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Behind the Scenes

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February 28, 2024 | by Tabitha Orth, IAES President and Founder

Thank you UCB for sponsoring all 2024 AE Awareness Month blogs.

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Some of you may be aware that IAES is completely powered by a volunteer staff. Volunteers are either caregivers or patients who have walked this walk and come out on the other side. After experiencing the trauma, they harbored a strong desire to create change so no one else would have to go through the experience without the help and support they so desperately needed. Some volunteer “AE Warriors” (a term I came up with in 2014 to denote the difference between an encephalitis ‘survivor’ versus an AE patient who has a long ongoing battle), are still receiving treatment themselves. Caregiver volunteers are also currently navigating the journey of their AE Warrior who is often still battling the disease. The quality of our volunteers, many of whom have medical backgrounds and their personal experience with AE, is the ‘secret sauce’ to IAES’ success. 

I began my patient advocacy in 2014, a year and a half after becoming ill in 2013.  Back then if you did a Google search for autoimmune encephalitis, nothing came up. I was able to find information on encephalitis, but nothing on AE. I did find a new organization whose mission was to build an alliance with doctors to further research. That was great to see. However, they only listed symptoms, tests, and a single paragraph defining AE which, while it was something, didn’t help me. It was an information desert.

My search for help led me to online forums. I found groups of people, largely undiagnosed, suffering, with no compass or light to guide them. These were dark days. I learned that before AE was identified in a 2007 paper by Dr. Josep Dalmau, patients were legally committed due to being misdiagnosed as a psychiatric case. They eventually perished.  “Frightening”, doesn’t begin to cover the situation we were in. The book Brain on Fire was on the New York Times best-seller list and catapulted awareness of this strange disease. As awareness ticked up slowly in the medical community, a great deal of misinformation accompanied it. There were only three locations in the U.S.A. with doctors familiar with this. They were: The Mayo Clinic, UPENN, and John Hopkins. That was it.

When people in need come to IAES, they may connect via our international telephone line, website inquiry, or one of our social media platforms. Everyone’s inquiry is handled with care for the best possible outcome for all. Many cases have an ongoing need. These are directed to different areas of IAES where a volunteer with the expertise required is assigned a case. IAES handles cases all over the world. Doctors regularly contact us via our website to learn about diagnosis and treatment and connect with experts who can confer on their cases. IAES is responsible for countless accurate diagnoses worldwide that would have gone misdiagnosed.

Members of our community have learned the value of self-advocacy. One of our goals in our mission is to help others become strong self-advocates. Daily personal attention is given to over 7,000 individuals on Facebook alone. The educational evidence-based private support group is the only one of its kind in the worldwide community. There, questions and advocacy advice are given based on what research reports and the talented administrators with specialized expertise on a variety of topics. Tools and techniques that support the patient’s deficits while utilizing their strengths are unique to IAES and the reason members can grasp complex information in a short period. Education is power and builds confidence. Feeling in control when facing a disease like AE is key.

When people contact us, it doesn’t dawn on them that they are speaking to someone who was once in the same situation their loved one is currently in. The hope and wonder of that realization immediately changes their perspective. AE can be reversed. The patient will improve. Hope is real. As strong as we volunteers are in our endeavor to create change and improve the lives of the people we serve, we struggle with our lasting deficits. All of us have cognitive impairments. Yet, what we have accomplished and how we manage it all daily, is something to witness.

Last week I reached out to members of the Board of Directors to ask if they could watch the awareness video for this year’s awareness month. How many AE Warriors did it take to find any typos or mistakes? It took five. I won’t complain about redoing the video 3 different times to make all the corrections. They were not caught in one go-round. That’s how it is behind the scenes. It takes 3-4 times longer to get a simple thing done. The important thing is that we get it done and reach our goal.  I thought you might like to be a fly on the wall and get a behind-the-scenes look into a typical daily phone call between staff members. 

Have you ever wondered what a telephone conversation between our President/Founder, Tabitha Orth, and another member of our Board of Directors is like? Two AE Warriors with memory issues and other cognitive deficits. Here’s a sample of a portion of a typical daily conversation with Board Secretary and Support Services Coordinator, Mari Wagner Davis with Tabitha. Mari’s time zone is two hours ahead of Tabitha’s. Both women return calls from the “Bat Phone”. Oh. The Bat Phone is IAES’ International Line. The name was coined by Tabitha’s husband Jim because when it rings Tabitha would jump up to answer it and he called after her, “Quick, It’s the bat phone!”.  When the bat phone rings, someone needs help, and it is usually crisis-driven.

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A few minutes into a conversation:

Tab: OMG, brain glitch. Not braining well. Just woke up.

Mari: Have you had your coffee?

Tab: Nooo.

Mari: That’s okay. That’s okay. Take your time. Make your coffee.

Tab: Yes, and while I’m waiting for my brain to unfreeze, what do you think of the idea of that new program we were discussing starting as an…oh. What’s the word I want? It means ‘experimental’?

Mari: Investigational?

Tab: No.

Mari: Exploratory?

Tab: No, that is good, it’s close to the word I’m thinking of.

Mari: Trial?

Tab: Yes! Thank you! Trial. My coffee is done.

Mari: Oh, Good!

Tab: Does that sound good to you? Starting the program as a trial program and building out from there?

Mari: I agree. It does. I was calling to tell you about that phone call I handled yesterday. You know the friend of a mother back east?

Tab: Was that the one who needed to learn about available support services and a waiver for a Mom?

Mari: No, it was the ICU pediatric case. Waiver Mom Case is taken care of though.

Tab: Oh, good to hear. Well done. Got it. Yes, Pediatric ICU.

Mari: I helped them to arrange a consult with an expert. That happened. Spoke to Mom at length so I answered all her questions and she felt so much better. That one is all good and done.

Tab: Oh! Great. Perfect. I love it when things flow the way you train people to do things for us. I swear you have a gift for telling people exactly what to do and why, have them check back with you about their progress, and then they are pleased to death when you compliment them on the amazing job they have done. You have people jump through hoops and check in with you to ask, ‘How am I doing’? as they go. It cracks me up as much as I am grateful to work with you.

Mari: Thanks! It is hilarious. Are we meeting with those people about that clinical trial on Tuesday or Thursday?

Tab: I think Tuesday is the clinical trial and Thursday is the website guy. But we better check.

While I have you I wanted to update you on the Christmas Eve/Christmas Day Crisis Case. This coffee is so good, that my brain is clicking in. It had a happy ending but my gosh it was a bad one. Seizure disorder went off her meds and was having major seizures. An ambulance transported the patient to the ER. The seizures triggered psychosis and they were threatening to have her handcuffed by police and transported to a psych hospital because there was no room for her at the inn (hospital) on Christmas Eve. I’m not too fond of holidays, skeleton crews, and packed ERs. Holidays and health emergencies are a terrible combination.  It took a lot of work, more than it should have because of the holidays. She was admitted to neurology, and all is right with the world. I don’t know if that would have been the outcome if she hadn’t had a seizure right in the middle of the discussion with the attending. Lord, I was thankful for the timing of that seizure. Crazy to say you have an angel on your shoulder about getting a seizure when you need one, but that’s how it is sometimes. So, happy ending. No traumatic psych hold on Christmas. Geez.

Mari:  ERs and holidays are the worst. I’m glad it all worked out.  We are going to have a good year.

Tab: We are going to have a GREAT year! I’m excited.

Mari: So am I.

Tab: I know there was something else I needed to talk to you about, but I can’t think of it now.

Mari: That’s fine. You’ll think of it as soon as you get off the phone, so just call me back.

Tab: OK. I’ll be behind the scenes working on e-mail and the awareness video. I’ll keep an eye out for any messages.

Mari: Okay. I have a slew of requests to join the support group and will answer questions.

Tab: I saw how crazy busy your team was there.

Mari: We’ve connected with several of them, so that’s looking good. Amanda connected with several. But, yes very busy.

Tab: I’ll watch out for your welcome post, so I can say hi to everyone. See you online.

Mari: See you there. Bye.

 

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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.

 

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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.   Trivia Playing cards 3 FB 500x419 - Behind the Scenes 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.   AE Warrior Store 300x200 - Behind the Scenes

Be a part of the solution by supporting IAES with a donation today.

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Critical thinking: How networks in the brain may be optimally organized

Critical thinking: How networks in the brain may be optimally organized

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February 14, 2024 | by Joseph Stucynski, 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/

Joeseph Stucynski has graciously allowed us to republish an article he recently wrote for the weekly PNK series the students participate in aside from the articles they write for IAES.

Thank you UCB for sponsoring all 2024 AE Awareness Month blogs.

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Introduction

Sleep is critical. Each one of us with AE has experienced fatigue at one time or another during our AE journeys. We, also, know how important it is to pay attention to the fatigue and do our best to get adequate rest for optimum recovery. Sleep is crucial for our brains. Joseph has explained another reason or in another way just how critical sleep is for us to be able to operate on a day-to-day basis to our best ability! We hope you enjoy this as much as we have.

If you’ve ever stared at falling sand in an hourglass, you might have noticed that when it accumulates on the pile below, every so often it will trigger an avalanche. Most of the time the avalanches are tiny and quick, just involving the top sand rolling lower, but sometimes the weight of the sand overcomes friction of the pile and a large chunk of sand fractures off and slides lower. It turns out that this seemingly simple sand pile is a mathematically interesting system that exhibits a trait called self-organizing criticality.1 The term ‘criticality’1,2 in this case refers to the fact the sand pile is constantly balancing at a critical transition point between stability (the sand pile building up), and chaos (sand avalanches triggering).  Notably, criticality doesn’t just apply to sand, it also may be an important part of how your brain works,2,3,4,5 and new research shows that sleep might be very important for maintaining this property!6

The edge of chaos

The idea that the brain, with its billions of neurons, operates at the edge of chaos might sound crazy at first, but it turns out that operating on this knife’s edge of criticality allows a system to process information at optimum efficiency.3,4,5,6 And since the brain needs to perform so many tasks, computations, and behaviors, it also needs to organize and activate its systems in an efficient manner.

Like avalanches on the sand pile, the firing of neurons throughout the brain seems to follow the mathematical criteria for criticality. That is, small numbers of neurons fire more frequently in mini avalanches of activity, but the larger the number of neurons that fire together, the more rare those neural avalanches are. For those interested, this is called a power law.3,4,5 In this way, the brain maintains balance between too few neurons firing, and too many at once, both of which may prevent the brain from functioning well.

