COV-2 is the cause of COVID-19 while spending time indoors with someone who has COVID is a risk factor. You’re much more likely to develop COVID-19 if you expose yourself to people who are infectious, but the ultimate cause of your illness would be infection with SARS-COV-2.

When it comes to AE, one of the clearest known causes is a tumor, which applies to a subset of AE called paraneoplastic AE². Patients with paraneoplastic AE have tumors in various parts of their body that abnormally produce components of brain cells. When the body’s immune system produces cells to attack the tumor, it sometimes creates cells that target these components. If those immune cells get to the brain, they can attack the brain’s own cells too^2,3.

Most of what we know about what leads to AE involves risk factors. For example, genetic risk factors have been shown to have a clear link to some types of limbic encephalitis. Specifically, a certain genetic mutation is found in 90% of patients with anti-LGI1 encephalitis, the most common form of limbic encephalitis that is not caused by a tumor^4,5. Genetic testing is not common for patients with AE because the results will not change how doctors treat the AE, and because many people will have this mutation but not develop AE. However, pinpointing genetic mutations can be important for researchers because it gives them a clear target for their research if they want to understand why some people develop AE while others do not. By understanding what effects the mutation has on regular bodily functions, they can understand why the mutation makes the patient more likely to have AE. They can then use this information to create treatments that counteract the effects of the mutation.

It is even trickier to understand the various environmental factors that can put someone at higher risk of developing AE. Like all risk factors, not everyone who is exposed will develop AE. Environmental risk factors are especially difficult to pinpoint for several reasons, including because the many possible risk factors make it difficult to narrow down the possibilities, doctors often rely on patients being able to report what they have been exposed to which isn’t always possible, and sometimes multiple environmental factors have to combine to have an effect. However, by sharing suspected risk factors and communicating with other doctors and scientists, sometimes doctors can identify new risk factors that help them make future diagnoses. One case in which this has been especially successful is in establishing a link between viral infection and AE.

What is the relationship between herpes simplex virus infection and AE?

One of the best understood links between viral infection and AE is the relationship between herpes simplex virus and anti-NMDAR AE^6,7. When herpes simplex virus infects the brain it causes a condition called herpes simplex encephalitis (HSE), in which the brain swells, just as it does in AE. Because they both cause brain swelling, AE and HSE have many similar symptoms, including seizures, headaches, and behavioral changes^8,9. Many people carry the virus that typically causes HSE (over 60% of people under the age of 50), but it very rarely leads to HSE¹⁰. When not properly treated, HSE has a high mortality rate, but with early detection it can be effectively treated with antivirals⁸.

For a while, doctors noticed that some patients with HSE had recurring or relapsing symptoms following treatment with antivirals. When they investigated further, they found that some of these patients had anti-NMDAR antibodies, indicating that their recurring symptoms were a result of anti-NMDAR AE^6,7. In several cases they were also able to show that patients did not have anti-NMDAR antibodies until well after developing HSE, suggesting that HSE is what triggered the production of anti-NMDAR antibodies^6,11. Now, doctors know that patients experiencing relapsing symptoms after HSE should be screened for anti-NMDAR AE so they can be treated with AE treatments instead of antivirals⁷.

But, as to be expected in the case of AE, the story gets a bit more complicated. Patients that previously had HSE who have relapsing symptoms don’t just have anti-NMDAR antibodies. They also have antibodies against several other components of healthy neurons⁷. It’s still not clear if only the anti-NMDAR antibodies are responsible for the relapsing symptoms, or if these cases are different from other cases of anti-NMDAR AE because patients have a diverse set of antibodies. For example, cases where patients with HSE were later diagnosed with anti-NMDAR AE show more widespread damage to their neurons than patients with cases of anti-NMDAR AE that were not attributed to HSE⁶. Some doctors think that HSE may be a more widespread trigger of autoimmunity against neurons beyond just the targets of anti-NMDAR antibodies⁷. Luckily, in a few documented cases, the treatments traditionally used for anti-NMDAR AE appear to work in treating HSE-induced anti-NMDAR AE as well^7,11.

Is there a relationship between other viral infections and AE?

There are several other possible connections between viral infection and AE, although none are as clearly observed or widely accepted as the link between herpes simplex virus and anti-NDMAR AE. In some very rare cases, AE cases follow COVID-19 infection¹². Other viruses that have been detected in patients with AE are varicella, Epstein-Barr, human herpes virus type 6, adenovirus, HIV, and hepatitis C⁷.

