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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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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?

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How does the brain heal from autoimmune encephalitis and why is there so much variability in the healing process?

December 7, 2022 | by Kara McGaughey, PennNeuroKnow

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/

——

The holy grail! The million-dollar question! How long will it take to get rid of AE, to heal from AE…when will we feel and act ‘normal’ again? Why do we not understand more of the healing process’ from a diagnosis of autoimmune encephalitis?

Kara McGaughey and the team at PennNeuroKnow help us further understand just how complex and individual our brains are!

——

Introduction

 

If you break a bone, your expectations about the healing process and how long it might last will vary depending on the nature and severity of the fracture. For example, a small fracture will come with a completely different timeline for recovery than a compound fracture (where the force of the break causes the bone to pierce through the skin).

Just like broken bones, no two cases of brain injury are exactly the same and the timeline of the healing process depends on the nature and severity of the injury. As such, when we consider healing from brain injuries, like autoimmune encephalitis (AE), the diversity of diagnoses and symptoms leads to a diversity of recovery trajectories, which can make navigating the healing process a confusing and isolating experience. Here, we dive into this diversity, exploring what healing from AE looks like, why the process takes so long, and why it varies so much.

How does the brain heal from autoimmune encephalitis?

 

“I felt like a robot controlling my body for the first time – speech, thought and movement all under shaky manual control. I felt like my brain was being reacquainted with my body.”

— Alexandrine Lawrie on AE recovery1

Autoimmune encephalitis (AE) is a collection of related conditions in which the body’s immune system produces antibodies that mistakenly attack the brain, causing inflammation. In order to begin the healing process, treatment is needed to shut down the overactive immune system, remove the antibodies mounting the attack, and reduce brain swelling.2-3 To accomplish this, doctors typically rely on a handful of treatments options:

  • Corticosteroids to reduce brain inflammation/swelling and immune system activity.
  • Blood plasma exchange to remove and replace the harmful antibodies circulating in the blood (which can find their way into the brain).
  • Intravenous immunoglobulin (IVIG), which includes helpful antibodies isolated from the blood plasma of thousands of healthy donors.
  • Immunosuppressant medications (like Cyclophosphamide and Rituximab) to directly suppress the immune system, if necessary.2-4

Steroids, blood plasma exchange, intravenous immunoglobulin, or a combination of the three represent the most common defense against AE.2,4 These first-line treatments can be helpful for stopping the immune system’s attack on brain tissue and reducing inflammation. Corticosteroids, for example, reduce brain swelling by preventing the production of inflammatory proteins by immune cells. These steroids also help to restore the integrity of the blood-brain barrier, a protective lining that shields the brain from inflammatory cells and  harmful antibodies that may be circulating in the bloodstream.5 In AE the blood-brain barrier can spring leaks, which allows antibodies from the bloodstream to penetrate the brain and wreak havoc.6 Closing up any leaks in the barrier that formed as a result of AE disease progression is a critical first step in the healing process.

However, recovery from AE can take time and is often not an abrupt rise and fall of symptoms (Figure 1, left). Instead, while many people do respond to available treatment options, the initial period of healing usually falls short of complete, giving way to a longer and more complicated recovery trajectory (Figure 1, center). For example, first-line therapies fail to resolve symptoms in about 50% of patients with AE, which means that additional and prolonged treatments are often required to suppress the immune system and give the brain an opportunity to repair and recover.4 In these cases, doctors turn to second-line therapies, like immunosuppressants. While having steroids on board promotes brain healing by stopping the leakage of antibodies from the bloodstream into the brain, immunosuppressants, like Rituximab, go after the cells that make the antibodies in the first place.5 When given long-term, Rituximab can be effective at reducing symptoms and keeping AE in remission.2,4

Figure 1: Rather than a simple rise in symptoms that is quickly attenuated with treatment (black line, left), the timeline of healing from AE often comes with a series of ups and downs (green line, center). The height of these highs and lows depends on many factors, such as the specific AE diagnosis (i.e., the type of antibody causing the attack and the brain areas involved) and the time between symptom onset and treatment. As such, each AE patient’s path to recovery looks different (right).

While therapies, like Rituximab, can be incredibly effective, outcomes are still highly variable. Because no two cases of AE are exactly the same, no two recovery trajectories are either (Figure 1, right). Both treatment options and outcomes often depend on details of the AE diagnosis, such as the type of antibody involved. For example, a recent study of 358 patients with AE demonstrated that people with anti-NMDAR antibodies, LGI1 antibodies, and CASPR2 antibodies respond differently to Rituximab immunotherapy.7 These groups of patients with AE caused by different antibodies not only reported differences in symptom relief, but they ultimately reached different levels of day-to-day independence. Nevertheless, regardless of treatment approach and AE diagnosis, early and aggressive therapy is consistently associated with better outcomes. This means that as diagnostic tools and treatments improve, more people with AE have the opportunity to heal.2

How long does the process of healing from autoimmune encephalitis take?

“Good, bad, up, down, round and round;

I feel as though I’m on a merry-go-round.

Full of uncertainty if it will ever stop spinning;

Full of frustration as I remain on my couch sitting.

It’s going to be alright; it’s going to be okay; I will continue the fight day to day.

I will keep the hope and learn to cope;

I will continue my way up this slippery slope with hopes of support and love of some sort.”

— Anonymous on living with AE8

Since people tend to differ in their response to AE treatments, they tend to recover at different paces. For some, AE symptoms decline steadily with continued immunotherapy, leading to recovery within a couple months. Others experience persistent relapses, leading to a recovery timeline on the order of years (Figure 1, right). Research studies show that most patients continue to improve 18 months to 2 years after starting treatment, but there are some people with AE who experience ongoing and life-changing symptoms.9

Similar to how some types of AE respond better or worse to particular treatments, AE diagnosis also affects the timeline of recovery and the risk of recurrence. A recent study followed up with AE patients 3, 6, and 12 months after starting treatment, assessing and comparing their symptoms using a measure of the degree of disability or dependence. Researchers and clinicians found that after three months, two thirds of patients with anti-LGI1 or CASPR2 antibodies recovered to “slight disability” compared to only 30% of patients with anti-NMDAR or other antibody-based AE.10

This persistence of symptoms among patients with anti-NMDAR vs. anti-LGI1 or CASPR2 AE may come from the fact that different AE antibodies carry different risks for relapse. For example, the risk of relapse within two years for anti-NMDAR AE is 12%.9 There are other AE diagnoses, like anti-AMPAR AE, where the relapse rate is even higher, pushing 50-60%.11 This increased risk of relapse is thought to stem from the fact that patients with anti-AMPAR AE often have psychiatric and memory dysfunction that make them less likely to keep up with medications. However, while it may be more prevalent for some types of AE than others, relapse is not a given. These same studies show that patients who receive (and continue) with first-line treatments have a lower risk of recurrence relative to untreated patients.11 Risk of relapse is further decreased in patients who have been given both first- and second-line therapies.5,9 This clear payoff of continued treatment suggests that as we continue to make improvements to AE therapies, there is potential for the percentage of patients reaching recovery to continue to increase.

All in all, vast differences in AE diagnoses and symptoms lead to lots of variability in treatment options, the healing process, and recovery timelines. This diversity of AE trajectories makes setting expectations for the healing process especially difficult. It also highlights the resilience of AE patients, their families, and their support systems who tirelessly endure and advocate despite prolonged uncertainty.

“A dear lady friend of mine (with the same illness) said this great quote that I reflect on frequently:

‘Not every day is good, but there is good in every day.’

And that has been absolutely true.

Each day presents itself with its own challenges and even though I don’t know what the future holds,

I am most calm when I focus on the good one day at a time.