In a related way, the brain must also maintain balance between order and chaos. If neurons fire too chaotically it results in a sub-critical state, and it is harder for the brain to process information, like when a person is under the influence of certain drugs or anesthetics.6 But if neurons fire in perfect order across the brain in a super-critical state, you can end up with an epileptic seizure.By operating in a critical state at the transition point between order and chaos, the brain processes information efficiently to deal with an ever-changing environment.

Admittedly, neuroscientists don’t all agree that the brain meets the definition for criticality, but the field is growing due to a steady trickle of evidence and a dedicated field of researchers. But still, what does all this mean for you? What does it mean for your brain to be at criticality, and could you even feel when it’s not? As it turns out, one of the reasons you need to sleep at night may be to maintain this criticality.

Sleep is critical

As you go about your day and the refreshing effects of a good night’s sleep wash away, you may feel like your brain is slipping further from an optimal state. In a recent paper, neuroscientists tested whether your brain moves increasingly farther away from criticality during the day, and if sleep can help restore this critical state for the next day.7

To do this, the neuroscientists recorded from many neurons in the brains of rats while they were awake and asleep. The team then measured mathematical aspects of criticality to compare the rats’ awake brains to their sleeping brains. They found that while their brains’ ‘closeness to criticality’ changed from moment to moment, in general their brains were farther from criticality the longer they were awake.7 Likewise, their brains were closer to criticality during sleep and closest just before they woke up after long durations of sleep. In other words, the longer the rats were awake, the further their brains were from criticality, while sleep reset their brains to a critical state.

While the authors of this study did not investigate exactly how sleeping moves the brain closer to a critical state, their findings present a provocative new view of the central function of sleep and why it is so important to maintaining brain health and function. Ultimately, this represents another piece of evidence suggesting that criticality is a core operating principle of how the brain works – just something to remember the next time you find yourself exhausted at the end of a workday feeling like you need to take a nap.

References

  1. Abelian sandpile model, Wikipedia.https://en.wikipedia.org/wiki/Abelian_sandpile_model
  2. Ouellette, J. Sand pile model of the mind grows in popularity. Scientific American, 2014.https://www.scientificamerican.com/article/sand-pile-model-of-the-mind-grows-in-popularity/
  3. O’Byrne, J., and Jerbi, K. How critical is brain criticality? Trends in Neurosciences, 2022.https://www.cell.com/trends/neurosciences/fulltext/S0166-2236(22)00164-3
  4. Beggs, J.M., Timme, N. Being critical of criticality in the brain. Frontiers in Psychology, 2012.https://www.frontiersin.org/articles/10.3389/fphys.2012.00163/full
  5. Cocchi, L., Gollo, L.L., Zalesky, A., Breakspear, M. Criticality in the brain: A synthesis of neurobiology, models and cognition. Progress in Neurobiology, 2017.https://www.sciencedirect.com/science/article/pii/S0301008216301630
  6. Maschke, C., O’Byrne, J., Colombo, M.A., Boly, M., Gosseries, O., Laureys, S., Rosanova, M., Jerbi, K., Blain-Moraes, S. Criticality of resting-state EEG predicts perturbational complexity and level of consciousness during anesthesia. BioRxiv, 2023. https://www.biorxiv.org/content/10.1101/2023.10.26.564247v1
  7. Xu, Y., Schneider, A., Wessel, R., Hengen, K.B. Sleep restores an optimal computational regime in cortical networks. Nature Neuroscience, 2024.https://www.nature.com/articles/s41593-023-01536-9

Cover photo by Nathan Dumlao on Unsplash

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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!

 

 

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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.

 

guidestar platinum logo 300x300 1 e1605914935941 - Critical thinking: How networks in the brain may be optimally organized

 

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.   Trivia Playing cards 3 FB 500x419 - Critical thinking: How networks in the brain may be optimally organized 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.   AE Warrior Store 300x200 - Critical thinking: How networks in the brain may be optimally organized

Be a part of the solution by supporting IAES with a donation today.

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Memory and Autoimmune Encephalitis

Memory and Autoimmune Encephalitis

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January 24, 2024 | by Ryan Rahman, 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

Our brains are what make us human – consciousness, emotion, and memory all come from a tapestry of over 100 trillion connections. When this intricate network is bombarded by misguided immune cells, as in the case of autoimmune encephalitis, the brain can no longer carry out some of its most important functions. One such function that is often prominently affected is memory.1,2 Memory is a central aspect of our daily lives, allowing us to recall cherished moments, learn from our experiences, and navigate the world. However, for individuals battling autoimmune encephalitis, memory can become a complex and challenging puzzle. In this blog post, we will describe the memory difficulties patients face when living with autoimmune encephalitis (AE).

What is memory?

Memory is a fundamental cognitive function that enables individuals to absorb, store, and recall information and experiences. It plays a crucial role in shaping our perception of the world and our ability to learn, make decisions, and navigate daily life. There are different types of memory that work together to enable us to learn, adapt, and navigate the complexities of life. Broadly, it can be helpful to think of grouping different types of memory by where they are in the brain because the brain organizes its functions into different locations. For example, the hippocampus is the main brain structure that helps record information and start the formation of memories.3 In addition, it is also important to consider the kind of information being stored and how long it is stored for (Figure 1). Here, we break down a few types of memory that are relevant to patients living with AE:

Sensory Memory: Sensory memory4 is responsible for briefly holding information from our sensory organs, such as vision and hearing. This short-lived memory lasts for a fraction of a second and is composed of all the information we get from our senses before our brain filters out the unimportant parts. It typically relies on parts of the brain that receive direct information from the sensory organs, such as the eyes and ears.

Short-Term Memory: Short-term memory4 is the next shortest type of memory, lasting for a few seconds to minutes. When you solve a quick math equation in your head or remember mid-conversation what someone just told you, you’re using your short-term memory.6 Short-term memory relies largely on communication between two parts of the brain called the prefrontal cortex and hippocampus.

Long-Term Memory (LTM): Long-term memory4 is exactly what it sounds like – the kind of memory that helps us remember things for long periods of time. It has an almost unlimited capacity and can last for a lifetime. Long-term memory includes our ability to remember personal experiences, facts, skills, and habits. Our ability to form these memories relies on the hippocampus and another part of the brain called the frontotemporal lobes, but where exactly long-term memory is stored is still unclear.

Procedural Memory: Procedural memory4 is a special type of long-term memory often mistakenly called “muscle memory” (because memory comes from the brain, of course!) that allows us to ride a bicycle, type on a keyboard, or tie our shoelaces with little conscious effort. Procedural memory does not depend on the hippocampus or prefrontal cortex. Instead, it tends to be formed and stored in the brain areas involved in planning motions, such as the cerebellum and the motor cortex.

Because different types of memory rely on different parts of the brain, sometimes patients with damage to only some parts of the brain can have deficits in only one type of memory, while the other types of memory are preserved.

Another concept that is central to most types of memory is the idea that brain cells, which are called neurons, can change the strength of their connections. Connections between neurons are called synapses, which are tiny gaps between the cells bridged by chemical and electrical signals.5 A bunch of neurons working together can mirror an electrical circuit, and the more synapses in a circuit are activated, the tighter and more numerous these connections become. This concept is known as synaptic plasticity, and the ability to retrieve memories may be dependent on how strong certain connections are.6

memory 1 - Memory and Autoimmune Encephalitis

Figure 1. Memories form in discrete steps over time and are associated with specific parts of the brain.

 

How does autoimmune encephalitis affect memory?

Over the course of many years and research studies, doctors and scientists have shown that AE causes changes in memory. Both short-term and long-term memory impairments can occur in patients with AE; however, procedural memory impairments do not usually occur in AE.1,7-9 For patients with AE, deficits in short term memory can take the form of confusion and attention challenges; whereas deficits in long term memory can take the form of difficulty remembering facts, struggles with planning/organizing, and loss of personal memories. Although many patients show significant improvement in their memory symptoms after treatment of AE, many patients can unfortunately continue to experience residual memory problems, even long after other symptoms of AE have gone away.10

As discussed in a prior IAES blog post, AE is divided into different types based on which brain protein is attacked by a patient’s immune system. People with some subtypes of AE are more likely to have certain memory challenges.11 For example, patients with LGI1 autoimmune encephalitis (patients who have antibodies against Leucine-rich Glioma Inactivated protein 1) tend to have the most severe memory deficits with a profound loss of memories about personal life events. In contrast, memory loss and confusion are less common in patients with GABAAR encephalitis (~27%) and GABABR encephalitis (~47%). The reason behind these differences may in part be due to the fact that some of these proteins are only present in specific parts of the brain, which, as we previously discussed, control specific types of memory. Additionally, these targeted proteins play different roles in the circuits of the brain and disruption of different parts may impair synaptic plasticity in various ways. Please see the table below for more details about the memory changes experienced in different types of AE.

antibodies - Memory and Autoimmune Encephalitis

Table 1. Different types of AE are associated with different memory challenges for patients. Adapted from Gibson et al. – Cognitive impact of neuronal antibodies: encephalitis and beyond (2020).

 

To understand more about how AE causes memory changes, scientists first worked with patients using magnetic resonance imaging (MRI) to look at changes in the physical structure of their brains.12 Even as early as 1968, scientists saw drastic changes in the temporal lobes of patients with AE, which is a large region of the brain that contains the hippocampus.13 Importantly, recent studies have directly demonstrated that most patients with autoimmune encephalitis have structural changes in the hippocampus, and those with more damage in the hippocampus have more severe challenges with memory.14  

In addition to large structural changes, the microscopic science behind how AE causes memory loss has been explored in animal studies, which are more manipulable models for scientists to determine how diseases work in an entire system.15,16 In one experiment, scientists injected mice with antibodies from human patients with AE. They then tested the mice for any memory changes. Mice that were given the AE-associated antibodies could not remember objects they had seen before and developed anxiety-like behaviors.15 Importantly, scientists also showed that antibodies targeting the Nmethyl-Daspartate (NMDA) glutamate receptor (as seen in patients with Anti-NMDAR encephalitis) reduced the number of these proteins at the connections between brain cells which in turn disrupted synaptic plasticity.16

As previously mentioned, synaptic plasticity refers to the dynamic strength of circuits in the brain which increases when more neurons are activated together. Since glutamate is the main activating signal of the brain, it may be that destruction of the glutamate signal in certain types of AE leads to impaired memory by changing the strength of connections in the brain.

Lastly, an exciting early development occurred when scientists discovered that injecting Ephrin-B2, a protein that helps in the development of connections in the brain, was able to prevent memory loss caused by anti-NMDA antibodies in mice.16,17 Based on these findings, Ephrin-B2 may one day become a potential treatment for memory loss in patients living with AE!

