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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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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 - 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/

—-

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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Tabitha Orth 300x218 - Memory 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 - Memory 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 - 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?

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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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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 - Can viral infections trigger 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 - Can viral infections trigger autoimmune encephalitis?

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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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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

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

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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

 

IAES PNK Partnership logo 500x419 - A link between COVID-19 and autoimmune encephalitis?

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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.

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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.

 

guidestar platinum logo 300x300 1 e1605914935941 - Who do you become when you are sleepy?

 

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?

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

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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).

 

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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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Treatments for Autoimmune Encephalitis

Treatments for Autoimmune Encephalitis


April 26, 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/

——-

Introduction

 

Though it can be challenging for doctors to correctly identify and diagnose autoimmune encephalitis (AE), once patients do indeed receive a proper diagnosis there are treatment options that can go a long way in alleviating their symptoms sending them down the road to recovery. A recent study reports that 94% of patients with AE have significant improvement in or complete resolution of symptoms in the first few years after their diagnosis.1,2  One important key to success is promptly starting treatment which both reduces the likelihood of long-term symptoms and prevents relapses.

The job of your body’s immune system is to find and eliminate invaders, like bacteria and viruses, that may be harmful. But in the case of AE, the immune system mistakes the brain as an invader and mounts an attack, leading to inflammation in the brain.3 This inflammation is what causes the symptoms of AE, like hallucinations, memory problems, and seizures. Therefore, all current medical treatments for AE are aimed at decreasing inflammation.4 But even if the ultimate goal is always to reduce brain inflammation, there may be slight variations in the choice of therapies depending on the type of AE and the patient’s unique medical history.

Physicians divide the treatments for AE into first-line and second-line therapies. First-line therapies are treatments that doctors generally prescribe first when a patient is diagnosed with AE. Second-line therapies are treatments that doctors reach for when the first-line therapies didn’t work, or if there are lingering symptoms following initial improvement with first-line therapies.

In this article, we’ll walk through some of the common treatments for AE, why doctors may or may not choose them for a given patient, and how these treatments are thought to reduce AE symptoms.

First-Line Treatments

Steroids

If you or a loved one has been diagnosed with AE, you’re probably familiar with steroids, the medicine that doctors often use first when treating AE. When many people hear the term “steroids,” they think of Barry Bonds or other professional athletes who have used performance-enhancing drugs to get an edge on the competition. But in reality, “steroids” is an umbrella term used to describe a group of chemicals that share a similar shape. Whereas athletes looking to circumvent the rules use steroids called anabolic steroids, doctors treating AE prescribe steroids called glucocorticoids.4

Though doctors can administer glucocorticoids to a patient as a pill or in an IV, we actually make glucocorticoids naturally in our bodies all the time! Our homemade glucocorticoids are essential for a wide range of our bodily functions – from controlling how our body manages sugars and fats, to telling our brain to be alert to our surroundings, to damping down inflamation.5 When prescribing glucocorticoids to patients with AE, doctors try to take advantage of the anti-inflammatory properties of these chemicals.

How exactly do glucocorticoids put the brakes on inflammation? They act quickly and powerfully at the source of inflammation: the cells of your immune system (Figure 1).5 Once they breach the walls of an immune cell, glucocorticoids enter the nucleus, which serves as the control center of a cell. It’s in the nucleus that the cell writes out the instructions for making the proteins that it needs to mount an immune attack. By breaching this nucleus control center, glucocorticoids can override the machinery that the cell uses to write these instructions. This ultimately prevents the immune cells from causing inflammation.

glucocorticoid mechanism summary V1 500x358 - Treatments for Autoimmune Encephalitis

Figure 1. How do glucocorticoids treat AE? Glucocorticoids enter the nucleus of an immune cell, where they override the messages that the cell writes as it tries to make inflammatory proteins.

 

Unfortunately, glucocorticoids don’t just interfere with the instructions that immune cells use for making inflammatory proteins. They also interfere with the instructions that many other kinds of cells in the body rely on for carrying out their own important functions.6 For example, glucocorticoids can affect the instructions that the cells in your bones use to tell themselves to grow and retain their strength. This can lead to the weakening of your bones, which is a common side effect of glucocorticoids.7 Other side effects include problems with your body’s metabolism, like the redistribution of body fat, as well problems with your skin, like impaired wound healing.6 When patients with AE are first diagnosed, they are often very sick, so very high doses of glucocorticoids may be required to stabilize their condition.8 But as AE symptoms improve, doctors try to slowly reduce the amount of glucocorticoids that a patient is prescribed to prevent some of the harmful and uncomfortable side effects of these powerful medications.

Plasma Exchange (PLEX)

Rather than targeting the inner workings of the immune cells, other treatments for AE target the proteins that are made by the immune cells. One type of protein that immune cells make is called an antibody. Antibodiesselectively stick to invaders and flag them for destruction by other cells in the immune system.9 But in the case of AE, the body accidentally makes antibodies against its own proteins in the brain. When the immune system sees these flags, it mistakenly attacks the healthy brain.

Plasma exchange (PLEX) is a therapy that tries to remove these antibodies that erroneously tell the immune system to attack the brain.10 Antibodies are generally transported in the plasma, which is the liquid-y component of blood. During PLEX therapy, tubes are placed in your veins so that your blood can pass through a machine as it is pumped around your body (Figure 2). This machine acts like a coffee filter, separating the liquid part of your blood (the coffee) from the blood cells (the grounds). Because the liquid part of your blood contains the harmful antibodies, the liquid is discarded and replaced with the plasma of a healthy donor. This healthy plasma is then recombined with your own blood cells that were trapped in the coffee filter, and sent back into your body through another tube.

PLEX summary V2 500x279 - Treatments for Autoimmune Encephalitis

Figure 2. What happens during plasma exchange (PLEX) therapy? Whole blood is removed from the patient’s vein, then separated into its plasma and red blood cell components. The patient’s plasma is discarded and replaced with donor plasma, which is recombined with the patient’s red blood cells and returned to the patient’s blood stream.

 

PLEX is generally safe and effective, and it can be especially useful for patients who are particularly vulnerable to the side effects of glucocorticoids.8 However, a major downside of PLEX is that it requires the placement of the tubes that are used to remove and return the blood to the body for the duration of the treatment. These tubes can be a source of infection or bleeding, and can make it logistically challenging for patients to receive PLEX if they aren’t already in the hospital.

Intravenous Immune Globulin (IVIG)

Intravenous immune globulin (IVIG) is another AE treatment that tries to interfere with the antibodies that mistakenly target a patient’s healthy brain in AE. Our blood contains thousands of different antibodies, most of which are designed to target the foreign invaders that we have encountered during our lifetimes. IVIG is the result of taking the blood of thousands of different people, extracting the antibodies from that blood, and then combining the antibodies of all of the different donors.11 This creates a very concentrated slushy of thousands and thousands of antibodies that target all sorts of different proteins. When IVIG is administered to a patient, these antibodies then enter their bloodstream and circulate with the rest of the patient’s blood.