–Amy on her AE journey12

Work Cited:

  1. Lawrie, A. My experience with autoimmune encephalitis: A year of recovery. The Health Policy Partnership (2022). Available at: https://www.healthpolicypartnership.com/my-experience-with-autoimmune-encephalitis-a-year-of-recovery/. (Accessed: 25th October 2022).
  2. Dinoto, A., Ferrari, S. & Mariotto, S. Treatment options in refractory autoimmune encephalitis. CNS Drugs 36, 919–931 (2022).
  3. Abboud, H. et al. Autoimmune encephalitis: Proposed best practice recommendations for diagnosis and Acute Management.Journal of Neurology, Neurosurgery, and Psychiatry 92, 757–768 (2021).
  4. Dalmau, J. & Rosenfeld, M. R. Autoimmune encephalitis update. Neuro-Oncology 16, 771–778 (2014).
  5. Shin, Y.-W. et al. Treatment strategies for autoimmune encephalitis. Therapeutic Advances in Neurological Disorders 11, 1–19 (2018).
  6. Platt, M. P., Agalliu, D. & Cutforth, T. Hello from the other side: How autoantibodies circumvent the blood–brain barrier in autoimmune encephalitis. Frontiers in Immunology 8, 442 (2017).
  7. Thaler, F. S. et al. Rituximab treatment and long-term outcome of patients with autoimmune encephalitis. Neurology: Neuroimmunology and Neuroinflammation 8, (2021).
  8. Fitch, A. AE Warrior Personal Stories Archives. Autoimmune Encephalitis (2022). Available at: https://autoimmune-encephalitis.org/category/ae-warrior-personal-stories/. (Accessed: 25th October 2022).
  9. 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 Neurology 12, 157–165 (2013).
  10. Seifert-Held, T. et al. Functional recovery in autoimmune encephalitis: A prospective observational study. Frontiers in Immunology 12, 641106 (2021).
  11. Leypoldt, F., Wandinger, K.-P., Bien, C. G. & Dalmau, J. Autoimmune encephalitis. European Neurological Review 8, 31–37 (2013).
  12. Amy. Amy’s story. The Encephalitis Society (2021). Available at: https://www.encephalitis.info/amys-story. (Accessed: 25th October 2022).

 

 

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

 

 

 

 

On June 16 th, 2022, Tabitha Orth, President and Founder of International Autoimmune Encephalitis Society officially became the 7,315 th “point of light”. Recognized for the volunteer work she and IAES has done to spark change and improve the world for those touched by Autoimmune Encephalitis. The award was founded by President George H.W. Bush in 1990.

 

 

Become an Advocate by sharing your story. It may result in accurate diagnosis for someone suffering right now who is yet to be correctly identified. Submit your story with two photos to IAES@autoimmune-encephalitis.org  

 

 

International Autoimmune Encephalitis Society (IAES), home of the AEWarrior®, is the only Family/Patient-centered organization that assists members from getting a diagnosis through to recovery and the many challenges experienced in their journey. Your donations are greatly appreciated and are the direct result of IAES’ ability to develop the first product in the world to address the needs of patients, Autoimmune Encephalitis Trivia Playing Cards. Every dollar raised allows us to raise awareness and personally help Patients, Families, and Caregivers through their Journey with AE to ensure that the best outcomes can be reached. Your contribution to our mission will help save lives and improve the quality of life for those impacted by AE.   For this interested in face masks, clothing, mugs, and other merchandise, check out our AE Warrior Store!  This online shop was born out of the desire for the AE patient to express their personal pride in fighting such a traumatic disease and the natural desire to spread awareness. Join our AE family and help us continue our mission to support patients, families and caregivers while they walk this difficult journey.  

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

Fatigue and Autoimmune Encephalitis: You’re Not Alone

November 30, 2022 | by Vanessa B. Sanchez, PennNeuroKnow

 

Introduction

Imagine you just pulled out a load of laundry from the dryer, and as you begin to get into the groove of folding clothes, out of nowhere, you have a profound loss of energy (1). What you are experiencing is called fatigue. Fatigue is different from drowsiness or sleepiness. For example, drowsiness is the need for sleep whereas sleepiness is the likelihood of being able to fall asleep (1, 3). To clarify, fatigue is the overwhelming feeling of tiredness, weakness, and a complete lack of energy (3).

Fatigue impacts millions of Americans every day. In fact, about 5 to 10% of visits to primary care doctors in the United States are due to patients reporting fatigue (3). Despite its pervasiveness, fatigue can be experienced differently across individuals. For example, males describe fatigue as feeling tired while females more often describe their fatigue as feeling anxious or depressed (2).

Fatigue is a common symptom of autoimmune encephalitis

Patients with autoimmune encephalitis (AE) describe fatigue as one of their main persistent symptoms, even after recovery (5). It can become so disabling that patients may drop out of school or work, thus negatively impacting their quality of life (6). Dr. Anusha K Yeshokumar, an autoimmune neurologist, conducted two studies to determine the outcomes of survivors of AE in order to find ways to improve patients’ quality of life (5). In both studies, she found that over 60% of patients reported experiencing fatigue (5).  Of these patients, she also found that over 80% of them reported feeling both physical (feeling weak, the need to rest, etc.) and cognitive fatigue (less alert, cannot think clearly, etc.) (5).

A notable finding in Dr. Yeshokumar’s study was that anti-NMDAR AE seems to act differently when it comes to fatigue, such that adults experience it much less than children (5). Another factor that influenced whether patients with AE experienced fatigue was the time of diagnosis and treatment. Anti-NMDAR AE is one of the most well-characterized AEs, so doctors tend to diagnose and treat patients faster than other types of AE. Other types of AE aren’t as well-characterized, which can interfere with a doctor’s ability to properly diagnose and treat patients quickly. Because of this interference, patients who do not get diagnosed as quickly are more likely to experience fatigue. For example, patients with other AEs reported the time from symptom onset to diagnosis and to treatment took almost 300 days while it only took 30 days for patients with anti-NMDAR AE! (5). As doctors and researchers learn more about other AEs, it can hopefully aid in earlier diagnosis and treatment to prevent chronic (≥6 months) fatigue.

Is your brain making you feel fatigued?

Fatigue is often associated with the sickness behavioral response, which occurs when the body tries to cope or fight off an infection (14). Scientists believe that the brain is responsible for this sickness behavioral response (7). In a recent study, scientists explored whether there are certain types of neurons that become activated when an infection occurs and may be responsible for sickness behaviors (7,8). To do so, scientists injected healthy mice with a molecule to induce a bacterial infection and make them sick (7,8). Afterwards, scientists performed a special technique called single-cell RNA sequencing (scRNA-seq) on the brains of mice who did or did not receive the bacterial injection (7,8). scRNA-seq is a widely used tool used to study the identity of different types of cells (To learn more and read about scRNA-seq, check out this Penn Neuro Know article!). By using this sequencing technique, scientists discovered two specific populations of neurons that reside in the brainstem, the part of our brain connected to the spinal cord (7,8). Scientists found that these populations in the brainstem are responsible for several sickness symptoms, like appetite, movement, and body temperature (7,8). Changes in mouse behavior like a reduction in physical activity and/or weight loss are how scientists can make inferences that mice are experiencing fatigue (17). This is because fatigue is often associated with a decline in physical and daily activities.

In another complementary study, a team of scientists found another specialized population of neurons in a brain region called the hypothalamus that are responsible for sickness behaviors like fever and nausea (7,9). These key findings are now pointing scientists in the right direction toward fully understanding these neuronal populations in order to mitigate or prevent sickness behaviors, including fatigue.

Are there other explanations for fatigue?

Another reason why patients experience fatigue is because they may have chronic or relapsing neuroinflammation (5). Neuroinflammation occurs when the body’s immune system is triggered following an infection, or in the case of AE, to attack healthy cells in the brain. The brain has a protective sheath called the blood-brain barrier (BBB), which prevents most infections and foreign invaders from getting to the brain. In the case that infection or inflammation does occur, the body’s immune cells will release a special signal that can pass through the BBB to let neurons and microglia know danger is near. These signals alert a special population of immune cells in the brain, called microglia, that they should begin to defend against infection. Once microglia are alerted, they will activate neighboring neurons. When neurons receive this signal, they become strongly active and communicate with nearby neurons and brain regions (14). Scientists have proposed that this increased neuronal activity is what also contributes to fatigue (14). In the case of AE or chronic neuroinflammation, scientists postulate that because microglia and other immune cells are constantly activated and releasing that special signal, neurons also remain persistently active, and so do feelings of fatigue (14). 