Conclusion

In conclusion, autoimmune encephalitis is a neurological disorder that can have a profound and lasting impact on memory. Memory deficits in autoimmune encephalitis are not only distressing for patients but can also pose challenges to their daily functioning and quality of life. A better understanding of the mechanisms underlying these memory impairments and the development of targeted treatments are crucial to improving outcomes for individuals affected by autoimmune encephalitis and their memory-related challenges.

 Research in this field is ongoing, and with continued advancements in science and treatment, we can piece back together the lives of those affected by autoimmune encephalitis, one memory at a time.

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References

1          Heine, J. et al. Long‐Term Cognitive Outcome in Anti–N‐Methyl‐D‐Aspartate Receptor Encephalitis. Annals of Neurology 90, 949-961 (2021). https://doi.org/10.1002/ana.26241

2          McKeon, G. L. et al. Cognitive outcomes following anti-N-methyl-D-aspartate receptor encephalitis: A systematic review. Journal of Clinical and Experimental Neuropsychology 40, 234-252 (2018). https://doi.org/10.1080/13803395.2017.1329408

3          Bird, C. M. & Burgess, N. The hippocampus and memory: insights from spatial processing. Nature Reviews Neuroscience 9, 182-194 (2008). https://doi.org/10.1038/nrn2335

4          Camina, E. & Güell, F. The Neuroanatomical, Neurophysiological and Psychological Basis of Memory: Current Models and Their Origins. Front Pharmacol 8, 438 (2017). https://doi.org/10.3389/fphar.2017.00438

5          Südhof, T. C. & Malenka, R. C. Understanding Synapses: Past, Present, and Future. Neuron 60, 469-476 (2008). https://doi.org/10.1016/j.neuron.2008.10.011

6          Citri, A. & Malenka, R. C. Synaptic Plasticity: Multiple Forms, Functions, and Mechanisms. Neuropsychopharmacology 33, 18-41 (2008). https://doi.org/10.1038/sj.npp.1301559

7          Dalmau, J. et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 7, 1091-1098 (2008). https://doi.org/10.1016/s1474-4422(08)70224-2

8          Finke, C. et al. Cognitive deficits following anti-NMDA receptor encephalitis. Journal of Neurology, Neurosurgery & Psychiatry 83, 195-198 (2012). https://doi.org/10.1136/jnnp-2011-300411

9          Hansen, N. Long-Term Memory Dysfunction in Limbic Encephalitis. Frontiers in Neurology 10 (2019). https://doi.org/10.3389/fneur.2019.00330

10        Titulaer, M. J. et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 12, 157-165 (2013). https://doi.org/10.1016/s1474-4422(12)70310-1

11        Gibson, L. L., McKeever, A., Coutinho, E., Finke, C. & Pollak, T. A. Cognitive impact of neuronal antibodies: encephalitis and beyond. Translational Psychiatry 10 (2020). https://doi.org/10.1038/s41398-020-00989-x

12        Kelley, B. P. et al. Autoimmune Encephalitis: Pathophysiology and Imaging Review of an Overlooked Diagnosis. American Journal of Neuroradiology 38, 1070-1078 (2017). https://doi.org/10.3174/ajnr.a5086

13        CORSELLIS, J. A. N., GOLDBERG, G. J. & NORTON, A. R. “LIMBIC ENCEPHALITIS” AND ITS ASSOCIATION WITH CARCINOMA. Brain 91, 481-496 (1968). https://doi.org/10.1093/brain/91.3.481

14        Finke, C. et al. Structural Hippocampal Damage Following Anti-N-Methyl-D-Aspartate Receptor Encephalitis. Biological Psychiatry 79, 727-734 (2016). https://doi.org/10.1016/j.biopsych.2015.02.024

15        Haselmann, H. et al. Human Autoantibodies against the AMPA Receptor Subunit GluA2 Induce Receptor Reorganization and Memory Dysfunction. Neuron 100, 91-105.e109 (2018). https://doi.org/10.1016/j.neuron.2018.07.048

16        Planagumà, J. et al. Ephrin‐B2 prevents N‐methyl‐D‐aspartate receptor antibody effects on memory and neuroplasticity. Annals of Neurology 80, 388-400 (2016). https://doi.org/10.1002/ana.24721

17        Hruska, M. & Dalva, M. B. Ephrin regulation of synapse formation, function and plasticity. Molecular and Cellular Neuroscience 50, 35-44 (2012). https://doi.org/10.1016/j.mcn.2012.03.004

Figure 1 and Table 1 made by Ryan Rahman in BioRender.com.

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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.

 

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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.   Trivia Playing cards 3 FB 500x419 - Memory and Autoimmune Encephalitis 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.   AE Warrior Store 300x200 - Memory and Autoimmune Encephalitis

Be a part of the solution by supporting IAES with a donation today.

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What is the connection between cancer and autoimmune encephalitis?

What is the connection between cancer and autoimmune encephalitis?

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/

—-

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).

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

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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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.

 

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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.   Trivia Playing cards 3 FB 500x419 - What is the connection between cancer and autoimmune encephalitis? 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.   AE Warrior Store 300x200 - What is the connection between cancer and autoimmune encephalitis?

Be a part of the solution by supporting IAES with a donation today.

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Can viral infections trigger autoimmune encephalitis?

Can viral infections trigger autoimmune encephalitis?


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/

—-

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 too2,3.

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 tumor4,5. 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 AE6,7. 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 changes8,9. 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 AE6,7. 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 antibodies6,11. 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 well7,11.

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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Tabitha Orth 300x218 - Can viral infections trigger autoimmune encephalitis?

 

 

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.

 

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Neuro MythBusters: The truth behind 10 common myths about your brain

Neuro MythBusters: The truth behind 10 common myths about your brain


September 13, 2023 | by Catrina Hacker, PennNeuroKnow and IAES Collaboration

A message from IAES Blog Staff:

When it comes to evidence-based answers about all thing’s neurology and neuro myth busting, who you going to call? Well, here at IAES it will be the PNK team of course! We hope you enjoy and learn from this myth busting blog as much as we have!!

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

Many people find neuroscience fascinating because learning about our brains teaches us about ourselves. Unfortunately, popular interest in brain research has led to several pervasive myths that misrepresent how our brains work. Combatting these neuromyths is difficult because the truth is often much more complicated than the myth and buried in intimidating scientific literature. However, correcting misconceptions about how our brains work can have important benefits for our everyday lives. In this post I’ll break down what some of these neuromyths claim, where they came from, whether there’s any truth behind them, and why we should care about correcting them.

Myth #1: Humans only use 10% of our brains.

This is arguably the most common neuromyth1, inspiring movies like Limitless (2011) and Lucy (2014) in which characters gain superhuman abilities by tapping into the large unused portions of their brains. It’s appealing to think that we all have potential superpowers sitting in our brains waiting to be unleashed, but there’s nothing to support this claim. The reality is that neuroscientists observe activity throughout the entire brain.

While nobody is certain where it came from, some believe that this myth originates from work done by neuroscientist Wilder Penfield in the 1930s1. Penfield was a neurosurgeon who studied the effects of stimulating the brains of patients undergoing neurosurgery to learn what each part of the brain was responsible for. He found that stimulating a large portion of the brain didn’t cause any noticeable effect2, meaning he could not learn what its function might be. However, new and less invasive methods of recording brain activity show that these “silent” parts of the brain are actually active. In fact, a network of brain regions called the default mode network is even active when we are at rest3.

The bottom line: We use 100% of our brains.

Why it matters: The number of drugs and treatments that claim to enhance brain function, collectively called neuroenhancers, is on the rise. While we can always learn and grow, understanding that there is no “hidden” brain waiting to be unlocked can protect you from wasting your money.

Myth #2: Right-brained people are creative while left-brained people are analytical.

The idea that you can be either right-brained or left-brained has captured the attention of people on social media and even teachers in classrooms. It’s tempting to think that people can be categorized so easily and that differences can be attributed to our brains, but the truth isn’t that simple. While people can tend to be more creative than analytical or vice versa, those differences cannot be explained by dominance of one half of the brain over the other4.

This myth has been tricky to combat because there is some important truth behind it. There are some differences between the two halves of your brain, but creativity versus logical reasoning isn’t one of them. Your brain has two hemispheres, left and right, that communicate via a bundle of neural connections called the corpus callosum. While almost everything we do involves communication between the two halves of our brain, sometimes one half of the brain contributes a little more than the other. For example, the left hemisphere typically takes the lead in language processing5, the right hemisphere seems to play an especially important role in visual attention6, and the left and right hemispheres might do slightly different things to aid in face processing7. Things like creativity and emotional processing rely on both hemispheres and complicated networks of brain activations8,9.

The bottom line: Being right-brained or left-brained can’t explain why some people are more creative than others, but there are some differences in what your left and right hemispheres do when it comes to things like language, attention, and face recognition.

Why it matters: Categorizing people as one thing or another (left-brained or right-brained) is restrictive and ultimately harmful. Many “logical” tasks require creativity and “creative” tasks require logic. If teachers, mentors, and bosses make these assumptions about members of their teams or classrooms they risk mischaracterizing people or preventing them from working up to their true potential.

Myth #3: Listening to Mozart makes babies smarter.

This neuromyth, sometimes called the “Mozart effect”, started in 1991 when Alfred Tomatis shared his thoughts about how listening to Mozart could help children with speech and auditory disorders10. When a group of researchers showed in 1993 that listening to 10 minutes of Mozart’s K. 448 improved college students’ ability to visualize and manipulate mental images11, the media took this result and ran with it. The effects in the original study only lasted 10 to 15 minutes and only impacted mental manipulation of images, but the media wrote about general boosts to intelligence and implied that they lasted much longer. Despite the original study being done with college students, the myth was somehow generalized to include babies. Several studies published since 1993 have provided alternate explanations for the original result or have failed to replicate it while studying the same or different skills12.

Although listening to Mozart can’t make you smarter, there is some truth behind this myth. Stimulating an infant’s brain helps with their development, but activities like direct interactions with a parent, reading a book, or talking and singing with an infant are much more effective13,14. When it comes to music, passively listening might not impact development, but learning to play an instrument positively impacts a child’s cognitive abilities and their performance in school15.

The bottom line: Listening to Mozart doesn’t make babies smarter, but stimulation from things like singing to your child is an important part of their development, and children who learn to play an instrument tend to perform better in school.

Why it matters: Belief in the Mozart effect and similar claims led many people to show their children the popular Baby Einstein videos in the early 2000s. However, in 2007 a study showed that not only did viewing these baby DVDs not improve children’s intelligence, children who watched the videos tended to have a worse vocabulary than other children16.

Myth #4: Everybody has a distinct style in which they learn best.