IVIG summary V1 500x323 - Treatments for Autoimmune Encephalitis

Figure 3. What is intravenous immune globulin (IVIG) therapy? The antibody-containing serum of thousands of donors is combined and then administered to the patient through an IV.

Given that AE is caused by a rogue antibody, it may seem crazy that doctors would give patients many more highly concentrated antibodies to treat AE. But, IVIG is very effective with minimal side effects beyond an increased risk of blood clots in some patients.12 So how does it work? Doctors think that IVIG overwhelms the immune system by flooding it with so many antibodies that the AE-causing antibodies just get swept up in the rush. In other words, the immune system may be so distracted by the onslaught of other antibodies that it forgets about the antibody that was driving the AE symptoms.11

Second-Line Treatments

 

Rituximab

If the first-line therapies don’t provide sufficient relief for a patient with AE, the most common second-line therapy is a drug called rituximab.8 Rituximab, which was initially designed to treat cancer, is, itself, an antibody.13 But, interestingly, its job is to “tag” the cells in the body’s own immune system that make other antibodies. This causes the body’s immune system to kill its own antibody-producing cells, ultimately halting the production of antibodies.

This means that rituximab can stop the immune system from making the harmful brain-targeting autoantibodies that cause AE symptoms. But Rituximab doesn’t just suppress the production of the AE-causing antibodies – it suppresses the production of all antibodies, including those necessary for fighting infections. This can leave patients vulnerable to bacterial and viral invaders that they would normally be able to fight off. Additionally, rituximab is known to cause other side effects like fevers, fatigue, and nausea.13Nevertheless, rituximab has been shown to be an effective at restoring functioning for patients with AE who need additional treatment on top of first-line therapies.14

Cyclophosphamide

Cyclophosphamide is another cancer drug that has been repurposed as a second-line agent in the treatment of AE.8 Cyclophosphamide works by entering the nucleus of a cell and attaching chemical “decorations” to the cell’s DNA.15 These “decorations” confuse the machinery that a cell uses to duplicate its DNA, which impairs the ability of a cell to replicate itself. Thus, cyclophosphamide can significantly impair the function of cells that rely on frequent replication to do their job, like immune cells.

Cyclophosphamide is very good at killing the immune cells that cause inflammation, which makes it a useful treatment for AE. The side effects of cyclophosphamide, however, can include nausea and hair loss, as well as more dangerous conditions such as bladder injuries and problems with fertility.16 Because of this, cyclophosphamide is generally recommended for patients whose symptoms aren’t eliminated by first-line therapies or rituximab.

Symptomatic Treatment of AE

 

The immune-targeting therapies for AE aim at eliminating the source of a patient’s symptoms. But oftentimes it can be beneficial to provide patients with additional therapies that can help alleviate the symptoms themselves. For example, the brain inflammation associated with AE can cause patients to experience seizures.17 Seizures are uncontrolled bursts of electrical activity in the brain. Depending on where a seizure starts and spreads, this electrical activity can result in phenomena ranging from the experience of strange sensations to full-body convulsions.18 Many patients with AE may be prescribed anti-seizures medications, which act to quiet down the electrical activity in the brain and decrease the likelihood of the uncontrolled activity of a seizure.

Medical therapies targeting inflammation dramatically reduce symptoms in the majority of patients diagnosed with AE. Some patients, however, will continue to have symptoms even after treatment, and some may be resistant to treatment altogether. We are still early in our research efforts to try to understand how and why people get AE. And as we deepen our understanding of this complex disorder, hopefully we can work towards developing more treatments specifically targeting the underlying causes of AE that are more effective with fewer side effects.

 

References

  1. Titulaer, M. J. et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. The Lancet Neurology 12, 157–165 (2013).
  2. Abboud, H. et al. Residual symptoms and long-term outcomes after all-cause autoimmune encephalitis in adults. Journal of the Neurological Sciences 434, 120124 (2022).
  3. Dalmau, J. & Rosenfeld, M. R. Paraneoplastic and autoimmune encephalitis.
  4. Lancaster, E. The Diagnosis and Treatment of Autoimmune Encephalitis. J Clin Neurol 12, 1–13 (2016).
  5. Ramamoorthy, S. & Cidlowski, J. A. Corticosteroids-Mechanisms of Action in Health and Disease. Rheum Dis Clin North Am 42, 15–31 (2016).
  6. Hodgens, A. & Sharman, T. Corticosteroids. in StatPearls (StatPearls Publishing, 2022).
  7. Briot, K. & Roux, C. Glucocorticoid-induced osteoporosis. RMD Open 1, e000014 (2015).
  8. Abboud, H. et al. Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management. J Neurol Neurosurg Psychiatry 92, 757–768 (2021).
  9. Janeway, C. A., Travers, P., Walport, M. & Shlomchik, M. J. Immunobiology. (Garland Science, 2001).
  10. Bobati, S. S. & Naik, K. R. Therapeutic Plasma Exchange – An Emerging Treatment Modality in Patients with Neurologic and Non-Neurologic Diseases. J Clin Diagn Res 11, EC35–EC37 (2017).
  11. Patient education: Intravenous immune globulin (IVIG) (Beyond the Basics) – UpToDate. https://www.uptodate.com/contents/intravenous-immune-globulin-ivig-beyond-the-basics.
  12. Lee, S. et al. The safety and efficacy of intravenous immunoglobulin in autoimmune encephalitis. Ann Clin Transl Neurol 9, 610–621 (2022).
  13. Hanif, N. & Anwer, F. Rituximab. in StatPearls (StatPearls Publishing, 2022).
  14. Thaler, F. S. et al. Rituximab Treatment and Long-term Outcome of Patients With Autoimmune Encephalitis: Real-world Evidence From the GENERATE Registry. Neurology – Neuroimmunology Neuroinflammation 8, (2021).
  15. Ahlmann, M. & Hempel, G. The effect of cyclophosphamide on the immune system: implications for clinical cancer therapy. Cancer Chemother Pharmacol 78, 661–671 (2016).
  16. Ogino, M. H. & Tadi, P. Cyclophosphamide. in StatPearls (StatPearls Publishing, 2022).
  17. Davis, R. & Dalmau, J. Autoimmunity, Seizures, and Status Epilepticus. Epilepsia 54, 46–49 (2013).
  18. Turek, G. & Skjei, K. Seizure semiology, localization, and the 2017 ILAE seizure classification. Epilepsy & Behavior 126, 108455 (2022).
  19. Feyissa, A. M., López Chiriboga, A. S. & Britton, J. W. Antiepileptic drug therapy in patients with autoimmune epilepsy. Neurol Neuroimmunol Neuroinflamm 4, e353 (2017).

 All figures made with biorender.com.

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

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

 

 

Tabitha Orth 300x218 - Treatments for 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 - Treatments for 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 - Treatments for 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 - Treatments for 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 - Treatments for Autoimmune Encephalitis
Peripheral monocytes and soluble biomarkers in autoimmune encephalitis

Peripheral monocytes and soluble biomarkers in autoimmune encephalitis

March 29, 2023 | Written by Dr. Robb Wesselingh. Edited by Dr Mastura Monif, Dr Loretta Piccenna, Ms Tiffany Rushen, Ms Amanda Wells (consumer representative) Ms Sasha Ermichina (consumer representative), and Ms. Michelle Mykytowycz.