Treatments for chronic fatigue

Doctors can prescribe some medications or over-the-counter drugs that can ease symptoms of chronic fatigue (13). Some doctors might suggest lifestyle changes to help manage and alleviate fatigue, such as practicing good sleep hygiene (i.e., getting a full 8 hours of sleep and keeping a sleep diary) and lifestyle changes (i.e., eating, drinking, exercising, etc.) (15, 16). Despite working for some patients, sometimes medications and lifestyle changes are not enough to alleviate chronic fatigue. In those cases, holistic interventions, like yoga or mindfulness, can also sometimes improve overall quality of life. For example, patients with multiple sclerosis (MS) – another type of autoimmune disease – who practiced yoga for 2 or 4 months reported lower levels of fatigue (11). Other studies have found that MS patients who practiced trait mindfulness (the ability to practice living in the present moment) also reported being able to maintain a higher health-related quality of life (10, 12).

Research studies such as the one by Dr. Yeshokumar are huge steps towards understanding how fatigue impacts survivors of AE and being able to better treat patients. Both scientists and doctors are getting closer to understanding the exact biological mechanisms of fatigue in AE, which will hopefully aid in the development of treatments that target these mechanisms to improve patients’ quality of life.

References:

1-Medline. Fatigue (https://medlineplus.gov/ency/article/003088.htm)

2-Rosenthal, T. C., Majeroni, B. A., Pretorious, R., & Malik, K. (2008). Fatigue: an overview. American family physician, 78(10), 1173-1179.

3-Dukes, J. C., Chakan, M., Mills, A., & Marcaurd, M. (2021). Approach to fatigue: best practice. Medical Clinics, 105(1), 137-148.

4-Son, C. G. (2019). Differential diagnosis between “chronic fatigue” and “chronic fatigue syndrome”. Integrative medicine research, 8(2), 89.

5-Diaz-Arias, L. A., Yeshokumar, A. K., Glassberg, B., Sumowski, J. F., Easton, A., Probasco, J. C., & Venkatesan, A. (2021). Fatigue in survivors of autoimmune encephalitis. Neurology-Neuroimmunology Neuroinflammation, 8(6). 

6-De Bruijn, M. A., Aarsen, F. K., Van Oosterhout, M. P., Van Der Knoop, M. M., Catsman-Berrevoets, C. E., Schreurs, M. W., … & Titulaer, M. J. (2018). Long-term neuropsychological outcome following pediatric anti-NMDAR encephalitis. Neurology, 90(22), e1997-e2005.

7-Hicks, A. I., & Prager-Khoutorsky, M. (2022). Neuronal culprits of sickness behaviours.

8-Ilanges, A., Shiao, R., Shaked, J., Luo, J. D., Yu, X., & Friedman, J. M. (2022). Brainstem ADCYAP1+ neurons control multiple aspects of sickness behaviour. Nature, 1-11.

9-Osterhout, J. A., Kapoor, V., Eichhorn, S. W., Vaughn, E., Moore, J. D., Liu, D., … & Dulac, C. (2022). A preoptic neuronal population controls fever and appetite during sickness. Nature, 1-8.

10-​​Grossman, P., Kappos, L., Gensicke, H., D’Souza, M., Mohr, D. C., Penner, I. K., & Steiner, C. (2010). MS quality of life, depression, and fatigue improve after mindfulness training: a randomized trial. Neurology, 75(13), 1141-1149.

11-Dehkordi, A. H. (2016). Influence of yoga and aerobics exercise on fatigue, pain and psychosocial status in patients with multiple sclerosis: a randomized trial.

12-Mioduszewski, O., MacLean, H., Poulin, P. A., Smith, A. M., & Walker, L. A. (2018). Trait mindfulness and wellness in multiple sclerosis. Canadian Journal of Neurological Sciences, 45(5), 580-582.

13-Cassoobhoy, A. (2020, December 13). Medications used to treat chronic fatigue syndrome (CFS). WebMD. Retrieved September 17, 2022, from https://www.webmd.com/chronic-fatigue-syndrome/medicines-treat-chronic-fatigue-syndrome 

14-Omdal, R. (2020). The biological basis of chronic fatigue: neuroinflammation and innate immunity. Current opinion in neurology, 33(3), 391-396.

15-Encephalitis Society. Managing fatigue after encephalitis.

16- Brazier, Y. (2022, August 10). Fatigue: Why am I so tired, and what can I do about it? Medical News Today. Retrieved August 31, 2022, from https://www.medicalnewstoday.com/articles/248002

17-Wolff, B. S., Raheem, S. A., & Saligan, L. N. (2018). Comparing passive measures of fatigue-like behavior in mice. Scientific reports, 8(1), 1-12.

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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.

 

 

Become an Advocate by sharing your story. It may result in accurate diagnosis for someone suffering right now who is yet to be correctly identified. Submit your story with two photos to IAES@autoimmune-encephalitis.org  

 

 

International Autoimmune Encephalitis Society (IAES), home of the AEWarrior®, is the only Family/Patient-centered organization that assists members from getting a diagnosis through to recovery and the many challenges experienced in their journey. Your donations are greatly appreciated and are the direct result of IAES’ ability to develop the first product in the world to address the needs of patients, Autoimmune Encephalitis Trivia Playing Cards. Every dollar raised allows us to raise awareness and personally help Patients, Families, and Caregivers through their Journey with AE to ensure that the best outcomes can be reached. Your contribution to our mission will help save lives and improve the quality of life for those impacted by AE.   For this interested in face masks, clothing, mugs, and other merchandise, check out our AE Warrior Store!  This online shop was born out of the desire for the AE patient to express their personal pride in fighting such a traumatic disease and the natural desire to spread awareness. Join our AE family and help us continue our mission to support patients, families and caregivers while they walk this difficult journey.  

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

Movement disorders as a window into the diversity of autoimmune encephalitis

September 14, 2022 | by Catrina Hacker, PennNeuroKnow

Whether it’s walking to the grocery store or hugging a friend, movement is a central part of how we interact with the world. We don’t usually think about how we’re able to move, but every motion is part of a beautifully efficient process that coordinates a complicated network of cells across the nervous system. When neurological disorders disrupt this coordination, the efficiency of our motor system breaks down, which can lead to a variety of movement disorders and produce a broad range of symptoms. Movement disorders are a common symptom across the many types of autoimmune encephalitis (AE) and can be especially important to the diagnosis of AE in children.

Learning the language of movement disorders

The scientific literature is littered with dozens of specialized terms doctors use to describe movement-related disorders. For doctors, these terms are helpful because they can precisely describe specific symptoms that help them distinguish between different diagnoses, but they can be intimidating to non-medical readers. To begin, let’s break down a few important terms describing the disorders most common in various types of AE. Please note that this is not an exhaustive list and is only meant to capture some of the most common movement disorders that can result from common types of AE. (Click the name of the disorder to watch a Youtube video demonstrating some of these symptoms.)

Ataxia. Ataxia describes difficulty balancing and coordinating movements. In the most classic presentation of ataxia patients struggle with walking and running, particularly in situations that require more coordination such as walking up and down stairs1. Patients with ataxia can have a high risk of falling and in some cases they might have difficulty coordinating the movements necessary for speaking or writing2. One type of ataxia is thought to be caused by degeneration of neurons in a brain region known to be important for movement called the cerebellum1,2.

Chorea. Patients with chorea make involuntary, random movements. These brief and random movements are not repetitive or rhythmic but do appear to flow from one muscle to the next3. Chorea can occur in any muscle group, ranging from fingers and toes to facial movements. Interestingly, chorea subsides when patients are asleep4. Chorea is associated with too much activity of a neurotransmitter called dopamine that plays an important role in coordinating and initiating movement3,4.

