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November 29, 2023 | by Sophie Liebergall and Ayan Mandal, 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

When a patient is admitted to the hospital with symptoms that suggest a diagnosis of autoimmune encephalitis (AE), doctors start ordering a dizzying array of lab tests and scans. Although AE is a disease of the brain, many of these tests, such as CT scans of the chest or ultrasounds of the pelvis, don’t seem to have much to do with the brain at all. The purpose of these scans is to search for a tumor that lies somewhere in the body. The reason why doctors conduct this search for a tumor is because some AE patients have a subtype of the disease, called paraneoplastic encephalitis, in which their disease is actually caused by a tumor outside of the brain. In this post we will shed some light on paraneoplastic encephalitis, why it occurs, and how its treatment compares to other types of AE.

What is paraneoplastic encephalitis?

As we explained in a previous post, paraneoplastic encephalitis is a type of AE caused by a tumor somewhere outside of the brain. The symptoms of paraneoplastic encephalitis, which could include seizures, memory loss, confusion, and dizziness, are often the first signs of an underlying cancer.1 For this reason, a patient who is suspected to have autoimmune encephalitis will often undergo scans of each organ in their body (colloquially called a “pan-scan”) to search for a possible cancer that may be responsible for the patient’s symptoms.

Some malignancies that are especially likely to trigger paraneoplastic encephalitis include cancers of the breast, ovaries, and lungs.2 But why would a tumor in one of these organs outside the brain cause the immune system to attack the brain? To understand why, we need to learn a bit about how the immune system responds to cancer.

How does the immune system respond to cancer?

Though it may be an unsettling thought, abnormal cells with the potential to become cancer are born in the body all the time. We tend not to be aware of this because most of the time the immune system successfully squashes these abnormal cells before they become a full-blown cancer. Many scientific experiments have proven how effectively the immune system monitors the body for these cancer cells. For example, when mice are genetically engineered to lack key immune cells, they become much more susceptible to developing tumors – implying that the removed immune cells were necessary to prevent tumor development.3 Because the immune system plays a crucial role in protecting the body from cancer, many cutting edge cancer treatments work by empowering the patient’s own immune system to kill their cancer cells.

The immune system prevents the growth of tumors by reacting to abnormal proteins that are a sign of cancer. Tumors tend to produce mutated proteins that are not found in the healthy body. Once an immune cell sniffs out one of these proteins it hasn’t seen before, it eats the protein and starts sending out alarm bells to other immune cells. These alarm signals tell one set of immune cells, called B cells, to start making antibodies that bind to this suspicious protein. Antibodies function like little flags that mark the cell with the mutated protein for destruction. Specifically, in the case of paraneoplastic AE, the initial alarm bells also activate another set of immune cells called cytotoxic T cells.4,5 The role of cytotoxic T cells is to expertly survey for cells that have been marked as harmful as potentially cancerous. Then, once they find these potentially dangerous cells, they release toxins that kill the cells (Figure 1).

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Figure 1. How the immune system responds to cancer. 1. A “first-line” immune cell chews up breast tumor cells, which contain proteins not normally found in breast cells. These proteins are represented as crabs. 2. The “first-line” immune cell realizes that it has eaten a cancer cell and so it sends signals that activate B and cytotoxic T cells. 3. Activated B cells produce antibodies which bind to the crab proteins. At the same time, activated cytotoxic T cells start to look for the cells that are tagged by the antibodies. 4. Antibodies bind to the crab protein in the breast tumor cells. Once the cytotoxic T cells find these tagged cells, they release toxins to kill the breast tumor cells. This figure was created using Biorender.com.

 

Why do some people get paraneoplastic encephalitis?

Sometimes, tumors produce suspicious proteins that look very similar to proteins also found in the brain. For example, some breast cancers can produce a protein that looks very similar to a protein inside of specific neurons in the cerebellum (a part of the brain important for balance and coordination).6 In this way, as the immune system prepares for battle against the breast cancer, sometimes the brain with it’s cancer look-alike cells can get caught in the crossfire. When an immune cell detects the breast cancer cells, it will chew up the proteins in those breast cancer cells, including the ones that look like cerebellum proteins. Because these cerebellum proteins were found inside a breast cancer cell, the immune cell thinks that they are harmful. Therefore, the immune cell will tell B cells to make antibodies targeting the cerebellum protein. At the same it will also tell cytotoxic T cells to kill all cells with the cerebellum protein. When these cytotoxic T cells try to find and kill more tumor cells, they may also try to kill healthy cells in the cerebellum that  make the protein.7

immune system paraneoplastic - What is the connection between cancer and autoimmune encephalitis?