 ——

A message from IAES Blog Staff:

It is our honor and pleasure to present to all of you an overview of Peripheral monocytes and soluble biomarkers in autoimmune encephalitis. This overview is by the esteemed team at Monash University in Australia & lead by Dr. Mastura Monif, who is a member of IAES’ Medical Advisory Board.

We are proud to be in collaboration with Dr. Monif and her team in the Australian Autoimmune Encephalitis Consortium Project as we work closely with them to best support AE patients, caregivers, and their families.

You can find out more about the Australian Autoimmune Encephalitis Consortium and its efforts to help those with AE and their families via the following link:

https://www.monash.edu/medicine/autoimmune-encephalitis

 —-—-

Peripheral monocytes and soluble biomarkers in autoimmune encephalitis

Source: R Wesselingh, S Griffith, J Broadley, D Tarlinton, K Buzzard, U Seneviratne, H Butzkueven, TJ O’Brien, M Monif, Peripheral monocytes and soluble biomarkers in autoimmune encephalitis, Journal of Autoimmunity, 2023; 135 https://doi.org/10.1016/j.jaut.2023.103000

Introduction

Autoimmune encephalitis (AE) is a condition in which inflammation occurs in various regions of the brain. In AE a person’s immune system produces antibodies (proteins) that mistakenly targets components of the person’s own neurons (nerve structures). This can result in inflammation and nerve tissue damage. As a result, a person with AE can present with different neurological symptoms including seizures (sudden, uncontrolled electrical disturbances in the brain) and memory problems. There are different types of AE based on which protein the immune system is mistakenly targeting. Two of the most common types of AE are:

  • NMDAR AE – antibodies targeting a brain protein called N-methyl-D-aspartate receptor or NMDAR and
  • LGI-1 AE – antibodies targeting a brain protein called leucine-rich, glioma inactivated-1 or LGI-1

While we know antibodies play a key role in the disease, we do not know what changes occur in other parts of the immune system during the course of AE.

The innate immune system is a part of the immune system that acts as a broad first line of defence against foreign invaders to the body like viruses and bacteria. This system can often start or increase inflammation in the body as a protective mechanism. Monocytes are a major type of cell in the innate immune system that drive this response. Monocytes can alert and activate other parts of the immune system through release of small signalling proteins. These small signalling proteins can be released into the blood and tissues and are called cytokines. In AE it is unknown whether the innate immune system or monocytes play a role in the disease.

For this research, we set out to find out answers to following –

  1. Are monocytes in people with AE different than in healthy people?
  2. Is there other evidence of inflammation in the blood of people with AE?
  3. Does the level of inflammation in AE determine disease severity?
  4. Are the inflammatory changes the same in different types of AE?

How we did this work

We recruited 40 people with AE and 28 healthy volunteers who provided blood samples. These blood samples were evaluated in the laboratory for:

  • Characteristics of the monocytes (whether they show signs of being active and more inflammatory), and
  • Levels of different cytokines in the blood that may show increased activity of the immune system and increased inflammation

These findings were then compared between people with AE and the healthy volunteers to see if there were any differences. We also compared these findings between people with different types and severities of AE.

What were the interesting things we found

  • We found that a certain type of monocyte known to play a key role in inflammation in other diseases are increased in number in people with AE compared with healthy volunteers
  • We also identified that certain cytokines (IL-6, TNF-a) that are important in starting and maintaining inflammation are also increased in people with AE compared with healthy volunteers
  • These changes were present in both severe and mild AE but were much stronger in people with LGI-1 antibody associated AE.

What do these findings mean?

This research showed that there is ongoing inflammation in the blood of people with AE. Also, monocytes and the innate immune system may play a role in the disease.

The research could help clinicians to –

  1. Identify new treatments that target monocytes and the innate immune system
  2. Use the inflammatory changes identified as a way to diagnose and monitor the disease.

———-

For more information and resources from Dr. Monif and her group at the Australian Autoimmune Encephalitis Consortium Project, visit this link here. To download a plain language PDF of the paper summarized in this blog, click the button below:

 

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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 - Peripheral monocytes and soluble biomarkers in 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 - Peripheral monocytes and soluble biomarkers in autoimmune encephalitis

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What is a headache?

What is a headache?


March 8, 2023 | by
 Marissa Maroni, 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/

We all suffer from headaches from time to time. For some a headache is a daily medical issue and they can range from mild and slightly bothersome to migraines that put us in bed for a day or more at a time. This wonderful article by Marissa Maroni helps to shed light on the various types of headaches and the biology behind an issue that we all encounter!

Introduction

We all suffer from headaches from time to time. For some a headache is a daily medical issue and they can range from mild and slightly bothersome to migraines that put us in bed for a day or more at a time. This wonderful article by Marissa Maroni helps to shed light on the various types of headaches and the biology behind an issue that we all encounter!

In the news or on your favorite medical drama you may have been startled to see patients are kept awake during brain surgery. If not, we’ve included an example here! Although it feels wild to witness awake surgeries, they’re possible because the brain itself cannot sense any pain. Despite the lack of pain sensed by the brain, most people do experience head pain at some point in their life, including headaches. The deep, throbbing pain, and sometimes nausea, experienced during a headache can be unbearable. But if brains can’t feel, what causes the pain of a headache and how is this treated?

What kinds of headaches are there?

There are three main types of primary headaches, primary meaning the headache is the issue, rather than a symptom from an underlying condition. The three types of primary headaches are:

  1. Tension-type headaches

Tension-type headaches are the most common primary headache and impact over 25% of people globally1. Tension-type headaches are characterized by mild to moderate head pain that feels like a tightening pressure (imagine hands gripped tightly around your head) that affects both sides of the brain, lasting minutes up to several days2.

  1. Migraines

Migraines effect approximately 14% of the global population1. Migraines are characterized as moderate to severe throbbing pain usually on one side of the brain with pain lasting from several hours to 3 days3. Migraines are usually accompanied by various symptoms such as nausea and light and sound sensitivity4.

  1. Cluster Headaches

Cluster headaches affect approximately 0.4% of people5. Cluster headaches are characterized by excruciating pain on one side of the brain usually surrounding the eye that lasts for minutes up to 3 hours5.

How do they start?

Each of the three primary types of headaches vary in their origin. Rather than extensively unpacking each, let’s focus in on migraines. Prior to a migraine starting a person can experience sound and light sensitivity, mood changes, thirst, and yawning among other symptoms. Scientists have used brain imaging prior to the start of migraines to try and understand why do they start in the first place and what could be causing pre-migraine symptoms?