Dystonia. Patients with dystonia experience involuntary muscle contractions that result in abnormal postures and repetitive movements. These contractions can occur anywhere on the body and are often painful. Like ataxia, dystonia can cause problems with speech and handwriting. In addition, patients with dystonia might experience foot cramps or drag their foot after prolonged exercise5.

Myoclonus. Myoclonus is a broad term describing sudden, involuntary jerking of muscles. This often involves twitching of a muscle followed by relaxation. If you’ve ever jerked awake while drifting off to sleep you’ve experienced a benign myoclonic jerk (this is not worrisome as an isolated event). Myoclonic jerks can occur on their own or be associated with different disorders6. The movements in myoclonus are quick and simple, while the movements in chorea tend to be slower and continuous. (Hear directly from a patient about her experience with dystonia and myoclonus here)

Movement disorders across different types of autoimmune encephalitis

While many types of AE can result in movement disorders, some subtypes have unique symptoms that distinguish them from others. Sometimes movement disorders are one of the most prominent symptoms to present themselves, whereas in other cases they may be more subtle and secondary to other psychiatric symptoms. Here we will discuss some of the subtypes of AE that most commonly result in movement disorders.

Several movement disorders often present together in patients with anti-NMDAR AE, the most common AE. Chorea and dystonia are observed in up to 90% of Anti-NMDAR patients7. While they can affect all limbs, in anti-NMDAR encephalitis they most characteristically affect the face and mouth8. In some cases these might be the first signs of the disease, so a clinician should consider the possibility of AE when patients visit the clinic with complaints of movement-related symptoms7.

Movement disorders are some of the most common symptoms of CASPR2-antibody associated encephalitis. Ataxia is observed in up to a third of patients and can be the only presenting symptom at disease onset, with other symptoms developing later7. The ataxia in CASPR2-encephalitis patients often manifests as a strong gait disturbance8 that occurs in brief, but frequent, bursts7. CASPR2-encephalitis can also present with a distinct form of myoclonus that distinguishes it from other kinds of AE. This form of AE is most common in elderly men9, and myoclonus of the lower limbs is often observed when patients are walking or standing. Spinal myoclonus leading to spasms around the abdomen has also been observed in CASPR2-encephalitis patients7. Finally, in some cases chorea is a prominent movement-related symptom of CASPR2-encephalitis7.

IGLON5-antibody associated encephalitis can also present with many movement disorders. While the best indicator of IGLON5-encephalitis is sleep disorders, some patients have also been reported to have chorea7. Another movement disorder reported in some IGLON5-encephalitis patients is axial rigidity, or rigidity in the trunk and hips. These movement disorders can make it difficult for patients with IGLON5-encephalitis to walk and balance and can put them at risk of falling8.

Many other types of AE are associated with movement disorders including (but not limited to) GlyR-, DDPX-, LGI1-, and mGluR1-antibody associated encephalitis7,8. It is important to note that although movement disruptions are common in many types of AE, they are rarely the only symptom and are not diagnostic on their own7,8,10. Instead, they can serve as one of many clues leading doctors toward a correct diagnosis. The neural explanation for how each type of AE leads to these movement disorders is not well understood. Determining the biological basis of the relationship between AE and movement disorders is an important area for future research that might help us to better understand these distinct subtypes of AE.

Movement disorders in children and adults with autoimmune encephalitis

In addition to distinguishing different types of AE, movement disorders are proving to be an especially important diagnostic tool for children with AE. Movement disorders can be observed in both children and adults, but they are more common in children, particularly those with anti-NMDAR AE. The presentation of anti-NMDAR AE in adults is now well understood and typically involves psychiatric symptoms and cognitive impairment as well as the movement disorders described above. The presentation of anti-NMDAR AE in children isn’t as well documented, but diverges from adults in that it more often includes seizures and movement disturbances7,10,11.

In many cases, movement disturbances are the first or only presenting symptom in children with anti-NMDAR AE. One set of case studies showed that four young patients eventually diagnosed with anti-NMDAR AE all initially presented with difficulties walking or coordinating movement10. Another study considered 50 cases of children with anti-NMDAR AE and found that motor deficits including dystonia of the hands and feet are key in diagnosing focal seizures that often accompany AE in these patients11. The initial presentation of anti-NMDAR AE can be ambiguous, and treatment is often delayed because a diagnosis is not immediately made. The presence of movement disorders and other disturbances (e.g., those accompanying seizures) along with other symptoms could be key signs to consider a diagnosis of AE in children10.

The diversity of movement disorders in various types of AE mirrors the diversity of the diseases themselves. Whether in distinguishing subtypes of AE or diagnosing children, they are a powerful spotlight under which the diversity of AE can be interrogated. Despite our growing understanding of how movement disorders can be used to diagnose various types of AE, there is still very little understanding of why different types of AE cause different types of movement disorders. Future work can leverage these known differences in movement disorders associated with different types of AE to better understand their biological basis and hopefully develop better treatments and cures. 

References

  1. Ataxias and Cerebellar or Spinocerebellar Degeneration | National Institute of Neurological Disorders and Stroke. https://www.ninds.nih.gov/health-information/disorders/ataxias-and-cerebellar-or-spinocerebellar-degeneration.
  2. Kuo, S.-H. Ataxia: Contin. Lifelong Learn. Neurol. 25, 1036–1054 (2019).
  3. Chorea | National Institute of Neurological Disorders and Stroke. https://www.ninds.nih.gov/health-information/disorders/chorea.
  4. Bhidayasiri, R. Chorea and related disorders. Postgrad. Med. J. 80, 527–534 (2004).
  5. Dystonia | National Institute of Neurological Disorders and Stroke. https://www.ninds.nih.gov/health-information/disorders/dystonia.
  6. Myoclonus | National Institute of Neurological Disorders and Stroke. https://www.ninds.nih.gov/health-information/disorders/myoclonus.
  7. Gövert, F. et al. Antibody-related movement disorders – a comprehensive review of phenotype-autoantibody correlations and a guide to testing. Neurol. Res. Pract. 2, 6 (2020).
  8. Uy, C. E., Binks, S. & Irani, S. R. Autoimmune encephalitis: clinical spectrum and management. Pract. Neurol. 21, 412–423 (2021).
  9. van Sonderen, A. et al. The clinical spectrum of Caspr2 antibody–associated disease. Neurology 87, 521–528 (2016).
  10. Yeshokumar, A. K., Sun, L. R., Klein, J. L., Baranano, K. W. & Pardo, C. A. Gait Disturbance as the Presenting Symptom in Young Children With Anti-NMDA Receptor Encephalitis. Pediatrics 138, e20160901 (2016).
  11. Favier, M. et al. Initial clinical presentation of young children with N-methyl- d -aspartate receptor encephalitis. Eur. J. Paediatr. Neurol. 22, 404–411 (2018).

 

 

 

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

 

 

 

 

On June 16 th, 2022, Tabitha Orth, President and Founder of International Autoimmune Encephalitis Society officially became the 7,315 th “point of light”. Recognized for the volunteer work she and IAES has done to spark change and improve the world for those touched by Autoimmune Encephalitis. The award was founded by President George H.W. Bush in 1990.

 

 

Become an Advocate by sharing your story. It may result in accurate diagnosis for someone suffering right now who is yet to be correctly identified. Submit your story with two photos to IAES@autoimmune-encephalitis.org  

 

 

International Autoimmune Encephalitis Society (IAES), home of the AEWarrior®, is the only Family/Patient-centered organization that assists members from getting a diagnosis through to recovery and the many challenges experienced in their journey. Your donations are greatly appreciated and are the direct result of IAES’ ability to develop the first product in the world to address the needs of patients, Autoimmune Encephalitis Trivia Playing Cards. Every dollar raised allows us to raise awareness and personally help Patients, Families, and Caregivers through their Journey with AE to ensure that the best outcomes can be reached. Your contribution to our mission will help save lives and improve the quality of life for those impacted by AE.   For this interested in face masks, clothing, mugs, and other merchandise, check out our AE Warrior Store!  This online shop was born out of the desire for the AE patient to express their personal pride in fighting such a traumatic disease and the natural desire to spread awareness. Join our AE family and help us continue our mission to support patients, families and caregivers while they walk this difficult journey.  