Figure 2. How the immune system responds to cancer causes paraneoplastic AE. 1. A “first-line” immune cell chews up breast tumor cells, which contain proteins not normally found in breast cells. These proteins are represented as crabs. 2. The “first-line” immune cell realizes that it has eaten a cancer cell and so it sends signals that activate B and cytotoxic T cells. 3. Activated B cells produce antibodies which bind to the crab proteins. At the same time, activated cytotoxic T cells start to look for the cells that are tagged by the antibodies. 4. Because the crab protein is normally found in healthy cerebellum cells, antibodies bind to the crab protein in the cerebellum. Once the cytotoxic T cells find tagged cerebellum cells, they release toxins to kill the cerebellum cells.

What is the difference between paraneoplastic and non-paraneoplastic AE?

In the case of paraneoplastic encephalitis, the immune system is trying to do its job correctly by killing tumor cells, and the harm that it does to healthy neurons is collateral damage.7 This is different than cases of non-paraneoplastic encephalitis, where the problem lies within the immune system itself. In non-paraneoplastic AE, the immune system mistakenly decides that proteins that are normally found on the outside of neurons are actually harmful.7 (See this previous IAES post for a more detailed explanation of antibodies against proteins on the inside vs. the outside of cells.) In both paraneoplastic and non-paraneoplastic autoimmune encephalitis, the patient’s immune system tells B cells to make antibodies that target a neuronal protein. These antibodies then bind to the target protein in neurons and cause the patient to experience symptoms. However, cases of paraneoplastic encephalitis tend to involve more permanent damage to the neurons and more severe and long-lasting symptoms than cases of non-paraneoplastic autoimmune encephalitis. This is because the tumor also activates cytotoxic T cells in addition to B cells. These cytotoxic T cells are responsible for the increased damage and more severe symptoms in paraneoplastic AE.9

 

Paraneoplastic Encephalitis

Non-paraneoplastic Autoimmune Encephalitis

Target Protein

Usually intracellular proteins (e.g. Hu, Ma1/2, Ri), sometimes cell surface proteins

Cell surface proteins (e.g. NMDA receptor, GABABreceptor, Caspr2)

Age

Mostly older people

All ages

Tumor present

Yes

No

Immune system involvement

Cytotoxic T cells + antibodies

Antibodies

Response to treatment

Treatment less effective

Generally good response to treatment

Adapted from Rosenfeld et al. Neurol Clin Pract. 20128

How is paraneoplastic autoimmune encephalitis treated?

When treating paraneoplastic AE, doctors often use the same therapies that are used for non-paraneoplastic AE.10The majority of these treatments, such as plasma exchange, IVIg, and rituximab, are aimed at eliminating the antibodies that target the neuronal protein.10-12 (You can learn more about antibody-targeting treatments in this post.) For patients with non-paraneoplastic AE, once the antibodies are no longer bound to the neuronal proteins their symptoms often go away. But, unfortunately, in the case of paraneoplastic encephalitis, both antibody-producing B cells and cytotoxic T cells are activated.9 The cytotoxic T cells can unfortunately do more permanent damage to their neurons than the antibodies alone. Because of this, patients with paraneoplastic encephalitis tend to have poorer responses to treatment when compared to patients with non-paraneoplastic autoimmune encephalitis.13

When treating paraneoplastic encephalitis, it is very important to treat the underlying cause of the encephalitis: the cancer.13-14 When patients receive treatment for their cancer, either in the form of surgery to remove the cancer or chemotherapy drugs to shrink the cancer, they can sometimes see some improvement in their paraneoplastic encephalitis symptoms.13 When treating patients with paraneoplastic AE, doctors are often faced with a particular challenge: the immune system serves as both friend and foe. On one hand, the immune system is what is causing the patient’s paraneoplastic AE symptoms. While on the other hand, as discussed above, a strong immune system is important for keeping cancer at bay. As such, doctors often must carefully consider whether they want to give patients drugs that suppress the immune system, especially if the patient is actively undergoing treatment for their cancer.9