Many people have memories like mine of being asked if they are a visual, auditory, or kinesthetic learner as a child. You may even have filled out a survey to learn what your learning style is. Even today, many teachers collect this information and personalize their teaching to each student’s supposed learning style. While this seems logical, there is no evidence that each person has a specific learning style in which they learn best17,18, and some research suggests that teaching to learning styles is more harmful than helpful19. While it’s true that people vary in ability on different kinds of tasks and that teachers should work with students as individuals to help them succeed, when “visual learners” are tasked with learning through auditory tasks, they do just as well19.

The bottom line: Everybody has different preferences, but matching teaching to a preferred learning style does not improve learning.

Why it matters: It is a waste of time and resources to focus on tailoring education to preferred learning styles when it has no impact on learning. In fact, teaching based on learning styles might actually harm students by limiting them to certain modalities and subjects that match their learning style and discouraging them from exploring20.

Myth #5: Your handwriting reveals aspects of your personality.

The use of handwriting to learn about someone’s personality is called graphology. Graphology became popular in the late 1800s, with German scientist William Preyer commenting that handwriting is “brain writing”21,22. Despite its dubious scientific validity, graphology was used to make decisions about a person’s value to society, such as in determining whether a person was trustworthy or a criminal. Fortunately, modern experiments have conclusively shown that handwriting cannot predict a person’s personality. In controlled settings, graphologists are no better at using a person’s handwriting to make judgments about them than if they were guessing23. However, many people still believe that aspects of a person’s personality can be learned from their handwriting, and some computer scientists are still trying to build computer models that can predict things like criminality and work ethic from handwriting24, repeating the mistakes of the past.

Despite the dubious link between handwriting and personality, there are some reliable links between handwriting and brain health. Our brains control the muscles that move as we write, and some neurological disorders can cause changes in the brain that impact handwriting21. For example, one early symptom of Parkinson’s Disease can be small, cramped handwriting25. For this and related disorders, handwriting can act as a window into brain health and an early warning sign that can lead to faster care and better outcomes.

The bottom line: A person’s handwriting cannot reliably predict their personality, but changes to handwriting can be early signs of neurological disorders like Parkinson’s Disease.

Why it matters: Despite there being no connection between a person’s handwriting and their personality, in 2017 then President Donald Trump tweeted about being able to tell from his handwriting that former United States Secretary of the Treasury, Jack Lew, “is secretive”22. Some scientists are still trying to build tools that can determine a person’s personality based on their handwriting to help with hiring decisions24. Without widespread acceptance that handwriting cannot predict personality, we risk repeating the mistakes of the past and using handwriting to unfairly discriminate against certain people.

Myth #6: A common sign of dyslexia is seeing letters backwards.

Dyslexia, characterized by difficulty reading, affects an estimated 20% of the population and is the most common neuro-cognitive disorder26. It is a popular misconception that a common sign of dyslexia is seeing words and letters backwards. People with dyslexia don’t see words and letters backwards, but they do have difficulty naming letters and words (think saying “was” while reading “saw”)27. When it comes to writing, there is some evidence that dyslexic children may be more likely than others to write letters and words backwards, a phenomenon called reversals. However, reversals are common in all children learning to read and write28, and not all children with dyslexia make reversals29.

There are many other reliable indicators that a person may have dyslexia. The signs of dyslexia change throughout a lifetime and range from preschool children who struggle to identify the letters in their names to high school students who struggle to read unfamiliar words30. Visit this fact page from the Yale Center for Dyslexia & Creativity for a full list of signs of dyslexia for all age groups.

The bottom line: Dyslexic children don’t see letters backwards, although they may read and write letters backwards. However, not all dyslexic readers write letters backwards and not all children who write letters backwards are dyslexic.

Why it matters: If parents and educators expect dyslexic children to describe seeing letters backwards or adults think they must see letters backwards to have dyslexia, then many people could go undiagnosed and not get the support they need to succeed.

Myth #7: Human memory works like a camera, perfectly recording what you experience.

As a child, one of my favorite book series starred Cam Jansen, a fifth grader who solves mysteries utilizing her flawless photographic memory. Any time she wanted to remember something she would say “click” and it would be perfectly captured in her memory. As an adult, I’ve watched plenty of TV shows and movies featuring similar characters who can use their perfect memory to save the day. Unfortunately, this kind of memory doesn’t exist outside books and other media.

For the rest of us here on earth, our brains forget and fill in details of our memories, even when we feel certain we remember things perfectly. A great example of this is the visual Mandela effect, wherein people consistently report strong false memories of things like whether Curious George has a tail or the Monopoly man wears a monocle (neither is true, but people consistently believe that they are)31. In general, it’s a good thing that our brains work in this imperfect way. We don’t want to get bogged down with irrelevant details of memories, so our brains act as a filter, prioritizing memory for the things that matter most and filling in the details and moments that are less important.

If our memory is so imperfect, where does the idea of photographic memory come from? This myth might have started after psychologist Ralph Haber noticed that a small percentage of children seemed to be able to hold pictures in their mind’s eye for seconds or minutes after they were removed from sight32. He called this kind of memory eidetic memory (often used interchangeably with “photographic memory” in popular media). However, these studies only looked at memory for short periods of time, and later research demonstrated that this “memory” is far from perfect33

The bottom line: Some people can remember things better or longer than others, but nobody’s memory works like a camera.

Why it matters: Our criminal justice system still relies heavily on eyewitness reports. If police officers, lawyers, and jurors don’t realize that memory is flawed, they risk inflating the value of this kind of testimony and incarcerating innocent people34.

Myth #8: People with bigger brains are smarter.

We’ve all heard or used the term “big-brained” to describe someone who does something smart, but the size of their brain has nothing to do with their intellect. If size was all that mattered, then elephants, whose brains are 3x heavier than ours, would be 3x smarter than us35. Even if we’re just looking at human brains, Albert Einstein’s brain was no bigger than average, and despite years of studying his brain, neuroscientists haven’t found any clear differences in its structure compared to other human brains36.

The myth that smarter people have bigger brains has a particularly harmful history. In the 1800s, scientists measured the skulls of people of different races and genders as an estimate of brain size to provide “scientific” evidence that Caucasian men were superior to women and other races. There are many reasons this approach was flawed, not least of which is that correcting for body size can account for many of the reported differences37. In 1898, a woman named Alice Lee challenged this idea by storming into the all-male meeting of the Anatomical Society at Trinity College Dublin, measuring the skulls of several prominent men in the audience, and demonstrating that many of these supposedly intelligent men had rather small skulls38.

Read my previous post, “The Problem of Brain Size”, for a more detailed look at this myth.

The bottom line: Brain size has nothing to do with intelligence.

Why it matters: Flawed measurements of brain size have historically been used as scientific “proof” that women and racial minorities are not as intelligent as Caucasian men. Dispelling this myth is critical to reverse the harm done by the claims made in these studies and to prevent making the same mistakes in the future.

Myth #9: Playing brain games makes you smarter.

We’ve all seen ads for games that claim to train your brain to make you smarter, or measure your IQ. However, these claims are misleading and overinflated. One study conclusively proved this by having over 11,000 people play online brain games for six weeks. At the end of the six weeks, people had gotten a little better at the specific games that they played, but they were no better at any other tests39. In other words, playing one memory game could make people better at that game, but it didn’t improve their memory overall.

In 2016, the brain game company Lumosity paid a $2 million settlement to the Federal Trade Commission (FTC) who filed false advertising charges against them40. The FTC asserted that Lumosity’s claims that playing their games could improve performance on everyday tasks, delay age-related cognitive decline, and reduce the effects of brain injuries like stroke were unfounded. Since the settlement, Lumosity has been forced to alter their claims so that they do not mislead consumers.

The bottom line: Playing brain games makes you better at those particular games, but not any smarter overall.

Why it matters: Before investing time and money into products that claim to improve brain function by playing fun brain training games, it’s important to understand that these effects are often small and improve performance on specific tasks, but don’t generalize.

Myth #10: Different regions of your tongue are specialized for different kinds of tastes.

There are five basic tastes: bitter, salty, sour, sweet, and umami41. The myth goes that there are different parts of your tongue that are specialized to sense different tastes, so sweet and salty tastes are sensed on the tip of your tongue, while bitter tastes are sensed toward the back. I remember learning this myth for the first time at a girl scout meeting where we tasted different foods by placing them on different parts of our tongue. Since then, I heard it repeated many times in school and even in some of my neuroscience classes as an undergrad. In fact, many textbooks that are still being used today include this false claim. However, the truth is that although some parts of the tongue might be more sensitive to one taste or another, all five basic tastes are sensed across the entire tongue42.

The tongue map myth started with a 1901 paper in which German scientist David Hänig measured how much taste sensitivities changed across the tongue. He noticed that some parts of the tongue were more sensitive to a particular taste than others, and he drew some graphs to show how those sensitivities changed across the tongue. In 1940, another scientist adapted these graphs for a book about the different senses. In his adaptation, he simplified things by showing a single taste that was most sensitive on each part of the tongue rather than the relative sensitivities of each taste. This gave the false impression that each region of the tongue could sense just one taste, and this oversimplified figure has been copied thousands of times into science textbooks to teach the neuroscience of taste.

The bottom line: Sensitivity to each taste varies somewhat across the tongue, but each part of the tongue senses all the basic tastes.

Why it matters: The negative consequences of this myth might not be as harmful as the others, but it’s always worth correcting our understanding of ourselves and our bodies.

Now that you’ve learned the truth behind 10 popular neuromyths, it’s worth asking how so many neuromyths have leaked into popular press and what we can do to prevent them in the future. Preventing the spread of disinformation about the brain starts at all levels. Scientists should be careful not to overgeneralize or oversimplify their findings and to always consider alternative explanations and how their work might be misinterpreted. Journalists and science communicators should carefully report the results of scientific studies and not overstate what a given experiment shows. Non-scientists should think critically about what they read, and fact check things they read from unknown sources on social media. And most importantly, now that you know the truth behind the myth, the best thing you can do is to teach it to others who still believe in these popular neuromyths.

References

1.         Jarrett, C. All You Need To Know About the 10 Percent Brain Myth, in 60 Seconds. Wired.

2.         Ferrier Lecture – Some observations on the cerebral cortex of man. Proc. R. Soc. Lond. Ser. B – Biol. Sci. 134, 329–347 (1947).

3.         Raichle, M. E. The Brain’s Default Mode Network. Annu. Rev. Neurosci. 38, 433–447 (2015).

4.         Nielsen, J. A., Zielinski, B. A., Ferguson, M. A., Lainhart, J. E. & Anderson, J. S. An Evaluation of the Left-Brain vs. Right-Brain Hypothesis with Resting State Functional Connectivity Magnetic Resonance Imaging. PLoS ONE 8, e71275 (2013).