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

Blood, Sweat, and Clusterin

January 26, 2022 | by Nitsan Goldstein, New insights into the link between exercise and improved cognition

If you’ve been following the developments in COVID-19 treatments over the last year, you’ve probably heard of monoclonal antibodies being used to treat people with severe cases of COVID. Monoclonal antibodies are produced and circulated through the blood when your body fights off an infection. Scientists have figured out how to extract these antibodies from the blood of patients who have recovered from COVID and inject them into patients that are in earlier stages of the disease. While treatments like these are certainly amazing medical feats, it is not all that surprising that contents from the blood of a person who has successfully fought off an infection might help someone else fight the same virus. It turns out, though, that antibodies are not the only proteins circulating in your blood that could improve someone’s health.

We’ve known for hundreds of years that certain qualities about a person make them more or less likely to have strong cognitive skills like memory. Being young, for example, means your memory is likely strong while being older or suffering from diseases like Alzheimer’s means your memory is weaker. Another such factor is the degree to which you exercise. Exercise improves cognitive skills and can help improve memory in people suffering from dementia. For many years, scientists have asked how these factors actually improve brain function. If we can figure out how things like youth and exercise improve memory, perhaps we can use those same pathways to develop treatments for dementia and related disorders.

In 2014, a study was published showing that simply taking blood from young mice and infusing it into older mice could improve the older mice’s performance on memory tasks1. This result was exciting because it suggested that not only could memory impairments of older mice be reversed, but also that they could be reversed by some molecule that was circulating in the blood of young mice. This month, the same group published another study showing that much like the blood of young mice, the blood of mice that had been exercising regularly could also improve other mice’s ability to perform a memory task2. Recent technological advancements allowed them to identify one of the specific proteins in the blood that was mediating the effects in the brain.

The researchers started by infusing plasma, or the liquid part of blood, that was taken from mice that had access to a running wheel for 28 days into mice that did not have access to a wheel. They found that sedentary mice that received plasma infusions from exercised mice (1) performed better on memory tasks, (2) displayed increased neurogenesis, a process believed to be important for memory, and (3) showed evidence of decreased inflammation in the brain. This last finding was intriguing considering the negative impact neuroinflammation can have on learning and memory and the strong link between neurodegenerative diseases like Alzheimer’s and a heightened inflammatory state3,4.

To further probe the relationship between inflammation and memory, the group decided to inject an inflammatory agent and measure changes in the brain with or without plasma taken from exercised mice. They focused on the hippocampus, a region that is crucial for the formation of memories and is prone to degeneration in neurodegenerative diseases. The scientists examined the changes in gene expression or the proteins that will be produced by cells in the hippocampus, after injecting mice with lipopolysaccharide (LPS), which causes an inflammatory response. LPS injection caused changes in gene expression in the hippocampus, but many of these changes were reversed after treatment with plasma from exercised mice. Next, the researchers wanted to pinpoint the protein or proteins in the blood that are responsible for reversing these LPS-induced changes in gene expression. After identifying several candidate proteins, they repeated the experiment, only this time some mice got plasma where one of the candidate proteins was removed before the infusion. They found that one protein, in particular, clusterin, was essential for the beneficial effects of exercised plasma on neuroinflammation. When clusterin was removed from exercised plasma, many of the effects on LPS-induced inflammation in the hippocampus were gone. Even more convincing, the researchers found that injecting clusterin alone was able to reverse some neuroinflammation caused by LPS.

So what are we waiting for? How can we get our hands on clusterin so that we can reap the benefits of exercise from the comfort of our couches? Before you start looking for clusterin vendors on the internet, it’s important to keep a few things in mind. First, it’s important to remember that these studies were performed in mice. The authors of the study did, however, begin to look at some of these pathways in exercised humans. They exposed one group of veterans with mild cognitive impairment to an exercise regimen and found that some of the changes in protein levels that they observed in mice were also present in humans, including increased levels of clusterin. Much more work is needed to further characterize gene expression and protein changes in humans after exercise and to link these changes to improved cognition. Another important point is that the true biological basis of the cognitive benefits of age and exercise is almost guaranteed to be more complicated than a single or even a handful of proteins circulating in the blood. Moreover, altering gene expression or proteins involved in these very crucial pathways can carry risks independent of their effects on memory. Therefore, highly controlled clinical trials must first conclude that these treatments are safe before even considering their efficacy. There are, however, ongoing clinical trials using plasma from young donors to treat neurodegenerative diseases like Alzheimer’s and Parkinson’s Disease5, giving us hope that one-day studies like these will lead to more informed and effective treatments for neurological diseases.

 

References

  1. Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med. 20, 659-63 (2014).
  1. De Miguel Z, Khoury N, Betley MJ, Lehallier B, Willoughby D, Olsson N, Yang AC, et al. Exercise plasma boosts memory and dampens brain inflammation via clusterin. Nature. Epub ahead of print (2021). 
  1. Monje ML, Toda H, Palmer TD. Inflammatory blockade restores adult hippocampal neurogenesis. Science 302, 1760-5 (2003).
  1. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell 140, 918-34 (2010).
  1. “Young Plasma.” Alzforum. https://www.alzforum.org/therapeutics/young-plasma 

Cover image by roxanawilliams1920 from Pixabay https://pixabay.com/photos/running-woman-fitness-runner-6252827/ 

 

 

 

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

 

Become an Advocate by sharing your story. It may result in accurate diagnosis for someone suffering right now who is yet to be correctly identified. Submit your story with two photos to IAES@autoimmune-encephalitis.org  

 

 

International Autoimmune Encephalitis Society (IAES), home of the AEWarrior®, is the only Family/Patient-centered organization that assists members from getting a diagnosis through to recovery and the many challenges experienced in their journey. Your donations are greatly appreciated and are the direct result of IAES’ ability to develop the first product in the world to address the needs of patients, Autoimmune Encephalitis Trivia Playing Cards. Every dollar raised allows us to raise awareness and personally help Patients, Families, and Caregivers through their Journey with AE to ensure that the best outcomes can be reached. Your contribution to our mission will help save lives and improve the quality of life for those impacted by AE.   For this interested in face masks, clothing, mugs, and other merchandise, check out our AE Warrior Store!  This online shop was born out of the desire for the AE patient to express their personal pride in fighting such a traumatic disease and the natural desire to spread awareness. Join our AE family and help us continue our mission to support patients, families and caregivers while they walk this difficult journey.  

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

Genetic Predisposition for Autoimmune Encephalitis

January 12, 2022 | by Greer Prettyman, PennNeuroKnow

You might have your dad’s brown eyes or your mother’s curly hair. Traits like eye color are heritable, which means they are passed from parents to offspring. While we can inherit a lot of good traits from our parents, risk for certain diseases can also be inherited. Some diseases, like Huntington’s, are strongly linked to genetic risk factors. If someone’s parent has Huntington’s Disease, there is a 50% chance that they will develop it as well1. This is because Huntington’s disease is caused by a specific, heritable mutation in the DNA.

 

Not many disorders have such a clear genetic cause. However, the set of genes inherited from the parents can increase someone’s risk, or predisposition, for developing certain diseases, even if it doesn’t directly cause the disease. For example, people can have genetic predispositions for some types of cancer, psychiatric illnesses, and health risks like high cholesterol2,3,4. Recent research suggests that certain types of autoimmune encephalitis (AE) may also be linked to genetic factors that put some people at higher risk of developing this disease than others5.

 

Genes and Heritability 

 

Let’s step back to understand how genetic risk is transferred from parents to offspring by taking a look at DNA. DNA is the biological material that makes us who we are. Humans and animals inherit half of their DNA from their mother and half from their father. The DNA itself is made up of four nucleotide base pairs called adenine (A), thymine (T), cytosine (C), and guanine (G). You can see in Figure 1 that the nucleotides form pairs with each other (A with T and C with G) on the two strands of the DNA double helix. The human genome has 3 billion of these nucleotide pairs6. The order of the nucleotides makes up a genetic “code” that dictates what proteins are made and eventually what traits we have. At every single position, a person can have one of these four nucleotides. Variation in the nucleotide sequence at particular locations on the DNA is what makes each individual unique. Changes of nucleotides at some positions, however, can increase risk for certain diseases.