There are already a number of new therapies on the horizon for paraneoplastic AE that will hopefully improve the symptoms and long-term outcomes of this disorder. For example, understanding the role of cytotoxic T cells in paraneoplastic AE has led scientists to start to test treatments that directly target cytotoxic T cells.15 Conducting clinical trials in a relatively rare disorder like paraneoplastic AE can be especially challenging. But a growing awareness among physicians about paraneoplastic AE has led to an increased number of patients receiving a proper diagnosis for their neurologic symptoms. Clinical trials that enroll larger numbers of patients with paraneoplastic AE will hopefully hasten the development of more effective treatments.

References:

  1. Overview of paraneoplastic syndromes of the nervous system – UpToDate. https://www.uptodate.com/contents/overview-of-paraneoplastic-syndromes-of-the-nervous-system.
  2. Dalmau, J. & Rosenfeld, M. R. Paraneoplastic syndromes of the CNS. Lancet Neurol 7, 327–340 (2008).
  3. Shankaran, V. et al. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410, 1107–1111 (2001).
  4. Raskov, H., Orhan, A., Christensen, J. P. & Gögenur, I. Cytotoxic CD8+ T cells in cancer and cancer immunotherapy. Br J Cancer 124, 359–367 (2021).
  5. Cano, R. L. E. & Lopera, H. D. E. Introduction to T and B lymphocytes. in Autoimmunity: From Bench to Bedside [Internet] (El Rosario University Press, 2013).
  6. Paraneoplastic cerebellar degeneration – UpToDate. https://www.uptodate.com/contents/paraneoplastic-cerebellar-degeneration.
  7. Melzer, N., Meuth, S. G. & Wiendl, H. Paraneoplastic and non-paraneoplastic autoimmunity to neurons in the central nervous system. J Neurol 260, 1215–1233 (2013).
  8. Neumann, Harald, Isabelle M. Medana, Jan Bauer, and Hans Lassmann. “Cytotoxic T Lymphocytes in Autoimmune and Degenerative CNS Diseases.” Trends in Neurosciences 25, no. 6 (June 1, 2002): 313–19.https://doi.org/10.1016/S0166-2236(02)02154-9.
  9. Chaigne, Benjamin, and Luc Mouthon. “Mechanisms of Action of Intravenous Immunoglobulin.” Transfusion and Apheresis Science 56, no. 1 (February 1, 2017): 45–49. https://doi.org/10.1016/j.transci.2016.12.017.
  10. Lehmann, Helmar C., Hans-Peter Hartung, Gerd R. Hetzel, Olaf Stüve, and Bernd C. Kieseier. “Plasma Exchange in Neuroimmunological Disorders: Part 1: Rationale and Treatment of Inflammatory Central Nervous System Disorders.” Archives of Neurology 63, no. 7 (July 1, 2006): 930–35.https://doi.org/10.1001/archneur.63.7.930.
  11. Taylor, Ronald P., and Margaret A. Lindorfer. “Drug Insight: The Mechanism of Action of Rituximab in Autoimmune Disease—the Immune Complex Decoy Hypothesis.” Nature Clinical Practice Rheumatology 3, no. 2 (February 2007): 86–95. https://doi.org/10.1038/ncprheum0424.
  12. Dalmau, Josep, and Myrna R. Rosenfeld. “Update on Paraneoplastic Neurologic Disorders.” Community Oncology 7, no. 5 (May 1, 2010): 219–24.
  13. Gultekin, S. H. et al. Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients. Brain 123 ( Pt 7), 1481–1494 (2000).
  14. Bastiaansen, Anna E M, Adriaan H C de Jongste, Marienke A A M de Bruijn, Yvette S Crijnen, Marco W J Schreurs, Marcel M Verbeek, Daphne W Dumoulin, Walter Taal, Maarten J Titulaer, and Peter A E Sillevis Smitt. “Phase II Trial of Natalizumab for the Treatment of Anti-Hu Associated Paraneoplastic Neurological Syndromes.” Neuro-Oncology Advances 3, no. 1 (January 1, 2021): vdab145.https://doi.org/10.1093/noajnl/vdab145.

Figures 1 and 2 were created using Biorender.com.

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