5.         Bradshaw, A. R., Thompson, P. A., Wilson, A. C., Bishop, D. V. M. & Woodhead, Z. V. J. Measuring language lateralisation with different language tasks: a systematic review. PeerJ 5, e3929 (2017).

6.         Chica, A. B. et al. Attention networks and their interactions after right-hemisphere damage. Cortex 48, 654–663 (2012).

7.         Meng, M., Cherian, T., Singal, G. & Sinha, P. Lateralization of face processing in the human brain. Proc. R. Soc. B Biol. Sci. 279, 2052–2061 (2012).

8.         Amir, O. & Biederman, I. The Neural Correlates of Humor Creativity. Front. Hum. Neurosci. 10, (2016).

9.         Fossati, P. Neural correlates of emotion processing: From emotional to social brain. Eur. Neuropsychopharmacol. 22, S487–S491 (2012).

10.      Tomatis, Alfred. Pourqoi Mozart? (Diffusion, Hachette, 1991).

11.      Rauscher, F. H., Shaw, G. L. & Ky, K. N. Music and spatial task performance. Nature 365, (1993).

12.      Cong, A. FROM MOZART TO MYTHS: Dispelling the ‘Mozart Effect’. Young Sci. J. 49–53 (2014).

13.      California Childcare Health Program, UCSF School of Nursing. Building Baby’s Intelligence: Why Infant Stimulation Is So Important. (2002).

14.      Walker, S. P. et al. Cognitive, psychosocial, and behaviour gains at age 31 years from the Jamaica early childhood stimulation trial. J. Child Psychol. Psychiatry 63, 626–635 (2022).

15.      Román-Caballero, R., Vadillo, M. A., Trainor, L. J. & Lupiáñez, J. Please don’t stop the music: A meta-analysis of the cognitive and academic benefits of instrumental musical training in childhood and adolescence. Educ. Res. Rev. 35, 100436 (2022).

16.      Zimmerman, F. J., Christakis, D. A. & Meltzoff, A. N. Associations between Media Viewing and Language Development in Children Under Age 2 Years. J. Pediatr. 151, 364–368 (2007).

17.      Pashler, H., McDaniel, M., Rohrer, D. & Bjork, R. Learning Styles: Concepts and Evidence. Psychol. Sci. Public Interest 9, 105–119 (2008).

18.      Cuevas, J. Is learning styles-based instruction effective? A comprehensive analysis of recent research on learning styles. Theory Res. Educ. 13, 308–333 (2015).

19.      Riener, C. & Willingham, D. The Myth of Learning Styles. Change Mag. High. Learn. 42, 32–35 (2010).

20.      Newton, P. M. & Salvi, A. How Common Is Belief in the Learning Styles Neuromyth, and Does It Matter? A Pragmatic Systematic Review. Front. Educ. 5, 602451 (2020).

21.      The Telltale Hand. Dana Foundation https://www.dana.org/article/the-telltale-hand/.

22.      Trubek, A. Sorry, Graphology Isn’t a Real Science. JSTOR Daily https://daily.jstor.org/graphology-isnt-real-science/ (2017).

23.      Dazzi, C. & Pedrabissi, L. Graphology and Personality: An Empirical Study on Validity of Handwriting Analysis. Psychol. Rep. 105, 1255–1268 (2009).

24.      Bandhu, K. C., Litoriya, R., Khatri, M., Kaul, M. & Soni, P. Integrating graphology and machine learning for accurate prediction of personality: a novel approach. Multimed. Tools Appl. (2023) doi:10.1007/s11042-023-15567-8.

25.      Small Handwriting | Parkinson’s Foundation. https://www.parkinson.org/understanding-parkinsons/non-movement-symptoms/small-handwriting.

26.      Dyslexia FAQ. Yale Dyslexia https://dyslexia.yale.edu/dyslexia/dyslexia-faq/.

27.      Shaywitz, S. E. & Shaywitz, B. A. Dyslexia (Specific Reading Disability).

28.      Cornell, J. M. Spontaneous mirror-writing in children. Can. J. Psychol. Rev. Can. Psychol. 39, 174–179 (1985).

29.      Brooks, A. D., Berninger, V. W. & Abbott, R. D. Letter Naming and Letter Writing Reversals in Children With Dyslexia: Momentary Inefficiency in the Phonological and Orthographic Loops of Working Memory. Dev. Neuropsychol. 36, 847–868 (2011).

30.      Signs of Dyslexia. Yale Dyslexia https://dyslexia.yale.edu/dyslexia/signs-of-dyslexia/.

31.      Prasad, D. & Bainbridge, W. A. The Visual Mandela Effect as Evidence for Shared and Specific False Memories Across People. Psychol. Sci.

32.      Haber, R. N. Twenty years of haunting eidetic imagery: where’s the ghost? Behav. Brain Sci. 2, 583–594 (1979).

33.      Gray, C. R. & Gummerman, K. The Enigmatic Eidetic Image: A Critical Examination of Methods, Data, and Theories.

34.      Report Urges Caution in Handling and Relying Upon Eyewitness Identifications in Criminal Cases, Recommends Best Practices for Law Enforcement and Courts | National Academies. https://www.nationalacademies.org/news/2014/10/report-urges-caution-in-handling-and-relying-upon-eyewitness-identifications-in-criminal-cases-recommends-best-practices-for-law-enforcement-and-courts.

35.      Herculano-Houzel, S. et al. The elephant brain in numbers. Front. Neuroanat. 8, (2014).

36.      Hines, T. Neuromythology of Einstein’s brain. Brain Cogn. 88, 21–25 (2014).

37.      Gould, S. The Mismeasure of Man. (WW Northon & Company, 1996).

38.      McNeill, L. The Statistician Who Debunked Sexist Myths About Skull Size and Intelligence. Smithsonian Magazine https://www.smithsonianmag.com/science-nature/alice-lee-statistician-debunked-sexist-myths-skull-size-intelligence-180971241/.

39.      Owen, A. M. et al. Putting brain training to the test. Nature 465, 775–778 (2010).

40.      Lumosity to Pay $2 Million to Settle FTC Deceptive Advertising Charges for Its “Brain Training” Program. Federal Trade Commission https://www.ftc.gov/news-events/news/press-releases/2016/01/lumosity-pay-2-million-settle-ftc-deceptive-advertising-charges-its-brain-training-program (2016).

41.      sarah. Accounting for taste. Curious https://www.science.org.au/curious/people-medicine/accounting-taste (2016).

42.      Caballar, R. D. Do Different Parts of the Tongue Taste Different Things? https://www.brainfacts.org:443/thinking-sensing-and-behaving/taste/2018/do-different-parts-of-the-tongue-taste-different-things-010319.

Cover photo made by Catrina Hacker in Biorender.com using image by GraphicMama-team from Pixabay.

 

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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.

 

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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.   Trivia Playing cards 3 FB 500x419 - Neuro MythBusters: The truth behind 10 common myths about your brain 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.   AE Warrior Store 300x200 - Neuro MythBusters: The truth behind 10 common myths about your brain

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10 Big Unanswered Questions in Neuroscience Part 1

10 Big Unanswered Questions in Neuroscience Part 1


August 30, 2023 | by Sophie Liebergall, 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 AE Warriors, caregivers, friends, family, loved ones and medical personnel we have been unwittingly thrown into a world we may or may not have been at all curious about previously. No matter where we are in our individual AE journeys, neurology and neuroscience are terms we all know well. AE may have sent us on this journey deep into the amazing world of neurology, but we all have found out just how interesting and fascinating our brains can be! In the first of a two-part series, Sophie Liebergall has helped us to better understand 10 big unanswered questions in neuroscience! We hope you enjoy this and look forward to Part II.

——

Introduction

 

This past year, astrophysicists used NASA’s James Webb Space telescope to observe a star that is over 33 billion light years away from earth. Back on earth, particle physicists used the Large Hadron Collider in Switzerland to confirm the existence of incomprehensibly tiny subatomic particles. But despite these astounding scientific and technologic advances, we still have a lot to learn about what is going on in the organ inside our own skulls! In part one of what will be a two-part series, we discuss a few of the fundamental questions about the brain that have remained mysterious to neuroscientists.  

1. Where do our memories go when we put them in long-term storage?

For a brain to perform complex tasks, such as telling the body to execute a series of movements or being able to recognize and evade a predator, it must be able to recall information that was gathered during previous experiences. Neuroscience researchers divide memory storage into two stages: short-term memory and long-term memory.1 When the brain senses something in its environment, it can hold that information for a few seconds to minutes as a short-term memory.2 Over time, scientists have gathered clues that short-term memories (at least those of conscious facts and events) are stored in the hippocampus, an almond-size region nestled on either side below the brain’s surface on either side.3 But sometimes the brain needs to hold onto information for longer periods of time (up to a lifetime) so that is can be recalled later. We’re fairly certain that long-term memories aren’t stored in the hippocampus; but where exactly these long-term memories go remains a mystery. Several recent studies seem to suggest that, unlike short-term memories, long-term memories may be widely distributed in the cerebral cortex (the large surface of the brain that is used for complex thought), with different features of the memory spread across different regions.4,5 You can read more about the process of memory formation and how it can go wrong in some diseases here!

2. Why do we need to sleep?

Evolution has shaped the human body into an elegant and efficient machine, with a versatile digestive system, a continuously beating heart, and a thinking brain. However, one of our basic biologic functions, sleep, seems like something that should have been stamped out by evolution many generations ago. When we sleep, we are essentially unconscious for up to one-third of the day. For our ancestors, this is a time when they were particularly vulnerable to predators and unable to gather food. So why, then, has sleep survived the test of natural selection? 

Sleep is absolutely necessary for all animals (from armadillos, who sleep up to twenty hours each day, to giraffes who need just two hours of sleep a day).6 After just a couple days of total sleep deprivation, many people will start to show symptoms of psychosis.7 And if the sleep deprivation continues, it can even be deadly. In a study from the 1980s, which would likely be forbidden under contemporary ethical standards, researchers subjected a group of rats to total sleep deprivation. All of the rats died by the 32nd day of the study.8 The ultrarare genetic disease Fatal familial insomnia gives further insight into the danger of insomnia in humans. Patients with Fatal familial insomnia slowly lose their ability to fall and stay asleep.9 Tragically, these patients always die soon after they completely lose their ability to sleep.

Sleep is important for a variety of our body and brain’s normal functions: solidifying events that occurred during the day as long term memories,10 recalibrating the strength of the connections between brain cells,11,12 balancing the hormones that control our appetites and metabolism,13 and clearing the toxic byproducts of brain cell activity.14 But scientists still do not know what function (or functions) of sleep are the primary reason why it is essential for survival. Read more about the possible hypothesis for why we sleep in this PNK article!

