Why does it feel like we know so little about autoimmune encephalitis?
February 22, 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/
As we wind up AE Awareness month 2023, I, for one, am grateful. Grateful for another year of stellar webinars and more information. For all the AE Warriors and our caregivers, we have a very optimistic future. As you have heard before, our road to recovery is no sprint, but it is a marathon we can and will complete. We receive questions all the time regarding the speed at which research proceeds and treatments are approved. And this is tough because although we know this is a marathon, we all truly want things to proceed much quicker. Catrina Hacker, a member of the amazing PNK team has done a wonderful job explaining the process. So, as I have heard said to me what seems like a million times, “trust the process” and we hope you enjoy this blog!
~Fellow Warrior and Editor-in-Chief, Jeri Gore
When you or someone you love is diagnosed with a disease like autoimmune encephalitis, the seemingly slow pace at which research progresses can feel frustrating. It’s hard to watch loved ones suffer while wondering why someone hasn’t used their knowledge and resources to find a solution that will make them feel better. In this post I will walk you through why the pace of research on diseases like autoimmune encephalitis can seem slow and what this means for scientific progress toward understanding autoimmune encephalitis.
The human body still has a lot of uncharted territory for biologists
One of the key reasons that biomedical research seems to progress slowly is that there is so much that we still don’t know. Our quest to understand the human body is much like the quest that European explorers once took to uncover the world beyond Western European countries: sometimes clumsy and a centuries-long process. Christopher Columbus’s crew famously stumbled upon North America on their way to India, and some of the earliest world maps were comically inaccurate by today’s standards (Figure 1 left). But over time the explorers made more observations and built new tools that ultimately led to the incredibly accurate and useful world maps that we have today (Figure 1 right).
Figure 1. Left: A world map generated in 1583. A lot of the general organization of the world has been figured out, but we now know that the proportions and specific shapes of individual continents aren’t correct. Right: A modern world map that shows how much our understanding of the organization of the world has grown in the last 400 years with detailed information about elevation across all 7 continents.
Today, biologists are still in the part of the journey where they’re constantly learning new things and updating their maps. Many biological discoveries still feel like the lucky discovery of the Americas by the Nina, Pinta, and Santa Maria. Making things even more difficult, the uncharted territory that biologists want to understand is even more complicated than the stable land masses of continents. Imagine trying to build a map of the world if small chunks of land moved around and interacted with each other in complicated ways. Now imagine that each explorer had to study a slightly different version of the world with small differences that made it unique, but that had the same general layout. That is the size of the challenge that biologists face when studying the human body.
The challenges of mapmaking for biologists go beyond just the fact that components of the maps move and interact. Biologists also have to build maps at different scales and understand how they relate to one another. Consider understanding the brain as an example. Some neuroscientists study how molecules inside individual brain cells work, others study how small groups of cells connect and send signals between each other, others study how large groups of cells send signals across the brain, and still others study how these signals relate to someone’s behavior or symptoms. Even neuroscientists studying things at the same scale often use different tools that make relating their discoveries to someone else’s challenging. As neuroscientists build maps at each of these levels it’s not always obvious how each map relates to the others and connecting the maps can be just as difficult as building them.
Diseases like autoimmune encephalitis can be hard to categorize and diagnose
Understanding how a healthy human body works is hard enough but extending that understanding to figure out how to treat and cure diseases is even more complicated. When it comes to diseases, many different things can go wrong but produce the same symptoms. And oftentimes when one thing goes wrong, it causes a cascade of other things to go wrong as well. This makes it difficult to pinpoint exactly what went wrong first to try to target that for treatment.
Autoimmune encephalitis is a good example of this kind of complexity. There are many different subtypes of autoimmune encephalitis that result from an immune response to several different kinds of proteins found in the brain. Despite being caused by reactions to different proteins, several subtypes have overlapping symptoms. On the other hand, each subtype is typically associated with several distinct symptoms that are all part of the same diagnosis. On top of that, each individual patient is different even before they get sick, so they will have a slightly different experience of their disease.
One thing this diversity can make difficult is deciding which patients to group together and which to consider separately. Should researchers group patients by their symptoms (e.g., fatigue, motor deficits, headaches) or by biological markers (e.g., testing for things in the blood or cerebrospinal fluid)? * Scientists’ answer to that question is constantly evolving as they learn more about patients with different kinds of autoimmune encephalitis. Until they know enough to separate subgroups of patients, it can be difficult to see through the diversity of symptoms and biological markers toward a clear understanding of exactly what’s going on.
All of these things only become more difficult the rarer a disease is. The more patients with a certain disease that can be studied, the more data points scientists have to work with. This can give them a better sense of the big picture, despite variability between individual patients. This is why the subtypes of autoimmune encephalitis that are most common, like Anti-NMDAR encephalitis, tend to be better understood than rarer subtypes. When there are more diagnosed patients, the disease is easier to study.