It’s important to note that in all these cases it is still unclear if a viral infection caused AE. All we can say is that these viruses were present in patients with AE. The reason we can be more certain of the connection between HSE and AE is because several studies have reported HSE that precedes detection of anti-NMDAR antibodies¹¹. More studies on the viruses listed above could eventually prove a similarly strong link between any of these viruses and AE if one exists.

AE isn’t the only autoimmune brain disorder that can be triggered by viruses. Perhaps the best example is Pediatric Acute-onset Neuropsychiatric Syndrome, or PANS. Patients with PANS are children who develop autoimmunity after infection with a virus. Strep throat, caused by infection with the streptococcus virus, is one common cause of PANS¹³. While the symptoms of PANS and AE are similar, there are some important differences that distinguish the two conditions. Another example is the possible link between infection with the Epstein-Barr virus and the development of multiple sclerosis, another autoimmune disorder of the nervous system¹⁴. Though still controversial, some research even suggests that Alzheimer’s Disease may be triggered by a viral infection¹⁵.

Concluding Thoughts

AE is very rarely the result of a viral infection, and only certain kinds of viral infections have been linked to AE. That being said, understanding the cases where viral infection puts someone at risk for AE, as with herpes simplex encephalitis, is important, because it can help doctors make a faster diagnosis of this otherwise difficult to diagnose disease. As scientists continue to find compelling links between viral infection and brain disorders, research that improves our understanding of how this process works has the potential to improve our understanding and treatment of these challenging brain disorders.

References

1. Shader, R. I. Risk Factors Versus Causes. J. Clin. Psychopharmacol. 39, 293–294 (2019).
2. Graus, F. & Dalmau, J. Paraneoplastic neurological syndromes in the era of immune-checkpoint inhibitors. Nat. Rev. Clin. Oncol. 16, 535–548 (2019).
3. Rees, J. H. Paraneoplastic syndromes: when to suspect, how to confirm, and how to manage. J. Neurol. Neurosurg. Psychiatry 75, ii43–ii50 (2004).
4. LGI1-antibody encephalitis. Autoimmune Encephalitis Alliance https://aealliance.org/ae-types/lgi1-antibody-encephalitis/.
5. Vogrig, A., Muñiz-Castrillo, S., Desestret, V., Joubert, B. & Honnorat, J. Pathophysiology of paraneoplastic and autoimmune encephalitis: genes, infections, and checkpoint inhibitors. Ther. Adv. Neurol. Disord. 13, 175628642093279 (2020).
6. Venkatesan, A. & Benavides, D. R. Autoimmune Encephalitis and Its Relation to Infection. Curr. Neurol. Neurosci. Rep. 15, 3 (2015).
7. Prüss, H. Postviral autoimmune encephalitis: manifestations in children and adults. Curr. Opin. Neurol.30, 327–333 (2017).
8. Gnann, J. W. & Whitley, R. J. Herpes Simplex Encephalitis: an Update. Curr. Infect. Dis. Rep. 19, 13 (2017).
9. Autoimmune Encephalitis Symptoms | AE Alliance. Autoimmune Encephalitis Alliancehttps://aealliance.org/patient-support/symptoms/.
10. Marcocci, M. E. et al. Herpes Simplex Virus-1 in the Brain: The Dark Side of a Sneaky Infection. Trends Microbiol. 28, 808–820 (2020).
11. Leypoldt, F. & Titulaer, M. J. Herpes Simplex Virus-1 Encephalitis Can Trigger Anti-NMDA Receptor Encephalitis: Case Report. Neurology 81, 1637–1639 (2013).
12. Stoian, A. et al. Autoimmune Encephalitis in COVID-19 Infection: Our Experience and Systematic Review of the Literature. Biomedicines 10, 774 (2022).
13. Gagliano, A., Carta, A., Tanca, M. G. & Sotgiu, S. Pediatric Acute-Onset Neuropsychiatric Syndrome: Current Perspectives. Neuropsychiatr. Dis. Treat. Volume 19, 1221–1250 (2023).
14. Bar-Or, A. et al. Epstein–Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies. Trends Mol. Med. 26, 296–310 (2020).
15. Wainberg, M. et al. The viral hypothesis: how herpesviruses may contribute to Alzheimer’s disease. Mol. Psychiatry 26, 5476–5480 (2021).

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