3. Why do we dream?

Even more mysterious than the question of why we sleep is the question of why we dream. Though sleep has been a target of neuroscience research for decades, there are inherent challenges to studying dreaming that prevent us from using some of the traditional tools of neuroscience research. The study of dreams still largely relies on dream reports, when a person wakes up and verbally reports or writes down whether they were dreaming and what their dream was about. Dream reports are often unreliable because of the bias and imperfect memory of the dreamer. This can prevent researchers from making objective scientific conclusions from dream reports. Furthermore, all animals clearly display some form of sleep, but there is no conclusive evidence that other animals have dreams. This makes it challenging or even impossible to study dreaming using laboratory animals, which generally allow us to perform important experiments that would take too long or be too dangerous in humans.

Though we have recently developed more sophisticated tools that allow us to correlate the dream reports of humans with measures of brain activity, many of these studies have only raised more questions. It was once thought that dreaming only occurred during rapid eye movement (REM) sleep, the phase of sleep during which brain waves look most similar to the waking state. But more recent evidence suggests that dreams occur during both REM and non-REM sleep (though dreams that occur during REM sleep do seem to be more vivid than the dreams that occur during non-REM sleep).15,16

Another strange aspect of dreaming is called the dream-lag effect, which describes a phenomenon in which you’re most likely to dream about real life events that happened 5-7 days ago.17 And we still don’t have a clue as to why some people are prone to sleepwalking: a state in which individuals are clearly deep in a dream, but somehow are aware of their surroundings enough to navigate a space, consume food, or even drive a motor vehicle.18 You can learn more about the neuroscience of dreaming here!

4. How do the general anesthesia drugs used during surgery make you unconscious?

General anesthetics, the class of drugs which cause temporary unconsciousness, have made it possible for doctors to perform lifesaving and life-altering surgeries that would otherwise be impossibly painful for patients. General anesthetics are some of the most safe and reliable medications that are administered by doctors. But we still don’t have an understanding of where general anesthetics act in the brain, or of what their ultimate effects are on brain processes. Even though anesthetic drugs all have the same end effect of making a patient unconscious, anesthetics can come in all different shapes and sizes. Some, like xenon gas, have a structure as simple a single atom, whereas others, like alfaxalone, have a complex structure with many branches and rings.19,20  Some are inhaled as a gas, whereas others are injected into the bloodstream. And, strangely, general anesthetics don’t just sedate animals with complex brains like humans. They also impair the movement and environmental responsiveness of plants and even single-celled organisms!21 You can learn more about the possible mechanisms of general anesthetics and their relationship with sleep in this PNK article.

5. How does each area of the brain know what function it is supposed to perform?

In the mid-19th century, in the early days of modern neuroscience, the French physician Paul Broca learned of a patient with a unique neurologic condition. This patient had lost the ability to generate speech, but had somehow maintained the ability to comprehend speech.22 When this patient died, Broca performed an autopsy, where he discovered that the patient had sustained an injury to a very specific area of their frontal lobe. Broca’s work inspired other physicians of his age to look for injuries to specific areas of their brains in their patients with specific neurologic symptoms. If multiple patients with the same symptoms had an injury in the same region, then it could be assumed that an injury to that region was the cause of the symptom. These studies of localized brain injuries led neurologists to believe that different regions of the brain are responsible for the different functions of the brain. For example, one region of the brain is required for the ability to move a hand, whereas another region of the brain is required to read language.

Modern-day neuroscientists and neurologists take the idea that certain regions of the brain are responsible for certain functions for granted. But there is a great deal of complexity to this picture that we have yet to understand. The exact mapping of the functions of the brain can vary between individuals – sometimes in dramatic ways. For example, most people have the speech control area of their brain somewhere on the left side of their brain. But occasionally, in people who are left-handed, the speech control area is instead found on the right side.23 This variability between individuals suggests that the process of assigning a function to a specific brain region doesn’t follow a simple blueprint. But we still don’t know how the brain knows which functions it needs to perform. And we also don’t know each function is assigned to a particular region of the brain.

Stay tuned for part two with five more big unanswered questions in neuroscience coming this summer!

References

1.         Cowan, N. What are the differences between long-term, short-term, and working memory? Prog Brain Res 169, 323–338 (2008).

2.         Atkinson, R. C. & Shiffrin, R. M. Human Memory: A Proposed System and its Control Processes11This research was supported by the National Aeronautics and Space Administration, Grant No. NGR-05-020-036. The authors are indebted to W. K. Estes and G. H. Bower who provided many valuable suggestions and comments at various stages of the work. Special credit is due J. W. Brelsford who was instrumental in carrying out the research discussed in Section IV and whose overall contributions are too numerous to report in detail. We should also like to thank those co-workers who carried out a number of the experiments discussed in the latter half of the paper; rather than list them here, each will be acknowledged at the appropriate place. in Psychology of Learning and Motivation (eds. Spence, K. W. & Spence, J. T.) vol. 2 89–195 (Academic Press, 1968).

3.         Duff, M. C., Covington, N. V., Hilverman, C. & Cohen, N. J. Semantic Memory and the Hippocampus: Revisiting, Reaffirming, and Extending the Reach of Their Critical Relationship. Frontiers in Human Neuroscience 13, (2020).

4.         Yadav, N. et al. Prefrontal feature representations drive memory recall. Nature 608, 153–160 (2022).

5.         Roy, D. S. et al. Brain-wide mapping reveals that engrams for a single memory are distributed across multiple brain regions. Nat Commun 13, 1799 (2022).

6.         Campbell, S. S. & Tobler, I. Animal sleep: a review of sleep duration across phylogeny. Neurosci Biobehav Rev 8, 269–300 (1984).

7.         Waters, F., Chiu, V., Atkinson, A. & Blom, J. D. Severe Sleep Deprivation Causes Hallucinations and a Gradual Progression Toward Psychosis With Increasing Time Awake. Front Psychiatry 9, 303 (2018).

8.         Everson, C. A., Bergmann, B. M. & Rechtschaffen, A. Sleep deprivation in the rat: III. Total sleep deprivation. Sleep 12, 13–21 (1989).

9.         Fatal Familial Insomnia – Symptoms, Causes, Treatment | NORD. https://rarediseases.org/rare-diseases/fatal-familial-insomnia/.

10.      Diekelmann, S. & Born, J. The memory function of sleep. Nat Rev Neurosci 11, 114–126 (2010).

11.       Frank, M. G. Erasing Synapses in Sleep: Is It Time to Be SHY? Neural Plast 2012, 264378 (2012).

12.      Tononi, G. & Cirelli, C. Sleep function and synaptic homeostasis. Sleep Medicine Reviews 10, 49–62 (2006).

13.      Sharma, S. & Kavuru, M. Sleep and Metabolism: An Overview. Int J Endocrinol 2010, 270832 (2010).

14.      Xie, L. et al. Sleep Drives Metabolite Clearance from the Adult Brain. Science 342, 10.1126/science.1241224 (2013).

15.      Foulkes, W. D. Dream reports from different stages of sleep. J Abnorm Soc Psychol 65, 14–25 (1962).

16.      Hobson, J. A., Pace-Schott, E. F. & Stickgold, R. Dreaming and the brain: toward a cognitive neuroscience of conscious states. Behav Brain Sci 23, 793–842; discussion 904-1121 (2000).

17.      Eichenlaub, J. et al. The nature of delayed dream incorporation (‘dream‐lag effect’): Personally significant events persist, but not major daily activities or concerns. J Sleep Res 28, e12697 (2019).

18.      Cochen De Cock, V. Sleepwalking. Curr Treat Options Neurol 18, 6 (2016).

19.      PubChem. Alfaxalone. https://pubchem.ncbi.nlm.nih.gov/compound/104845.

20.      PubChem. Xenon. https://pubchem.ncbi.nlm.nih.gov/compound/23991.

21.      Kelz, M. B. & Mashour, G. A. The Biology of General Anesthesia from Paramecium to Primate. Current Biology 29, R1199–R1210 (2019).

22.      Dronkers, N. F., Plaisant, O., Iba-Zizen, M. T. & Cabanis, E. A. Paul Broca’s historic cases: high resolution MR imaging of the brains of Leborgne and Lelong. Brain 130, 1432–1441 (2007).

23.      Packheiser, J. et al. A large-scale estimate on the relationship between language and motor lateralization. Sci Rep 10, 13027 (2020).

Cover photo made with biorender.com.

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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.

 

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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.   Trivia Playing cards 3 FB 500x419 - 10 Big Unanswered Questions in Neuroscience Part 1 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.   AE Warrior Store 300x200 - 10 Big Unanswered Questions in Neuroscience Part 1

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A link between COVID-19 and autoimmune encephalitis?

A link between COVID-19 and autoimmune encephalitis?


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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Your generous Donations allow IAES to continue our important work and save lives!

 

 

Tabitha Orth 300x218 - A link between COVID-19 and autoimmune encephalitis?

 

 

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.

 

guidestar platinum logo 300x300 1 e1605914935941 - A link between COVID-19 and autoimmune encephalitis?

 

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.   Trivia Playing cards 3 FB 500x419 - A link between COVID-19 and autoimmune encephalitis? 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.   AE Warrior Store 300x200 - A link between COVID-19 and autoimmune encephalitis?

Be a part of the solution by supporting IAES with a donation today.

why zebra - Aphasia as a Symptom of Autoimmune Encephalitis
image - A link between COVID-19 and autoimmune encephalitis?
Who do you become when you are sleepy?

Who do you become when you are sleepy?


July 12, 2023 | by
 Lindsay Ejoh, 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/

For all of us with AE, sleep can be an ongoing issue whether it be too little, too much, interrupted sleep cycles and everything in-between! Sleep issues often go hand in hand with an AE diagnosis. PNK author Lindsay Ejoh wrote this piece for the PNK weekly series and graciously gave IAES permission to publish it in our monthly series. We hope you find this as informative as we have!

——-

Introduction

Sleep experts recommend that most adults get 7-9 hours of good-quality sleep each day1,2 to avoid the myriad of issues that can occur when the brain and body are sleep-deprived. We all know what it is like to be tired. We may feel cranky and sluggish, as well as physically and mentally exhausted. We may also face issues with memory and attention3, emotional regulation, and diminished sex drive4,11. It is hard to feel like yourself when sleep-deprived- so what occurs in the brain during sleep deprivation, and how does it affect our daily lives?