Figure 1. Cartoon schematic of a DNA double helix with nucleotide base pairs (A,T,C, and G). At each position on the DNA, a person can inherit one of the four nucleotides and variation in the sequence produces the genetic code.

 

Genetic Risk for AE

Researchers can learn about genetic risk factors for specific diseases or conditions by collecting data about individuals’ genotypes. A genome-wide association study (GWAS) is used to assess the whole genomes of many people to identify genetic mutations that are associated with that disease. Researchers have conducted GWAS studies in patients with autoimmune encephalitis (AE) to search for clues about genetic predisposition5. In contrast to a GWAS study that looks at the entire genome, other genetic research focuses only on select genes that are hypothesized to relate to a disease. AE is a disorder that involves the immune system incorrectly targeting the brain’s own cells. In the case of AE, researchers often look at genes that encode proteins involved in the immune system, which are likely locations for genetic mutations that might increase risk for this disease.

It turns out that some types of AE, like limbic encephalitis, are more closely tied to genetic risk factors than others7. The main genetic factor that has been associated with limbic encephalitis is called human leukocyte antigen (HLA). HLA genes are found on chromosome 6 and are categorized into three classes, class I, II, and III, which have genes that encode different proteins that help to regulate the immune system7. Mutations in these genes have been associated with a variety of disorders that involve autoantibodies, including limbic encephalitis7.

The most common form of limbic encephalitis that is not caused by cancer involves anti-leucine-rich glioma-inactivated 1 (anti-LGI1) antibodies7. Anti-LGI1 limbic encephalitis is associated with a mutation in part of the class II HLA gene complex. Anti-LGI1 antibodies are in the IgG4 isotype, which has been associated with HLA genes in a variety of autoimmune conditions7,8. A genetic mutation called DRB1*07:01 was found to be carried in up to 90% of people with anti-LGI1 encephalitis9. This suggests that this specific HLA mutation is associated with the development of limbic encephalitis, although the exact biological mechanisms are still unknown7.

In contrast to anti-LGI1 limbic encephalitis, anti-NMDAR encephalitis has not been found to have a strong relationship to HLA mutations7. A GWAS study found evidence for some weak links with HLA mutations, but there were no genetic mutations common to both anti-LGI1 limbic encephalitis and anti-NMDAR encephalitis5. Anti-NMDAR encephalitis is caused by antibodies of the IgG1 isotype, which may explain why there is a weaker association with genetic variations in HLA, which are more strongly associated with the IgG4 isotype7. One study did find differences in genes that encode inflammatory cytokines related to anti-NMDAR encephalitis in a small Southern Han Chinese population10, but more research is needed to determine if this association holds true in other populations.

The heterogeneous nature of AE makes it hard to pinpoint exact genetic risk factors. It is clear, however, that the interaction between a person’s genes and their environment is a stronger predictor of whether they will experience a particular outcome than genetics alone. For example, environmental factors like contracting a virus can lead to AE. Someone with a genetic predisposition may be more likely to get AE after a virus than someone without those genetic mutations. Although researchers have learned that individuals with particular mutations in HLA genes are likely at greater risk for developing limbic encephalitis, more work will be needed to understand the biological mechanisms and links with environmental risks that lead to AE. Ultimately, the goal would be to use what we can learn about a person’s genetic risks to predict and prevent AE.

 

References:

 

  1. Caron NS, Wright GEB, Hayden MR. Huntington Disease. 1998 Oct 23 [updated 2020 Jun 11]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2021. PMID: 20301482.
  2. Garber JE, Offit K. (2005). Hereditary cancer predisposition syndromes. J Clin Oncol. 23(2):276-92.
  3. Baselmans BML, Yengo L, van Rheenen W, Wray NR. (2021). Risk in Relatives, Heritability, SNP-Based Heritability, and Genetic Correlations in Psychiatric Disorders: A Review. Biol Psychiatry. 89(1):11-19.
  4. Bouhairie VE, Goldberg AC. (2015). Familial hypercholesterolemia. Cardiol Clin. 33(2):169-79.
  5. Mueller SH, Färber A, Prüss H, Melzer N, Golombeck KS, Kümpfel T, Thaler F, Elisak M, Lewerenz J, Kaufmann M, Sühs KW, Ringelstein M, Kellinghaus C, Bien CG, Kraft A, Zettl UK, Ehrlich S, Handreka R, Rostásy K, Then Bergh F, Faiss JH, Lieb W, Franke A, Kuhlenbäumer G, Wandinger KP, Leypoldt F; German Network for Research on Autoimmune Encephalitis (GENERATE). (2018) Genetic predisposition in anti-LGI1 and anti-NMDA receptor encephalitis. Ann Neuro. 83(4):863-869.
  6. National Research Council (US) Committee in Mapping and Sequencing the Human Genome. Mapping and Sequencing the Human Genome. Washington (DC): National Academies Press (US); 1988. 2, Introduction. Available from: https://www.ncbi.nlm.nih.gov/books/NBK218247/
  7. Muñiz-Castrillo, S., Vogrig, A., & Honnorat, J. (2020). Associations between HLA and autoimmune neurological diseases with autoantibodies. Auto- immunity highlights, 11(1), 2.
  8. Koneczny, I., Yilmaz, V., Lazaridis, K., Tzartos, J., Lenz, T. L., Tzartos, S., Tüzün, E., & Leypoldt, F. (2021). Common Denominators in the Immunobiology of IgG4 Autoimmune Diseases: What Do Glomerulonephritis, Pemphigus Vulgaris, Myasthenia Gravis, Thrombotic Thrombocytopenic Purpura and Autoimmune Encephalitis Have in Common?. Frontiers in immunology, 11, 605214.
  9. Vogrig, A., Muñiz-Castrillo, S., Desestret, V., Joubert, B., & Honnorat, J. (2020). Pathophysiology of paraneoplastic and autoimmune encephalitis: genes, infections, and checkpoint inhibitors. Therapeutic advances in neurological disorders, 13, 1756286420932797.
  10. Li X, Zhu J, Peng Y, Guan H, Chen J, Wang Z, Zheng D, Cheng N, Wang H. (2020). Association of Polymorphisms in Inflammatory Cytokines Encoding Genes With Anti-N-methyl-D-Aspartate Receptor Encephalitis in the Southern Han Chinese. Front Neurol.

 

Images:

https://commons.wikimedia.org/wiki/File:DNA_strands.png 

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International Autoimmune Encephalitis Society (IAES), home of the AEWarrior®, is the only Family/Patient-centered organization that assists members from getting a diagnosis through to recovery and the many challenges experienced in their journey. Your donations are greatly appreciated and are the direct result of IAES’ ability to develop the first product in the world to address the needs of patients, Autoimmune Encephalitis Trivia Playing Cards. Every dollar raised allows us to raise awareness and personally help Patients, Families, and Caregivers through their Journey with AE to ensure that the best outcomes can be reached. Your contribution to our mission will help save lives and improve the quality of life for those impacted by AE.   For this interested in face masks, clothing, mugs, and other merchandise, check out our AE Warrior Store!  This online shop was born out of the desire for the AE patient to express their personal pride in fighting such a traumatic disease and the natural desire to spread awareness. Join our AE family and help us continue our mission to support patients, families and caregivers while they walk this difficult journey.  

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Why getting better at baseball might require just a little sleep

December 22, 2021 | by Claudia Lopez LloredaPennNeuroKnow

A new study found that activating memories through learning-associated sound cues during sleep improved the performance of a motor task.

Not every experience you have or fact that you encounter turns into a long-lasting memory. Many of these moments slip away, while others become stable, long-lasting memories in your brain. This process of stabilization, called memory consolidation, is influenced by many aspects that impact learning. One such factor is sleep, which is critical for the consolidation of a memory. But not all memories are the same, and scientists still wonder whether sleep could help improve a memory associated with a motor skill. A new study published in the Journal of Neuroscience found that activating a motor memory during sleep could improve performance of that motor skill1.