It is theorized that the brainstem, the stalk of your brain that controls breathing and heart rate among other functions, is the generator of migraines6. A brain imaging study found activity in a subregion of the brainstem was associated with the time until the next migraine starts7. Further, a set of researchers from Germany imaged the brain of a migraine patient for 30 consecutive days to understand what events occur in the brain leading up to a migraine8. They found that before and during a migraine there is altered communication between the brainstem and the hypothalamus, a part of the brain important in controlling sleep, hunger, thirst, and more. Additionally, they found increasing activity in the hypothalamus in the time leading up to a migraine.

Scientists have identified critical brain regions that have altered brain activity prior to a migraine, but can any of this explain pre-migraine symptoms? Researchers hypothesize that the increased activity in the hypothalamus could explain pre-migraine symptoms such as yawning and thirst. Interestingly, migraine patients with light sensitivity have increased activation of the occipital cortex, a brain region responsible for vision perception, in comparison to migraine patients who did not experience light sensitivity9. Although the answer is not precise, scientists have identified altered brain signaling that may prime a brain for a migraine attack and identified specific brain regions that can explain pre-migraine symptoms.

Where does the pain come from?

A main piece to the migraine pain puzzle is a group of nerves that carry pain signals from the face to the brain, referred to as trigeminal ganglion. The trigeminal ganglion connect to the blood vessels surrounding your brain and various parts of the brain including the brainstem, hypothalamus, and thalamus (Figure 1). The thalamus is a place for information to be relayed to your cortex. The activation of trigeminal ganglion lead to a cascade of events that have roles in migraine pain. Let’s explore what events occur and how they contribute to migraine pain.

headache 2 496x500 - What is a headache?

Figure 1. The trigeminal ganglion, in blue, makes connections to the brainstem, thalamus, and hypothalamus. The thalamus relays information to the cortex.

Sensitization of the brain

During a migraine, it is thought that the trigeminal ganglion become sensitized, meaning they can activate and send pain signals in response to nonpainful stimuli (Figure 2)3. Trigeminal ganglion sensitivity causes throbbing head pain, and pain felt when coughing or bending over during a migraine. Even though you are not doing anything to cause this pain, the trigeminal ganglion is sensitized and sending pain signals anyway! The sensitized trigeminal ganglion lead to the activation and sensitization of the brainstem, and thalamus10. Sensitization of the brainstem and thalamus contribute to allodynia, perception of pain by something not normally painful, like a gentle touch or glasses resting on your nose. Collectively, the sensitization of the trigeminal ganglion, brainstem, and thalamus play a critical role in migraine pain.

migraine pain 500x177 - What is a headache?

Figure 2. Three contributors to migraine pain: sensitization, hyperexcitability, and CGRP release.

Hyperexcitability

Hyperexcitability refers to neurons that are more likely to become active and send signals. General hyperexcitability is seen in individuals with migraines and is hypothesized to contribute to sensitization in the brain as there is more activation in pain signaling regions (Figure 2)3. Brain imaging studies identified that during a migraine the brain is hyper-responsive to sensory information3. This hyper-responsiveness is hypothesized to cause light sensitivity during migraines. Interestingly, when scientists examined shared mutations in the genes of migraine patients, they found that many of the mutated genes were important in neuronal signaling, further suggesting a role for hyperexcitability in migraines11.

Neuropeptide release

The activation of the trigeminal ganglion causes the release of neuropeptides. Neuropeptides are small proteins that cause changes in neuronal signaling (oxytocin is a well-known example of a neuropeptide). An important neuropeptide released after trigeminal ganglion activation is calcitonin-gene related peptide (CGRP). CGRP modulates pains signals, mediates inflammation in the brain, and has cardiovascular, functions among other roles 3,12. There is evidence that CGRP initiates and maintains the sensitization of trigeminal ganglion and is involved in signaling between trigeminal nerves3,13. Further, intravenous administration of CGRP triggers a migraine in migraine patients but not in healthy individuals, suggesting CGRP plays a key role in migraines10. Additionally, CGRP causes blood vessels surrounding the brain to dilate, meaning they expand however, the contribution of blood vessel expansion in migraine pain is disputed14.

What are some treatment for migraines?

Scientists have identified several changes in brain function before and during a migraine that contribute to migraine pain. With all this known, how are migraines treated and how do these treatments work?

A popular and effective treatment for migraines during an active attack are triptans. Triptans act on serotonin receptors. Serotonin is a chemical messenger within our brain responsible for a variety of functions, including mood and digestion. When triptans act on serotonin receptors, they inhibit pain neurotransmission in the trigeminal ganglion, inhibit the release of pain-promoting neuropeptides (like CGRP!), and constrict blood vessels15. Given what we know about headaches, this drug works by halting the cascade of events that occur during a migraine including sensitization, hyperexcitability, and neuropeptide release.

Overall, we’ve uncovered changes in brain signaling that occur before and during a migraine, along with a current treatment. Even though the brain itself cannot feel any pain, it plays a critical role in communicating pain to different parts of your body!

References

  1. Stovner, L. J., Hagen, K., Linde, M., & Steiner, T. J. (2022). The global prevalence of headache: an update, with analysis of the influences of methodological factors on prevalence estimates. The journal of headache and pain23(1), 1-17.
  2. Ashina, S., Mitsikostas, D. D., Lee, M. J., Yamani, N., Wang, S. J., Messina, R., … & Lipton, R. B. (2021). Tension-type headache. Nature Reviews Disease Primers7(1), 1-21.
  3. Dodick, D. W. (2018). A phase‐by‐phase review of migraine pathophysiology. Headache: the journal of head and face pain58, 4-16.
  4. Pescador Ruschel MA, De Jesus O. Migraine Headache. 2022 Jul 6. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 32809622.
  5. Rossi, P., Whelan, J., Craven, A., & De La Torre, E. R. (2016). What is cluster headache? Fact sheet for patients and their families. A publication to mark Cluster Headache Day 2016. Functional Neurology31(3), 181.
  6. Puledda, F., Messina, R., & Goadsby, P. J. (2017). An update on migraine: current understanding and future directions. Journal of neurology264(9), 2031-2039.
  7. Stankewitz, A., Aderjan, D., Eippert, F., & May, A. (2011). Trigeminal nociceptive transmission in migraineurs predicts migraine attacks. Journal of Neuroscience31(6), 1937-1943.
  8. Schulte, L. H., & May, A. (2016). The migraine generator revisited: continuous scanning of the migraine cycle over 30 days and three spontaneous attacks. Brain139(7), 1987-1993.
  9. Karsan, N., & Goadsby, P. J. (2018). Biological insights from the premonitory symptoms of migraine. Nature Reviews Neurology14(12), 699-710.
  10. Pietrobon, D., & Moskowitz, M. A. (2013). Pathophysiology of migraine. Annual review of physiology75, 365-391.
  11. Burstein, R., Noseda, R., & Borsook, D. (2015). Migraine: multiple processes, complex pathophysiology. Journal of Neuroscience35(17), 6619-6629.
  12. Russo, A. F. (2015). Calcitonin gene-related peptide (CGRP): a new target for migraine. Annual review of pharmacology and toxicology55, 533.
  13. Iyengar, S., Johnson, K. W., Ossipov, M. H., & Aurora, S. K. (2019). CGRP and the trigeminal system in migraine. Headache: The Journal of Head and Face Pain59(5), 659-681.
  14. Buture, A., Gooriah, R., Nimeri, R., & Ahmed, F. (2016). Current understanding on pain mechanism in migraine and cluster headache. Anesthesiology and Pain Medicine6(3).
  15. Johnston, M. M., & Rapoport, A. M. (2010). Triptans for the management of migraine. Drugs70(12), 1505-1518.