Memory

As a child, I remember learning to trick my mother, a sleep-deprived emergency room nurse that worked the night shift, by asking her for permission to do things while she was coming home from work in the mornings, half-asleep. When I’d approach her in bed to ask for permission to go on a sleepover across town or to eat food we were saving for an occasion, she would always say yes. Eventually, she caught on, and warned me against waiting until she was sleepy to get my way, but the reason it worked at first is because sleep deprivation impacts decision-making5.

It also affects short-term memory, so as a result, my mother would never remember giving her approval. Long-term memory is affected as well, as sleep is very important for consolidation, or storage of memories. This is also why you may not remember everything you studied after cramming for an exam all night.

Reaction time

Being awake is not the same thing as being alert. When we are sleepy, we tend to have slow reaction times, or time to respond to a change in our environment. This can have devastating effects for those who operate cars and other heavy machinery while sleepy and can be dangerous for people who work with under these conditions. Sleep deprivation can make you 70% more likely to get into work-place accidents, which happen at higher rates in people with insomnia6. Additionally, missing just a couple hours of sleep can substantially increase the risk of having a car accident7. It may seem in the moment like you can stay awake while driving, but as explained in a previous NeuroKnow article, going 24 hours without sleep can be just as dangerous as driving drunk.

Changes in the brain

Sleep deprivation impacts many regions of your brain, but two are of notable importance: amygdala and prefrontal cortex.

Amygdala

Scientists can measure brain activity by taking functional magnetic resonance imaging (fMRI) scans. Using this method, researchers found that sleep deprivation leads to a hyperactive amygdala3. The amygdala is critical for emotional regulation, and its dysfunction may be related mood issues that occur from sleep deprivation. A single sleepless night can trigger a 30% increase in anxiety levels9, due to the loss of ability to regulate emotions or deal with stress, and people with anxiety disorders also have hyperactive amygdalae when faced with unpleasant changes in their environment10. In other words, sleep deprivation causes disruption in emotional centers in the brain, which is linked to increased anxiety.

Prefrontal Cortex

Another brain region with altered activity during sleep deprivation is the prefrontal cortex, which is important for rational thinking and decision-making3.  This region has decreased activity during sleep deprivation, and these activity patterns are associated with impaired judgment, a common symptom of sleep deprivation.  

Chronic sleep deprivation and sleep apnea

Most of us have experienced sleep-deprivation in our lives, but for some, it is the norm. People who suffer from inadequate sleep for a prolonged period of time (weeks to years) are in a state of chronic sleep deprivation6. Many people wake up in the mornings feeling symptoms of sleep deprivation despite getting a long night of sleep, which may be indicative of a sleep disorder known as sleep apnea. Patients with sleep apnea wake up over a hundred times throughout the night, due to difficulty breathing12. A research lab in Australia found that sleep apnea patients have altered brain activity during wakefulness13. Certain parts of their brains “go offline” briefly, despite being awake, and brain activity resembles that of a sleeping person14. Sleep disorder patients aren’t the only ones that experience this- it can occur from other forms of sleep deprivation. When sleep intrudes into the waking brain, this can lead to errors in tasks like driving. Despite being abnormal for humans, this brain activity phenomenon is not uncommon in the animal kingdom. Some animals like seals and dolphins sleep with half of their brains “awake” while the other halves are “asleep.”

Conclusion

Neuroscientists are working to understand the neurobiological consequences of sleep deprivation, so that we can inform and treat people who must continue to perform daily tasks despite running on little sleep. Though harmful for the brain, sleep deprivation is a normal part of daily life for 30-40% of US adults15, including parents of newborns, procrastinating college students, night-shift workers, military and medical personnel, sleep disorder patients, and many others. We live in a sleep-deprived society, where people are often celebrated for trading rest for productivity. I encourage you to take this as your sign to go to bed early tonight- you are not yourself when you’re sleepy!

References

  1. Watson NF, Badr MS, Belenky G, et al. Recommended amount of sleep for a healthy adult: a joint consensus statement of the American Academy of Sleep Medicine and Sleep Research Society. Sleep. 2015;38(6):843–844.
  2. Consensus Conference Panel, Watson, N. F., Badr, M. S., Belenky, G., Bliwise, D. L., Buxton, O. M., Buysse, D., Dinges, D. F., Gangwisch, J., Grandner, M. A., Kushida, C., Malhotra, R. K., Martin, J. L., Patel, S. R., Quan, S. F., Tasali, E., Non-Participating Observers, Twery, M., Croft, J. B., Maher, E., … Heald, J. L. (2015). Recommended Amount of Sleep for a Healthy Adult: A Joint Consensus Statement of the American Academy of Sleep Medicine and Sleep Research Society. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine, 11(6), 591–592. https://doi.org/10.5664/jcsm.4758
  3. Krause, A. J., Simon, E. B., Mander, B. A., Greer, S. M., Saletin, J. M., Goldstein-Piekarski, A. N., & Walker, M. P. (2017). The sleep-deprived human brain. Nature reviews. Neuroscience, 18(7), 404–418. https://doi.org/10.1038/nrn.2017.55
  4. Chen, K. F., Liang, S. J., Lin, C. L., Liao, W. C., & Kao, C. H. (2016). Sleep disorders increase risk of subsequent erectile dysfunction in individuals without sleep apnea: a nationwide population-base cohort study. Sleep medicine, 17, 64–68. https://doi.org/10.1016/j.sleep.2015.05.018
  5. Rasch, B., & Born, J. (2013). About sleep’s role in memory. Physiological reviews, 93(2), 681–766. https://doi.org/10.1152/physrev.00032.2012
  6. Suni, E. (2023, April 5). The relationship between sleep and workplace accidents. Sleep Foundation. Retrieved April 26, 2023, from https://www.sleepfoundation.org/excessive-sleepiness/workplace-accidents#references-197012
  7. AAA. (2016, December 6). Missing 1-2 hours of sleep doubles crash risk: Study reveals the dangers of getting less than 7 hours of sleep. ScienceDaily. Retrieved April 26, 2023 from www.sciencedaily.com/releases/2016/12/161206110235.htm
  8. Wong, M. M., Robertson, G. C., & Dyson, R. B. (2015). Prospective relationship between poor sleep and substance-related problems in a national sample of adolescents. Alcoholism, clinical and experimental research, 39(2), 355–362. https://doi.org/10.1111/acer.12618
  9. Ben Simon, E., Rossi, A., Harvey, A. G., & Walker, M. P. (2020). Overanxious and underslept. Nature human behaviour, 4(1), 100–110. https://doi.org/10.1038/s41562-019-0754-8
  10. Etkin, A., & Wager, T. D. (2007). Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. The American journal of psychiatry, 164(10), 1476–1488. https://doi.org/10.1176/appi.ajp.2007.07030504
  11. Sleep Center of Middle Tennessee. (2022, June 22). Sleep deprivation and its effects on the brain. Sleep Centers of Middle Tennessee. Retrieved April 26, 2023, from https://sleepcenterinfo.com/blog/sleep-deprivation-effects-on-brain/
  12. Slowik, J. M., Sankari, A., & Collen, J. F. (2022). Obstructive Sleep Apnea. In StatPearls. StatPearls Publishing.
  13. Hung, C. S., Sarasso, S., Ferrarelli, F., Riedner, B., Ghilardi, M. F., Cirelli, C., & Tononi, G. (2013). Local experience-dependent changes in the wake EEG after prolonged wakefulness. Sleep, 36(1), 59–72. https://doi.org/10.5665/sleep.2302
  14. Mannix, L. (2019, January 27). Your brain could be sleeping … even while you’re awake. The Sydney Morning Herald. Retrieved April 26, 2023, from https://www.smh.com.au/national/your-brain-could-be-sleeping-even-while-you-re-awake-20190124-p50tgg.html
  15. Centers for Disease Control and Prevention. (2022, November 2). Adults – sleep and sleep disorders. Centers for Disease Control and Prevention. Retrieved April 26, 2023, from https://www.cdc.gov/sleep/data-and-statistics/adults.html

Cover image by Karollyne Videira Hubert on Unsplash

References

  1. Zeng, J. & James, L. C. Intracellular antibody immunity and its applications. PLOS Pathog. 16, e1008657 (2020).
  2. CDC. COVID-19 and Your Health. Centers for Disease Control and Preventionhttps://www.cdc.gov/coronavirus/2019-ncov/your-health/about-covid-19/antibodies.html (2020).
  3. Elkon, K. & Casali, P. Nature and functions of autoantibodies. Nat. Clin. Pract. Rheumatol. 4, 491–498 (2008).
  4. Hermetter, C., Fazekas, F. & Hochmeister, S. Systematic Review: Syndromes, Early Diagnosis, and Treatment in Autoimmune Encephalitis. Front. Neurol. 9, 706 (2018).
  5. Graus, F. et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 15, 391–404 (2016).
  6. Anti-NMDA receptor encephalitis. Autoimmune Encephalitis Alliance https://aealliance.org/ae-types/anti-nmda-receptor-encephalitis/.
  7. Anti-AMPAR encephalitis. Autoimmune Encephalitis Alliance https://aealliance.org/ae-types/anti-ampar-encephalitis/.
  8. Anti-GABAA receptor encephalitis. Autoimmune Encephalitis Alliance https://aealliance.org/ae-types/anti-gabaa-receptor-encephalitis/.
  9. Anti-GABAB receptor encephalitis. Autoimmune Encephalitis Alliance https://aealliance.org/ae-types/anti-gabab-receptor-encephalitis/.
  10. LGI1-antibody encephalitis. Autoimmune Encephalitis Alliance https://aealliance.org/ae-types/lgi1-antibody-encephalitis/.
  11. CASPR2-antibody encephalitis. Autoimmune Encephalitis Alliance https://aealliance.org/ae-types/caspr2-antibody-encephalitis/.
  12. Malter, M. P., Helmstaedter, C., Urbach, H., Vincent, A. & Bien, C. G. Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis. Ann. Neurol. 67, 470–478 (2010).
  13. Voltz, R. & Eichen, J. A Serologic Marker of Paraneoplastic Limbic and Brain-Stem Encephalitis in Patients with Testicular Cancer. N. Engl. J. Med. (1999).
  14. Graus, F. & Dalmau, J. Paraneoplastic neurological syndromes in the era of immune-checkpoint inhibitors. Nat. Rev. Clin. Oncol. 16, 535–548 (2019).
  15. Lancaster, E. Encephalitis and antibodies to synaptic and neuronal cell surface proteins. (2011).

 

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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.

 

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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.   Trivia Playing cards 3 FB 500x419 - Who do you become when you are sleepy? 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.   AE Warrior Store 300x200 - Who do you become when you are sleepy?

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What are intracellular and extracellular antibodies and what do the differences mean for patients with autoimmune encephalitis?