So how can a motor memory be activated? The technique used in this study, called targeted memory reactivation (TMR), consists of presenting a sensory aspect of a recently learned memory, like a sound or smell, to “activate” a memory while the person sleeps. One analysis found that TMR improved declarative memory, the ability to remember facts and personal experiences. Additionally, they found that TMR during deeper, non-rapid eye movement (non-REM) sleep was more effective than during REM sleep2. Another study found that learning-associated sound cues helped participants solve puzzles that they had left unsolved before sleep3.

But while TMR helped to improve declarative memory and problem solving, whether TMR could also improve motor skills had been a big question in the field. While some studies found that TMR improved a learned motor skill, like learning a finger tapping sequence, others found that activating motor memories had little effect on motor performance. Additionally, most of the motor skills tested relied on well-learned tasks that left little room for improvement, so the researchers in the new study decided to test a more complex task that emphasized action execution. 

To do this, the researchers trained and tested 20 participants in a complex motor task. They had to learn to control specific arm muscles to move a cursor on a computer to a particular target on the screen. With each of the eight different target locations, a unique sound was played — a bell or a dog’s bark for example — while the participants were being trained. After training, the participants learned to reliably flex and contract arm muscles to move the cursor to the target area associated with a specific sound.

Then the participants took a nap. During their approximately 60-minute nap, researchers played the same sounds that participants had learned to associate with certain targets in the task. In this case, they cued, or played, the sounds associated with about half of the targets. When the participants woke up, the researchers tested how well they performed for the targets that had been cued with sound while participants slept, which presumably activated the memory during sleep when the sound was played, versus the targets that had not been cued during sleep.

Participants showed an improved cursor control in the memories that were activated during their nap, with performance times on cued targets being faster than their performance times prior to sleeping and faster than those that had not been cued. On the other hand, movement towards targets that had not been cued were slower than before the participants went to sleep. Researchers also found that participants were able to move the cursor in a more direct and efficient way to the targets that were cued. These results suggest that re-activating motor memories, by presenting the learning-associated sound cue during sleep, strengthens the memories.

However, the improvement could be due to two things: participants could be remembering the task better or they could be executing it better. To pinpoint in what aspect participants were improving in, researchers looked at the time that it took the, to begin moving the cursor when they heard the sound associated with a target. The researchers identified that, for the cued targets, participants took less time moving the cursor, but the time it took for them to start participants was similar. Participants got better at controlling their muscles to move the cursor towards a specific target associated with a unique sound. This means that participants got faster and more accurate at the motor skill because they got better at the execution of the skill and not necessarily because they remembered better.

This new study reflects what other studies looking at memory activation during sleep have found: if a memory is re-activated it can be better consolidated. In this case, the researchers showed that memory activation during sleep can actually improve and enhance the performance of a motor skill learned previously. In fact, re-activation of these motor control memories may be necessary to strengthen memories and consequently the movements and motor skills learned. The authors suggest that this strategy could be used to help with rehabilitation in patients with injuries that impair movement. Activating certain motor memories while a patient sleeps could potentially help them recover and improve their daily lives. But beyond clinical applications, it may mean that getting better at a skill, be it throwing a baseball or driving a car, may just require a little sleep.

Images

Cover image. From Pixabay.

References

  1. Cheng, L. Y., Che, T., Tomic, G., Slutzky, M. W., & Paller, K. A. (2021). Memory reactivation during sleep improves execution of a challenging motor skill. The Journal of Neuroscience. https://doi.org/10.1523/jneurosci.0265-21.2021
  2. Hu, X., Cheng, L. Y., Chiu, M. H., & Paller, K. A. (2020). Promoting memory consolidation during sleep: A meta-analysis of targeted memory reactivation. Psychological Bulletin, 146(3), 218–244. https://doi.org/10.1037/bul0000223
  3. Sanders, K. E., Osburn, S., Paller, K. A., & Beeman, M. (2019). Targeted memory reactivation during sleep improves next-day problem solving. Psychological Science, 30(11), 1616–1624. https://doi.org/10.1177/0956797619873344

 

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International Autoimmune Encephalitis Society (IAES), home of the AEWarrior®, is the only Family/Patient-centered organization that assists members from getting a diagnosis through to recovery and the many challenges experienced in their journey. Your donations are greatly appreciated and are the direct result of IAES’ ability to develop the first product in the world to address the needs of patients, Autoimmune Encephalitis Trivia Playing Cards. Every dollar raised allows us to raise awareness and personally help Patients, Families, and Caregivers through their Journey with AE to ensure that the best outcomes can be reached. Your contribution to our mission will help save lives and improve the quality of life for those impacted by AE.   For this interested in face masks, clothing, mugs, and other merchandise, check out our AE Warrior Store!  This online shop was born out of the desire for the AE patient to express their personal pride in fighting such a traumatic disease and the natural desire to spread awareness. Join our AE family and help us continue our mission to support patients, families and caregivers while they walk this difficult journey.  

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Ataxia and Autoimmune Encephalitis

October 27, 2021 | by Vanessa B. Sanchez, PennNeuroKnow

Imagine you are at a playground with your friends playing hopscotch. It is your turn. You jump with both feet, hop on one foot, hop on the other, all just to get to the end. This type of motor control and balance is controlled by a particular brain structure called the cerebellum. The cerebellum (Latin for “little brain”) is traditionally known as the hub for motor coordination, balance, and posture, but recently has been recognized for its role in cognition (attention and language) and emotion regulation (like fear)1

  1. Damage to the cerebellum results in a condition known as Ataxia. Ataxia symptoms vary between each individual, but hallmark symptoms include trouble with coordination, walking, swallowing, speech, and on rare occasions, eye or heart problems2,3,6. Anyone is susceptible to developing ataxia. It can be acquired through alcohol abuse, head trauma, stroke, vitamin deficiency, and/or autoimmunity2. In some cases, ataxia is hereditary; someone can inherit either a dominant gene from one parent (autosomal dominant disorder), or a recessive gene from both parents (autosomal recessive disorder)2,3. A common cause of ataxia and/or problems with balance and gait is due to the progressive loss and degeneration of cerebellar neurons, specifically Purkinje cells. Purkinje cells are one of the largest neurons in the brain and are the cerebellum’s main communicators with the rest of the brain8.Once a patient is diagnosed with ataxia, physicians will try to identify the root cause by performing neurological examinations and laboratory tests5. While the neurological examination is used to determine the extent and severity of symptoms, the laboratory tests can help to ascertain if the ataxia is genetic, infectious, or immune related3. For instance, if a patient develops ataxia through a nutritional or immune-mediated cause, their abnormal vitamin or antibody levels would be detected during the laboratory tests5. A patient’s cerebrospinal fluid (CSF), the bodily fluid that surrounds the brain and spinal cord, can be examined to measure specific antibody levels and provide information about specific types of immune-mediated ataxia3,4.

    The cerebellum is particularly susceptible to damage and autoimmune attacks5. Autoimmune-related ataxias can encompass a spectrum of disorders including autoimmune encephalitis (AE), gluten ataxia, and Hashimoto’s encephalopathy4. This type of ataxia can also be episodic – presenting as sudden and intense episodes of ataxia accompanied by vertigo and dizziness. These episodes are especially prevalent in a type of AE called anti–CASPR2 antibody-associated autoimmune encephalitis5-7.

    Is cerebellar degeneration observed in autoimmune-related ataxias? Not really3. For example, scientists who study anti-NMDA receptor (anti-NMDAR) encephalitis use magnetic resonance imaging (MRI) to produce detailed images of the cerebellum and found that 2 out of 15 patients exhibited cerebellar atrophy, which was a surprise because it has never been reported in this disease9. While it is not exactly clear why cerebellar atrophy is occurring in these anti-NMDAR encephalitis patients, one hypothesis posits that NMDAR antibodies act like NDMAR antagonists (blocking and inhibiting an NMDA receptor from turning on)9. NMDA receptors are critical for relaying signals between neurons and for a signal to be passed, the receptor must open. So, if an antibody is acting like an antagonist, the receptor can’t open and the signal won’t be relayed. In other words, if a cerebellar neuron (Purkinje cell) cannot receive or relay a signal to another neuron, then there is improper communication throughout the whole brain, resulting in impaired balance or coordination.