Cover photo by Robin Higgins from Pixabay

Figures created 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.

 

guidestar platinum logo 300x300 1 e1605914935941 - What is a headache?

 

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 a headache? 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 a headache?

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

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Why does it feel like we know so little about autoimmune encephalitis?

Why does it feel like we know so little about autoimmune encephalitis?

February 22, 2023 | by Catrina Hacker, PennNeuroKnow and IAES Collaboration

A message from IAES Blog Staff:

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

As we wind up AE Awareness month 2023, I, for one, am grateful. Grateful for another year of stellar webinars and more information. For all the AE Warriors and our caregivers, we have a very optimistic future. As you have heard before, our road to recovery is no sprint, but it is a marathon we can and will complete. We receive questions all the time regarding the speed at which research proceeds and treatments are approved. And this is tough because although we know this is a marathon, we all truly want things to proceed much quicker. Catrina Hacker, a member of the amazing PNK team has done a wonderful job explaining the process. So, as I have heard said to me what seems like a million times, “trust the process” and we hope you enjoy this blog!

~Fellow Warrior and Editor-in-Chief, Jeri Gore

Introduction

When you or someone you love is diagnosed with a disease like autoimmune encephalitis, the seemingly slow pace at which research progresses can feel frustrating. It’s hard to watch loved ones suffer while wondering why someone hasn’t used their knowledge and resources to find a solution that will make them feel better. In this post I will walk you through why the pace of research on diseases like autoimmune encephalitis can seem slow and what this means for scientific progress toward understanding autoimmune encephalitis.

The human body still has a lot of uncharted territory for biologists

One of the key reasons that biomedical research seems to progress slowly is that there is so much that we still don’t know. Our quest to understand the human body is much like the quest that European explorers once took to uncover the world beyond Western European countries: sometimes clumsy and a centuries-long process. Christopher Columbus’s crew famously stumbled upon North America on their way to India, and some of the earliest world maps were comically inaccurate by today’s standards (Figure 1 left). But over time the explorers made more observations and built new tools that ultimately led to the incredibly accurate and useful world maps that we have today (Figure 1 right).

1583 map - Why does it feel like we know so little about autoimmune encephalitis?

Figure 1. Left: A world map generated in 1583. A lot of the general organization of the world has been figured out, but we now know that the proportions and specific shapes of individual continents aren’t correct. Right: A modern world map that shows how much our understanding of the organization of the world has grown in the last 400 years with detailed information about elevation across all 7 continents.

Today, biologists are still in the part of the journey where they’re constantly learning new things and updating their maps. Many biological discoveries still feel like the lucky discovery of the Americas by the Nina, Pinta, and Santa Maria. Making things even more difficult, the uncharted territory that biologists want to understand is even more complicated than the stable land masses of continents. Imagine trying to build a map of the world if small chunks of land moved around and interacted with each other in complicated ways. Now imagine that each explorer had to study a slightly different version of the world with small differences that made it unique, but that had the same general layout. That is the size of the challenge that biologists face when studying the human body.

The challenges of mapmaking for biologists go beyond just the fact that components of the maps move and interact. Biologists also have to build maps at different scales and understand how they relate to one another. Consider understanding the brain as an example. Some neuroscientists study how molecules inside individual brain cells work, others study how small groups of cells connect and send signals between each other, others study how large groups of cells send signals across the brain, and still others study how these signals relate to someone’s behavior or symptoms. Even neuroscientists studying things at the same scale often use different tools that make relating their discoveries to someone else’s challenging. As neuroscientists build maps at each of these levels it’s not always obvious how each map relates to the others and connecting the maps can be just as difficult as building them.

Diseases like autoimmune encephalitis can be hard to categorize and diagnose

Understanding how a healthy human body works is hard enough but extending that understanding to figure out how to treat and cure diseases is even more complicated. When it comes to diseases, many different things can go wrong but produce the same symptoms. And oftentimes when one thing goes wrong, it causes a cascade of other things to go wrong as well. This makes it difficult to pinpoint exactly what went wrong first to try to target that for treatment.

Autoimmune encephalitis is a good example of this kind of complexity. There are many different subtypes of autoimmune encephalitis that result from an immune response to several different kinds of proteins found in the brain. Despite being caused by reactions to different proteins, several subtypes have overlapping symptoms. On the other hand, each subtype is typically associated with several distinct symptoms that are all part of the same diagnosis. On top of that, each individual patient is different even before they get sick, so they will have a slightly different experience of their disease.

One thing this diversity can make difficult is deciding which patients to group together and which to consider separately. Should researchers group patients by their symptoms (e.g., fatigue, motor deficits, headaches) or by biological markers (e.g., testing for things in the blood or cerebrospinal fluid)? * Scientists’ answer to that question is constantly evolving as they learn more about patients with different kinds of autoimmune encephalitis. Until they know enough to separate subgroups of patients, it can be difficult to see through the diversity of symptoms and biological markers toward a clear understanding of exactly what’s going on.

All of these things only become more difficult the rarer a disease is. The more patients with a certain disease that can be studied, the more data points scientists have to work with. This can give them a better sense of the big picture, despite variability between individual patients. This is why the subtypes of autoimmune encephalitis that are most common, like Anti-NMDAR encephalitis, tend to be better understood than rarer subtypes. When there are more diagnosed patients, the disease is easier to study.

*For a deeper dive into this issue, Penn NeuroKnow writer, Margaret Gardner, wrote about how the same problem impacts our ability to study psychiatric disorders in this PNK article.

Rigorous science can’t be rushed

There are also practical components of how research is conducted that contribute to its slow and steady pace. Research needs to be funded and that is typically done through federal grants from organizations like the National Institute of Health (NIH). Grant funding is competitive, and researchers can spend months working on a proposal before submitting a grant. Once submitted, the grant undergoes rigorous review by other scientists. These reviewers are looking to fund science that they think will be successful, so this means that the best proposals aim to take small and manageable steps in our understanding based on past research. After review, many grants are rejected. So, scientists often have to shake off the disappointment, consider the reviewer feedback, and write an updated proposal. And, as it turns out, getting funding is only half the battle. Once a grant is funded and the project can begin, it takes time to train students and lab workers in the skills needed to conduct the research. Sometimes scientists even have to invent new technology to collect or analyze their data because they’re trying to do something that’s never been done before.