What are intracellular and extracellular antibodies and what do the differences mean for patients with autoimmune encephalitis?


June 14, 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/

——-

Introduction

There are many subtypes of autoimmune encephalitis (AE) that vary in their causes, the symptoms that patients experience, and what treatments are most effective. One of several factors that distinguish these different subtypes of AE is whether they involve intracellular or extracellular antibodies. In this post we will explore exactly what these terms mean and how they contribute to the differences between types of AE.

cell surface intracellular for website dalmau - What are intracellular and extracellular antibodies and what do the differences mean for patients with autoimmune encephalitis?

N Engl J Med 2018;378:840-51. DOI: 10.1056/NEJMra1708712 Copyright © 2018 Massachusetts Medical Society

What are intracellular and extracellular antibodies?

When a virus or bacteria enters our body, our immune system mounts an attack to destroy the foreign invader and protect us from harm. If our immune system is like an army ready for battle, then antibodies are like the scouts sent ahead of the battalion, patrolling for signs of a threat. Just like security personnel might scan ID badges to determine who is allowed in a building, each antibody is tasked with looking for a particular feature of something that the body has deemed harmful, called an antigen1. You might have heard antibodies discussed in reference to COVID-19, where infection with COVID-19 or vaccination can cause your body to produce antibodies that recognize features of the COVID-19 virus2. When antibodies are already present in the body, they can recognize the newly-arrived COVID-19 virus and mount an attack more quickly, helping to avoid a more serious infection.

This ability to quickly mount a defense against a threat before getting too sick is what makes antibodies an important part of our body’s immune system army. However, antibodies are only helpful if they recognize and defend against foreign substances that are harmful. Unfortunately, this isn’t the case in AE. Patients with AE have antibodies that bind to proteins found in their own cells, called autoantibodies (the prefix “auto” means self, so autoantibodies are antibodies that bind the body’s own proteins)3. Autoantibodies trigger the body’s immune system to attack itself, leading to the many symptoms of AE.

Each antibody can recognize only a small part of a whole cell, and there are many different parts of a cell that an antibody can recognize. What distinguishes extracellular from intracellular antibodies is whether their antigen (the ID badge they’re looking for) is inside or outside of the cell1,4. Extracellular antibodies recognize antigens that are on the outer surface of the cell (“extra” meaning outside). Conversely, intracellular antibodies recognize antigens that are inside the cell (“intra” meaning inside). The intracellular antibodies inside the cell trigger a different set of immune reactions than the extracellular antibodies outside of the cell.

Which kinds of AE involve intracellular versus extracellular antibodies?

Subtypes of AE are distinguished by what kind of autoantibody a patient has4, which is why they are typically named after the antigen that the autoantibody recognizes. For example, patients with anti-NMDAR AE have antibodies that recognize NMDA receptors. Types of AE associated with antigens outside the cell involve extracellular antibodies and types of AE associated with antigens inside the cell involve intracellular antibodies.

Many of the most common subtypes of AE involve extracellular antibodies4,5. Most are associated with antibodies that recognize a kind of protein that sits on the surface of the cell called a receptor. Receptors recognize and bind specific molecules and send signals that tell the cell how to respond. The receptors on neurons, a type of brain cell, are especially important because one neuron communicates with another by releasing molecules that can be recognized by the other neuron’s receptors. When antibodies bind the receptors, they activate an immune response and disrupt the ability of those receptors to participate in neural signaling. This leads to the many neurological symptoms of AE. Subtypes with these kinds of antibodies include anti-NMDAR AE6, anti-AMPAR AE7, anti-mGLUR5 antibody encephalitis4,5, GlyR antibody encephalitis4, anti-GABAa AE8, and anti-GABAb AE9. Several other extracellular antibodies associated with AE have antigens that sit on the cell’s surface and help with neuronal signaling but aren’t receptors themselves. Subtypes of AE with these kinds of antibodies include LGI1-antibody encephalitis10, CASPR2-antibody encephalitis11, and DPPX-antibody encephalitis4,5.

Subtypes of AE associated with intracellular antibodies are less common4,5. One example is GAD-antibody encephalitis12. Patients with this form of AE have antibodies that target Glutamic Acid Decarboxylase (GAD), a protein found inside the cell that is needed to synthesize GABA, a special type of molecule that is necessary for some kinds of neural signaling. Other subtypes of AE that target intracellular proteins are anti-Hu encephalitis5, and Ma2-antibody encephalitis13.

How are subtypes of AE associated with intracellular antibodies different from subtypes of AE associated with extracellular antibodies?

One big distinction is that most subtypes of AE associated with intracellular antibodies are also associated with tumors4. These subtypes of AE are called paraneoplastic. Paraneoplastic AE can occur when tumor cells express proteins on their surface that are normally expressed elsewhere. Sometimes this includes proteins that are normally found inside healthy neurons. To recognize and fight the tumor, the body’s immune system creates antibodies that recognize these proteins. These antibodies don’t distinguish the proteins found in the tumor cells from the healthy proteins found in neurons, so when they reach the brain, they also bind the naturally-occurring proteins in neurons and trigger the immune response responsible for the symptoms of AE14.

Patients with subtypes of AE associated with intracellular antibodies also tend to have poorer outcomes and respond worse to immunotherapy than patients with subtypes associated with extracellular antibodies4,15. This is because many of the symptoms of AE associated with extracellular antibodies are thought to result from the antibodies disrupting the normal function of the cell-surface proteins that they target. Conversely, the presence of intracellular autoantibodies typically accompanies an immune response against neurons more broadly that results in neuronal death. This means that successful treatment can often reverse symptoms of AE resulting from extracellular antibodies, as limiting the action of the antibodies allows the neurons to function normally, whereas even after treatment, symptoms do not typically reverse in subtypes of AE associated with intracellular antibodies, as many neurons have already died. For patients with paraneoplastic AE, removing the tumor is also an important step toward relieving symptoms15.

Despite general differences in outcomes for subtypes of AE associated with extracellular and intracellular antibodies, early detection and treatment are key to successful outcomes for all subtypes of AE4. Determining which type of AE a patient has can have an important impact on how doctors choose to treat and manage the disease. This distinction is also important for researchers developing new treatments and possible cures, as approaches that might work for one type of AE may not work for others. Determining which patients will be most receptive to a particular new treatment leads to better outcomes for clinical trials, which means more treatment options for all patients.

References

  1. Zeng, J. & James, L. C. Intracellular antibody immunity and its applications. PLOS Pathog. 16, e1008657 (2020).
  2. CDC. COVID-19 and Your Health. Centers for Disease Control and Preventionhttps://www.cdc.gov/coronavirus/2019-ncov/your-health/about-covid-19/antibodies.html (2020).
  3. Elkon, K. & Casali, P. Nature and functions of autoantibodies. Nat. Clin. Pract. Rheumatol. 4, 491–498 (2008).
  4. Hermetter, C., Fazekas, F. & Hochmeister, S. Systematic Review: Syndromes, Early Diagnosis, and Treatment in Autoimmune Encephalitis. Front. Neurol. 9, 706 (2018).
  5. Graus, F. et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 15, 391–404 (2016).
  6. Anti-NMDA receptor encephalitis. Autoimmune Encephalitis Alliance https://aealliance.org/ae-types/anti-nmda-receptor-encephalitis/.
  7. Anti-AMPAR encephalitis. Autoimmune Encephalitis Alliance https://aealliance.org/ae-types/anti-ampar-encephalitis/.
  8. Anti-GABAA receptor encephalitis. Autoimmune Encephalitis Alliance https://aealliance.org/ae-types/anti-gabaa-receptor-encephalitis/.
  9. Anti-GABAB receptor encephalitis. Autoimmune Encephalitis Alliance https://aealliance.org/ae-types/anti-gabab-receptor-encephalitis/.
  10. LGI1-antibody encephalitis. Autoimmune Encephalitis Alliance https://aealliance.org/ae-types/lgi1-antibody-encephalitis/.
  11. CASPR2-antibody encephalitis. Autoimmune Encephalitis Alliance https://aealliance.org/ae-types/caspr2-antibody-encephalitis/.
  12. Malter, M. P., Helmstaedter, C., Urbach, H., Vincent, A. & Bien, C. G. Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis. Ann. Neurol. 67, 470–478 (2010).
  13. Voltz, R. & Eichen, J. A Serologic Marker of Paraneoplastic Limbic and Brain-Stem Encephalitis in Patients with Testicular Cancer. N. Engl. J. Med. (1999).
  14. Graus, F. & Dalmau, J. Paraneoplastic neurological syndromes in the era of immune-checkpoint inhibitors. Nat. Rev. Clin. Oncol. 16, 535–548 (2019).
  15. Lancaster, E. Encephalitis and antibodies to synaptic and neuronal cell surface proteins. (2011).

 

IAES PNK Partnership logo 500x419 - What are intracellular and extracellular antibodies and what do the differences mean for patients with autoimmune encephalitis?

Click here or the image below to subscribe to our mailing list:

subscribe - Halloween Ideas

Your generous Donations allow IAES to continue our important work and save lives!

 

 

Tabitha Orth 300x218 - What are intracellular and extracellular antibodies and what do the differences mean for patients with autoimmune encephalitis?

 

 

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.

 

guidestar platinum logo 300x300 1 e1605914935941 - What are intracellular and extracellular antibodies and what do the differences mean for patients with autoimmune encephalitis?

 

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.   Trivia Playing cards 3 FB 500x419 - What are intracellular and extracellular antibodies and what do the differences mean for patients with autoimmune encephalitis? 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.   AE Warrior Store 300x200 - What are intracellular and extracellular antibodies and what do the differences mean for patients with autoimmune encephalitis?

Be a part of the solution by supporting IAES with a donation today.

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Our website is not a substitute for independent professional medical advice. Nothing contained on our website is intended to be used as medical advice. No content is intended to be used to diagnose, treat, cure or prevent any disease, nor should it be used for therapeutic purposes or as a substitute for your own health professional's advice. Although THE INTERNATIONAL AUTOIMMUNE ENCEPHALITIS SOCIETY  provides a great deal of information about AUTOIMMUNE ENCEPHALITIS, all content is provided for informational purposes only. The International Autoimmune Encephalitis Society  cannot provide medical advice.


International Autoimmune Encephalitis Society is a charitable non-profit 501(c)(3) organization founded in 2016 by Tabitha Andrews Orth, Gene Desotell and Anji Hogan-Fesler. Tax ID# 81-3752344. Donations raised directly supports research, patients, families and caregivers impacted by autoimmune encephalitis and to educating healthcare communities around the world. Financial statement will be made available upon request.

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