*For a deeper dive into this issue, Penn NeuroKnow writer, Margaret Gardner, wrote about how the same problem impacts our ability to study psychiatric disorders in this PNK article.
Rigorous science can’t be rushed
There are also practical components of how research is conducted that contribute to its slow and steady pace. Research needs to be funded and that is typically done through federal grants from organizations like the National Institute of Health (NIH). Grant funding is competitive, and researchers can spend months working on a proposal before submitting a grant. Once submitted, the grant undergoes rigorous review by other scientists. These reviewers are looking to fund science that they think will be successful, so this means that the best proposals aim to take small and manageable steps in our understanding based on past research. After review, many grants are rejected. So, scientists often have to shake off the disappointment, consider the reviewer feedback, and write an updated proposal. And, as it turns out, getting funding is only half the battle. Once a grant is funded and the project can begin, it takes time to train students and lab workers in the skills needed to conduct the research. Sometimes scientists even have to invent new technology to collect or analyze their data because they’re trying to do something that’s never been done before.
Once scientists have their first set of results, these results often lead to new questions that need to be answered. So, scientists must do many follow-up experiments to understand what’s going on before they can feel confident adding their new discovery to the map of the human body. Once they think they know what’s going on, they then need to replicate their results several times to be sure that what they’re studying is generally true and not specific to whatever patient, animal, or dish of cells they ran their first experiment on. After that scientists will spend months putting their results together into a paper which is then reviewed by other scientists who might ask for more experiments or analyses to make their results more convincing. Finally, the paper is published, and that project can be considered complete. A lot of biomedical research is done by first studying cells in a dish, then studying animal models, and then testing treatments in humans. Each step of this process requires scientists to go through the same process of getting funding, verifying their results, and eventually publishing their work.
While all of these steps contribute to the seemingly slow pace of science, they’re also beneficial to scientific progress. Doing many follow-up experiments, replicating results, and incorporating feedback from other scientists means that once a paper is published scientists can be pretty sure that everything in the paper is accurate. This is important because if scientists couldn’t believe most things that are published then they wouldn’t know what foundation to build on when they design new experiments. Such rigorous requirements for publishing research also help to keep patients safe. Ultimately, the goal is that everything we learn from these papers can be used to develop a treatment or a cure for a disease, which means using that knowledge to help human patients. Once scientists know enough to think about possible treatments, scientists and doctors work together to test these treatments in human patients through a process called clinical trials. Doctors and scientists need to be certain of as much as they can so that those treatments are safe.
While there’s plenty left to learn about autoimmune encephalitis and thinking about that can feel daunting, it’s important to celebrate that we’ve learned a lot already. Successful treatments that work for many people have already been developed, and treatments are only getting better. An increasing understanding of what autoimmune encephalitis is and how to treat it has also led to the creation of research centers, like the Center of Autoimmune Neurology at the University of Pennsylvania, that make researching the disease and connecting patients and doctors easier. Centralized organizations like the International Autoimmune Encephalitis Society also help raise awareness about these issues and facilitate connections between patients, doctors, and researchers that continue to push our understanding forward.
Altogether, there are a lot of reasons to feel optimistic about the future and to trust in the system of slow and steady scientific research that has already delivered trustworthy, safe treatment options.
Cover photo: Photo by Ousa Chea on Unsplash.
Figure 1: Left: Girolamo Porro,, Public domain, via Wikimedia Commons; Right: © OpenStreetMap-Mitwirkende, Public domain, via Wikimedia Commons
Click here or the image below to subscribe to our mailing list:
Your generous Donations allow IAES to continue our important work and save lives!
On June 16 th, 2022, Tabitha Orth, President and Founder of International Autoimmune Encephalitis Society officially became the 7,315 th “point of light”. Recognized for the volunteer work she and IAES has done to spark change and improve the world for those touched by Autoimmune Encephalitis. The award was founded by President George H.W. Bush in 1990.
Become an Advocate by sharing your story. It may result in accurate diagnosis for someone suffering right now who is yet to be correctly identified. Submit your story with two photos to IAES@autoimmune-encephalitis.org
International Autoimmune Encephalitis Society (IAES), home of the AEWarrior®, is the only Family/Patient-centered organization that assists members from getting a diagnosis through to recovery and the many challenges experienced in their journey. Your donations are greatly appreciated and are the direct result of IAES’ ability to develop the first product in the world to address the needs of patients, Autoimmune Encephalitis Trivia Playing Cards. Every dollar raised allows us to raise awareness and personally help Patients, Families, and Caregivers through their Journey with AE to ensure that the best outcomes can be reached. Your contribution to our mission will help save lives and improve the quality of life for those impacted by AE. For this interested in face masks, clothing, mugs, and other merchandise, check out our AE Warrior Store! This online shop was born out of the desire for the AE patient to express their personal pride in fighting such a traumatic disease and the natural desire to spread awareness. Join our AE family and help us continue our mission to support patients, families and caregivers while they walk this difficult journey.