Once scientists have their first set of results, these results often lead to new questions that need to be answered. So, scientists must do many follow-up experiments to understand what’s going on before they can feel confident adding their new discovery to the map of the human body. Once they think they know what’s going on, they then need to replicate their results several times to be sure that what they’re studying is generally true and not specific to whatever patient, animal, or dish of cells they ran their first experiment on. After that scientists will spend months putting their results together into a paper which is then reviewed by other scientists who might ask for more experiments or analyses to make their results more convincing. Finally, the paper is published, and that project can be considered complete. A lot of biomedical research is done by first studying cells in a dish, then studying animal models, and then testing treatments in humans. Each step of this process requires scientists to go through the same process of getting funding, verifying their results, and eventually publishing their work.

While all of these steps contribute to the seemingly slow pace of science, they’re also beneficial to scientific progress. Doing many follow-up experiments, replicating results, and incorporating feedback from other scientists means that once a paper is published scientists can be pretty sure that everything in the paper is accurate. This is important because if scientists couldn’t believe most things that are published then they wouldn’t know what foundation to build on when they design new experiments. Such rigorous requirements for publishing research also help to keep patients safe. Ultimately, the goal is that everything we learn from these papers can be used to develop a treatment or a cure for a disease, which means using that knowledge to help human patients. Once scientists know enough to think about possible treatments, scientists and doctors work together to test these treatments in human patients through a process called clinical trials. Doctors and scientists need to be certain of as much as they can so that those treatments are safe.

Concluding Thoughts

While there’s plenty left to learn about autoimmune encephalitis and thinking about that can feel daunting, it’s important to celebrate that we’ve learned a lot already. Successful treatments that work for many people have already been developed, and treatments are only getting better. An increasing understanding of what autoimmune encephalitis is and how to treat it has also led to the creation of research centers, like the Center of Autoimmune Neurology at the University of Pennsylvania, that make researching the disease and connecting patients and doctors easier. Centralized organizations like the International Autoimmune Encephalitis Society also help raise awareness about these issues and facilitate connections between patients, doctors, and researchers that continue to push our understanding forward.

Altogether, there are a lot of reasons to feel optimistic about the future and to trust in the system of slow and steady scientific research that has already delivered trustworthy, safe treatment options.

Image Credits

Cover photo: Photo by Ousa Chea on Unsplash.

Figure 1: Left: Girolamo Porro,, Public domain, via Wikimedia Commons; Right: © OpenStreetMap-Mitwirkende, Public domain, via Wikimedia Commons

 

 

 

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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 - Why does it feel like we know so little about 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 - Why does it feel like we know so little about 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 - Why does it feel like we know so little about autoimmune encephalitis?

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

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Peripheral monocytes and soluble biomarkers in autoimmune encephalitis

Psychiatric Manifestations of Autoimmune Encephalitis


January 25, 2023 | Written by Dr.
 Hannah Ford. 
Edited by Dr Mastura Monif, Dr Loretta Piccenna, Ms Sarah Griffith, Ms Tiffany Rushen, Ms Amanda Wells (consumer representative) and Ms Sasha Ermichina (consumer representative).

image - Psychiatric Manifestations of Autoimmune Encephalitis

A message from IAES Blog Staff:

It is our honor and pleasure to present to all of you an overview of typical psychiatric manifestations of autoimmune encephalitis This overview is by the esteemed team at Monash University in Australia & lead by Dr. Mastura Monif, who is a member of IAES’ Medical Advisory Board.

We are proud to be in collaboration with Dr. Monif and her team in the Australian Autoimmune Encephalitis Consortium Project as we work closely with them to best support AE patients, caregivers, and their families.

You can find out more about the Australian Autoimmune Encephalitis Consortium and its efforts to help those with AE and their families via the following link:

https://www.monash.edu/medicine/autoimmune-encephalitis

 —-

Psychiatric Manifestations of Autoimmune Encephalitis

WHY WE DID THIS WORK

Autoimmune encephalitis is a disorder in which antibodies accidentally created by the immune system attack parts of the brain. This can lead to inflammation and nerve damage.

Psychiatric problems are common in autoimmune encephalitis and can imitate mental health conditions, for example psychotic illnesses like schizophrenia. It is important to separate patients with AE from those with mental illness as treatments are very different.

There are different subtypes of AE. Some cases are due to the presence of detectable auto antibodies (a protein targeting the person’s own nerve endings) which is known as ‘sero positive’ AE. In ‘sero negative’ AE, there is no detectable antibody when using currently available techniques for detection.

Within the ‘sero positive’ group are different AE categories depending on the type of antibody. We discuss this further in the next section.

Anti-NMDAR encephalitis

  • The most common type of AE and typically occurs in young women. Psychiatric problems are the presenting feature in most patients and many are seen first by a psychiatrist. Symptoms start abruptly and progress rapidly over days to weeks.
  • Common features include psychosis (disruption of person’s thoughts and perceptions that can make it difficult for them to understand what is real versus what is not real). They can present with hallucinations (seeing or hearing things that are not there) and paranoia (false beliefs; for example, believing that people are out there to get you, or having unfounded mistrust of others), agitation, and elevated mood. Occasionally, anti NMDAR encephalitis patients can present with catatonia (complete lack of movement or lack of communication). Almost 90% of patients develop other related neurologic features (including seizures, abnormal movements and speech, and drowsiness) within a month, however some may have only psychiatric problems without neurologic signs.

Anti-LGI1 encephalitis

  • The second most common AE and typically affects older males. Seizures are usually the first symptom and often occur before patients develop psychiatric and/or memory problems. These seizures can be very brief, i.e. seconds long, and subtle (face and arm twitching known as “faciobrachial dystonic seizures”), but can be very frequent (up to 100s of times per day).
  • Memory difficulties develop slowly over months and may be accompanied by disinhibition (actions or words that might seem inappropriate or rude or inconsiderate).
  • They can also present with compulsive behaviors (performing an action persistently repetitively), including excessive eating, cleaning and hoarding.
  • Psychotic symptoms such as hallucinations and paranoia can occur but are less common, and usually are not an early or major feature.

Anti-CASPR encephalitis

  • Involves confusion, memory difficulties and ‘slow’ thinking which may be associated with depressed mood. Memory problems can slowly worsen over 12 months or longer in a proportion of patients. These individuals may appear like they have dementia.
  • Psychotic symptoms such as hallucinations, delusions and paranoia can occur as inflammation of the brain worsens, and usually develop with other neurologic symptoms including seizures, unsteadiness and abnormal jerking and twitching movements.

Anti-AMPAR encephalitis

  • Typically presents with short-term memory problems, confusion and behavioral changes which get worse over weeks to months.
  • Psychotic symptoms are variable (20-90% of patients) and may be associated with manic (abnormally elevated or extreme in mood, emotions, energy or activity levels) and aggressive behavior.
  • Seizures are rare. This type of encephalitis is frequently associated with cancer.

Anti-GABA-A encephalitis

  • Most commonly presents with seizures.
  • Memory loss and confusion develop slowly over weeks to months and are associated with personality and behavioral changes in approximately half of patients.
  • Features of psychosis with hallucinations and paranoia are uncommon but can occur later in severe cases.

Anti-GABA-B encephalitis

  • Also commonly presents with seizures.
  • Memory difficulties, confusion and abnormal behavior develop with or after seizures start.
  • Patients often become depressed and/or anxious at a later stage, usually 1 to 2 years after other symptoms have started.
  • Memory difficulties are slow to improve and may remain even after treatment.
  • Psychosis is not a feature.

Anti-DPPX encephalitis

  • Preceded by diarrhea and weight loss for several months, followed by mild, slowly worsening memory and cognitive difficulties associated with depression and anxiety.
  • Months or even years later patients develop psychotic features including hallucinations, delusions and aggression with neurologic symptoms such as seizures, limb shaking and jerking.

Anti-mGluR5 encephalitis

  • A rare type of AE with three major features – psychosis, memory problems and drowsiness.
  • Patients experience headaches, fevers, weight loss and nausea followed by rapid onset of memory problems, slowed thinking and severe psychiatric symptoms including hallucinations, depression, anxiety and major mood swings.
  • Many different neurologic symptoms can occur, including seizures, abnormal movements and difficulty using the eyes and face.

Anti-Neurexin-3a encephalitis

  • The disorder develops quickly over several days with headaches, fevers and nausea, followed by confusion and agitation.
  • Patients then experience severe neurologic symptoms of drowsiness, abnormal movements, seizures and breathing problems.

Diagnosis and treatment

  • Features (“red flags”) that may indicate AE as a cause of psychiatric presentation are shown in table 1.
  • Diagnosis of AE is challenging, and is confirmed by identifying the antibody in the blood or fluid from around the brain and spinal cord (cerebrospinal fluid), however these tests are not always available and may take a long time to return. Other test results that indicate AE may be the cause of psychiatric symptoms include high white cells or inflammation in cerebrospinal fluid, abnormal brain imaging on MRI and abnormal brain electrical activity on EEG (electroencephalogram; refer to our previous summary on EEG here: https://autoimmune-encephalitis.org/using-eeg-nmda
  • Early treatment of AE can lead to partial or full recovery.

Table 1.

Red Flags for Autoimmune Encephalitis in Psychiatric Presentations

·       Preceding physical symptoms such as fever, headache, stomach upset and dizziness

·       Seizures

·       Neurologic symptoms such as abnormal movements, speech difficulties, clumsiness, weakness and changes in sensation

·       “Catatonic” features such as abnormal posturing, repeating another person’s speech (echolalia), lack of movement or erratic movements

·       Memory problems

·       Psychotic symptoms that start rapidly and/or worsen quickly

 

What do the findings mean?

  • Each subtype of AE presents with different psychiatric features. Our research can help clinicians identify patients with psychiatric symptoms due to AE rather than a mental illness.
  • Early consideration of AE as a differential for psychiatric presentations is important as patients respond well to appropriate treatment (immunotherapy), particularly if given early.
  • Further studies are needed to continue describing the syndromes associated with each subtype. Fast and accurate testing for the diagnosis of AE is an important area for future research.

—-

For more information and resources from Dr. Monif and her group at the Australian Autoimmune Encephalitis Consortium Project, visit this link here. To download a plain language PDF of the paper summarized in this blog, click the button below:

 

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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 - Psychiatric Manifestations of 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 - Psychiatric Manifestations of Autoimmune Encephalitis

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What are the different types of autoimmune encephalitis?

What are the different types of autoimmune encephalitis?

December 28, 2022 | 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/

——

Introduction

Receiving a diagnosis of autoimmune encephalitis can be a stressful and uncertain time for many patients and their families. And to make it even more confusing, doctors often don’t just give patients a diagnosis of autoimmune encephalitis, but rather anti-NMDAR or anti-Hu or anti-GABAA encephalitis. There are many different types and subtypes of autoimmune encephalitis that can have distinct symptoms, underlying causes, and responses to treatment.1However, the terminology that doctors use to refer to these different subtypes is complex and can sometimes feel like wading into a bowl of alphabet soup! Here, we will try to break down some of the ways that doctors distinguish types of autoimmune encephalitis to help patients and their families make sense of this complicated and rapidly evolving field.

What is autoimmune encephalitis?

Before we break down the different types of autoimmune encephalitis, it is important to understand what autoimmune encephalitis is. What do doctors mean when they use the term autoimmune encephalitis? The suffix -itis can be applied to any part of the body to describe an inflammatory state. So, when -itis is added to the end of the word encephalon (which is the ancient Greek word for inside the head), it means inflammation of the brain. Therefore, encephalitis is a word that describes any sort of inflammation in the brain.

But what exactly is inflammation? What does it mean when a part of the body is inflamed? Inflammation occurs when the body’s immune system is activated.2 Typically, the immune system is activated when there are invaders in the body, such as bacteria or viruses. Once the immune system is alerted to the presence of this invader, it tries to eliminate the invader using a variety of different weapons. Some of the weapons that the immune system uses are called antibodies.3Antibodies act as signals for the immune system so that it knows where to direct its attack. One battalion of the immune system’s cell soldiers makes antibodies that specifically stick to the target. Then, the immune system sends another battalion of cell soldiers to eliminate the target that has been flagged by the antibody.

Even though the immune system’s main job is to mount attacks against invaders like bacteria and viruses, things can go wrong in the fog of biological warfare. Sometimes the immune system accidentally mounts an attack against healthy proteins in a person’s body. When the body’s immune system targets itself, it can result in what is called an autoimmune process (from combining auto-, meaning self, and -immune, as in the immune system).

Now we can put all of these terms together! When the body’s immune system accidentally targets healthy proteins in a person’s brain, resulting in inflammation in the brain, it is called autoimmune encephalitis.4

It is important to note that when the body mounts an autoimmune attack against the brain, it isn’t trying to target everyhealthy protein in the brain. Rather, it’s generally trying to target specific proteins that are found in the brain. When the immune system attacks these proteins, it can damage the proteins and the cells in which they are found. As a result, the type of autoimmune encephalitis and the symptoms associated with that autoimmune encephalitis are based on the type of protein that is targeted for attack by the immune system.5

What part of the brain is affected by autoimmune encephalitis?

Though we are still relatively early in our understanding of how the brain works, we do know that different regions of the brain control different brain functions. For example, some areas of the brain are dedicated to controlling movement, whereas others are dedicated to processing sensory stimuli. One way in which these different regions of the brain are distinct is that their brain cells can contain different proteins. This means that when the immune system mounts an attack against a protein in the brain, this attack is targeted to the regions in the brain where that protein is found. Therefore, the distinct types of autoimmune encephalitis target different regions in the brain and may affect different brain functions.1

Doctors will sometimes describe a patient’s encephalitis based on which part of the brain they suspect is being attacked. Some common terms that you may hear a doctor use to describe autoimmune encephalitis include:

  • Limbic encephalitis: inflammation of the limbic system. The limbic system includes brain regions such as the hippocampus, amygdala, and hypothalamus that are involved in emotional regulation. People with limbic encephalitis most commonly have changes in their mood and memory, along with seizures starting in the limbic system.6
  • Brainstem encephalitis: inflammation of the brainstem which is the long stalk at the base of the brain that connects the brain to the spinal cord. The brainstem is the center of many important functions necessary for survival, so people with brainstem encephalitis can have problems ranging from abnormal eye movements to trouble swallowing or breathing.7
  • Encephalomyelitis: inflammation of the brain plus inflammation of the spinal cord. Sometimes patients with autoimmune encephalitis can also mount an autoimmune attack on their spinal cord. Inflammation in the spinal cord interferes with the sensory and movement signals that are sent between the brain and the rest of the body, which can result in symptoms like weakness, paralysis, numbness, or tingling.8

Is autoimmune encephalitis caused by a tumor?

Another way that doctors distinguish between the types of autoimmune encephalitis is by using the terms paraneoplastic vs. non-paraneoplastic encephalitis. In paraneoplastic autoimmune encephalitides, the reason that the patient’s immune system is attacking their brain is because they have a tumor somewhere in their body.13 A tumor, which is a growth of abnormal cells, can be one of the most common causes of autoimmune encephalitis. This is because the abnormal cells in a tumor can sometimes do strange things to proteins normally found in the brain. For example, tumor cells can place a protein that is normally supposed to be inside of the cell on the outside of the cell, or they can begin to make a brain protein in a different part of the body where it is not normally supposed to be made. This can confuse the immune system, which causes it to attack a normal brain protein that it would otherwise leave alone.9

In contrast to these cases of paraneoplastic encephalitis, non-paraneoplastic autoimmune encephalitis occurs when there is an autoimmune encephalitis but doctors can’t find a tumor anywhere in the person’s body.1 In these cases, what is causing the immune system to all of a sudden decide to attack a healthy protein in the brain is less clear. The cause of cases of non-paraneoplastic autoimmune encephalitis is the subject of ongoing and future research by many doctors and scientists.

Which protein in the brain is the immune system trying to attack?

Perhaps the most specific way in which doctors can distinguish between different types of autoimmune encephalitis is by determining exactly which protein in the brain is being targeted. As discussed above, when the immune system mounts an attack against its target, it makes antibodies to specifically flag this target. These antibodies circulate in the blood and/or the fluid that bathes the brain. Therefore, if doctors can collect these antibodies, they can provide a clue about which protein the immune system is targeting.

As doctors and scientists have identified more antibodies involved in autoimmune encephalitis, they have started to name these types of autoimmune encephalitis after the antibody that is present. For example, one of the most common forms of autoimmune encephalitis is caused by the body mounting an attack against the NMDA receptor, which is a protein found on the surface of many cells in the brain.10 These antibodies against the NMDA receptor are called “anti-NMDA receptor antibodies” so these patients are said to have “anti-NMDA receptor autoimmune encephalitis.” Some of the most common types of autoimmune encephalitis that are named based on the antibody found against their protein target are listed in the table below.

Antibody

% of Cases with Presence of Tumor

Common symptoms

Anti-NMDAR

40% (varies)

Limbic encephalitis, psychosis, repetitive movements, unstable blood pressure and heart rate, decreased breathing, seizures

Anti-AMPAR

70%

Limbic encephalitis

Anti-GABAA

 

Severe, prolonged seizures

Anti-GABAB

70%

Limbic encephalitis, frequent seizures

Anti-Caspr2

40%

Limbic encephalitis, confusion, abnormal muscle tone

Anti-LGI1

<10%

Limbic encephalitis, seizures

Anti-Hu

>90%

Limbic encephalitis, problems with cognition

Anti-Ma2

>90%

Limbic encephalitis, brainstem encephalitis

Anti-CV2/CRMP5

>90%

Limbic encephalitis

Anti-Amphiphysin

>90%

Limbic encephalitis, widespread paralysis

 

Table Caption: Different antibodies that are found in patients with autoimmune encephalitis are associated with distinct symptoms and the likelihood that the disease is a result of having a tumor somehwere in the body. Adapted from Davis & Dalmau – Autoimmunity, seizures & status epilepticus (2013).11

In some patients doctors are unable to find an antibody that is known to be associated with autoimmune encephalitis, even if the doctor is pretty sure that the patient’s symptoms are caused by an autoimmune encephalitis. This might be because either the patient’s immune system is not making an antibody, or that doctors don’t yet have a laboratory test that is capable of identifying an antibody associated with that patient’s disease. These cases of autoimmune encephalitis are said to be seronegative.12 Doctors and scientists are still looking to identify new proteins and antibodies that are associated with autoimmune encephalitis in hopes of providing a more specific diagnosis for patients who would have previously been thought to have seronegative autoimmune encephalitis.

It is important to remember that autoimmune encephalitis can look different in every patient. For example, one patient may be diagnosed with anti-NMDA encephalitis after she has multiple seizures and is found to have an ovarian tumor. Whereas another patient may be diagnosed with anti-NMDA encephalitis after he has dramatic changes in his personality and memory, but doctors are not able to find a tumor. Nevertheless, breaking down a disease into distinct boxes can help guide doctors in their diagnostic and treatment decisions for an individual patient. And a greater understanding of the subtypes and causes of autoimmune encephalitis may be crucial for developing more targeted and effective treatments for this uniquely challenging disease.

References:

  1. Dalmau, J. & Rosenfeld, M. R. Paraneoplastic and autoimmune encephalitis.
  2. Chen, L. et al. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget 9, 7204–7218 (2017).
  3. Janeway, C. A., Travers, P., Walport, M. & Shlomchik, M. J. Immunobiology. (Garland Science, 2001).
  4. Abboud, H. et al. Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management. J Neurol Neurosurg Psychiatry 92, 757–768 (2021).
  5. Lancaster, E. The Diagnosis and Treatment of Autoimmune Encephalitis. J Clin Neurol 12, 1–13 (2016).
  6. 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).
  7. Tan, I. L. et al. Brainstem encephalitis: etiologies, treatment, and predictors of outcome. J Neurol 260, 2312–2319 (2013).
  8. Dalmau, J., Graus, F., Rosenblum, M. K. & Posner, J. B. Anti-Hu–associated paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical study of 71 patients. Medicine (Baltimore) 71, 59–72 (1992).
  9. Dalmau, J. & Graus, F. Antibody-Mediated Encephalitis. N Engl J Med 378, 840–851 (2018).
  10. Barry, H., Byrne, S., Barrett, E., Murphy, K. C. & Cotter, D. R. Anti-N-methyl-d-aspartate receptor encephalitis: review of clinical presentation, diagnosis and treatment. BJPsych Bull 39, 19–23 (2015).
  11. Davis, R. & Dalmau, J. Autoimmunity, Seizures, and Status Epilepticus. Epilepsia 54, 46–49 (2013).
  12. Lee, W. J. et al. Seronegative autoimmune encephalitis: clinical characteristics and factors associated with outcomes. Brain awac166 (2022) doi:10.1093/brain/awac166.
  13. Rees, J H. “Paraneoplastic Syndromes: When to Suspect, How to Confirm, and How to Manage.” Journal of Neurology, Neurosurgery & Psychiatry 75, (June 1, 2004): ii43–50. https://doi.org/10.1136/jnnp.2004.040378.

 

 

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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 - What are the different types of 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 the different types of 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 the different types of 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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