    Above all, ataxia is an extremely rare condition and sometimes manifests with AE. Motor deficits are an early indicator that something is wrong and are typically the first thing doctors use to properly diagnose an autoimmune-related ataxia. Because there is no direct treatment, current methods focus on improving a patient’s balance and gait, in addition to immunotherapy and/or medications that may ease a patient’s symptoms like fatigue or muscle cramps2. The cerebellum remains an enigma and everyday new research is coming to light. With new work, scientists are constantly able to develop new treatment options. For example, Dr. Beverly Davidson, a renowned scientist at the Children’s Hospital of Philadelphia has dedicated over 20 years of her work towards developing genetic therapies for cerebellar ataxias, giving hope to the next generation of ataxia research!

    References:

    1. Reeber, S. L., Otis, T. S., & Sillitoe, R. V. (2013). New roles for the cerebellum in health and disease. Frontiers in systems neuroscience, 7, 83.
    2. What is ataxia? National Ataxia Foundation. (2021, April 26). https://www.ataxia.org/what-is-ataxia/.
    3. Kuo, S. H. (2019). Ataxia. Continuum (Minneapolis, Minn.), 25(4), 1036.
    4. Nanri, K., Yoshikura, N., Kimura, A., Nakayama, S., Otomo, T., Shimohata, T., … & Yamada, J. (2018). Cerebellar Ataxia and Autoantibodies. Brain and nerve= Shinkei kenkyu no shinpo, 70(4), 371-382.
    5. Lim, J. A., Lee, S. T., Moon, J., Jun, J. S., Kim, T. J., Shin, Y. W., … & Lee, S. K. (2019). Development of the clinical assessment scale in autoimmune encephalitis. Annals of neurology, 85(3), 352-358.
    6. Orsucci, D., Raglione, L. M., Mazzoni, M., & Vista, M. (2019). Therapy of episodic ataxias: Case report and review of the literature. Drugs in context, 8.
    7. Joubert, B., Gobert, F., Thomas, L., Saint-Martin, M., Desestret, V., Convers, P., … & Honnorat, J. (2017). Autoimmune episodic ataxia in patients with anti-CASPR2 antibody-associated encephalitis. Neurology-Neuroimmunology Neuroinflammation, 4(4).
    8. Voogd, J. & Glickstein, M. The anatomy of the cerebellum. Trends Neurosci. 21, 370–375 (1998).
    9. Iizuka, T., Kaneko, J., Tominaga, N., Someko, H., Nakamura, M., Ishima, D., … & Nishiyama, K. (2016). Association of progressive cerebellar atrophy with long-term outcome in patients with anti-N-methyl-D-aspartate receptor encephalitis. JAMA neurology, 73(6), 706-713.

    To learn more about ataxia, read this fact-sheet provided by the National Ataxia Foundation.

 

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

 

Become an Advocate by sharing your story. It may result in accurate diagnosis for someone suffering right now who is yet to be correctly identified. Submit your story with two photos to IAES@autoimmune-encephalitis.org  

 

 

International Autoimmune Encephalitis Society (IAES), home of the AEWarrior®, is the only Family/Patient-centered organization that assists members from getting a diagnosis through to recovery and the many challenges experienced in their journey. Your donations are greatly appreciated and are the direct result of IAES’ ability to develop the first product in the world to address the needs of patients, Autoimmune Encephalitis Trivia Playing Cards. Every dollar raised allows us to raise awareness and personally help Patients, Families, and Caregivers through their Journey with AE to ensure that the best outcomes can be reached. Your contribution to our mission will help save lives and improve the quality of life for those impacted by AE.   For this interested in face masks, clothing, mugs, and other merchandise, check out our AE Warrior Store!  This online shop was born out of the desire for the AE patient to express their personal pride in fighting such a traumatic disease and the natural desire to spread awareness. Join our AE family and help us continue our mission to support patients, families and caregivers while they walk this difficult journey.  

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

PANS and PANDAS: What are they and how do they relate to autoimmune encephalitis?

September 22, 2021 |  Nitsan Goldstein, PennNeuroKnow

PANS and PANDAS: what are they and how do they relate to autoimmune encephalitis?

Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is an autoimmune condition that occurs in children as young as three years old1. It is difficult to know how common PANS is due to the difficulty in diagnosing this relatively newly-recognized disease. PANS results in a very rapid (seemingly overnight) development of obsessive-compulsive behaviors in previously healthy children. Behavioral symptoms can also include separation anxiety, irritability, screaming, emotional and developmental regression, and even depression and suicidal thoughts1. The sudden onset of these symptoms can be terrifying for children and parents, making early diagnosis and proper treatment critical.

What causes PANS/PANDAS?

PANS occurs in a small subset of children in response to a bacterial infection. If the cause of the psychiatric symptoms is determined to be a streptococcal infection (the bacteria that causes strep throat), the disease is called Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS), which is a specific kind of PANS. However, a child can also develop PANS after contracting other infections like the flu, varicella, or herpes simplex virus1. PANS and PANDAS are typically very difficult to diagnose because the initial bacterial infection is often asymptomatic. For example, it is common that a sibling or classmate of a child with PANDAS was previously ill with strep, but the child who has PANDAS did not show symptoms at that time2. Because of this, the infection can go undetected and untreated, often for months, until psychiatric symptoms arise2. It is not yet clear why some children develop PANS/PANDAS and others do not. It is possible that some strains of bacteria can be more or less likely to cause PANS. Genetic differences in the immune and nervous systems have also been considered as potential risk factors2.

PANS and PANDAS are autoimmune diseases because they involve a hyperactive immune response that attacks the brain. Streptococcal infection is a common cause of PANS because the virus that causes strep mimics human cells in order to “hide” from the human immune system1. Because of this, antibodies that are made to target the virus can target human proteins as well. In PANS and PANDAS, the antibodies cross into the brain and start attacking brain cells, which results in the psychiatric symptoms.  

It is not fully understood which antibodies are produced in PANS and what proteins in the brain they target. Studies in mice and rats show that antibodies produced in response to a streptococcal infection targeted a receptor for the chemical dopamine in a region called the striatum3. Interestingly, dopamine signaling in the striatum is thought to be dysregulated in obsessive-compulsive disorder, and mice that were given these antibodies developed obsessive behaviors similar to those observed in PANDAS3. However, studies that attempted to isolate a specific marker for PANS or PANDAS have not been successful, making it likely that the conditions can be caused by a variety of antibodies1. Unfortunately, the lack of a consistent biological marker adds to the difficulty in diagnosing PANS and PANDAS. Doctors use the symptoms themselves along with a detailed patient history that might suggest a previous asymptomatic infection1

How is PANS treated?

Once a PANS/PANDAS diagnosis is made, a pediatrician will begin treatment by focusing on both the underlying cause and the psychiatric symptoms of the disease. Treatment of the underlying cause is simply a course of antibiotics to kill the infection. Though psychiatric symptoms may improve with antibiotics, children may also require cognitive behavioral therapy (CBT) to address lingering obsessive-compulsive behaviors. In some cases, treatment may also include immune modulators to try to prevent the antibodies from attacking the brain1,4

Though many children fully recover, it is common for children to have flare-ups of symptoms when a new infection occurs. Long-term antibiotics can be used to prevent future infections if flare-ups are common, along with CBT and immune modulators4

PANS/PANDAS and autoimmune encephalitis

There are many similarities between PANS/PANDAS and autoimmune encephalitis (AE). Both conditions involve an immune attack on the brain’s own cells that can cause rapid-onset psychiatric changes. AE can be caused by a bacterial or viral infection like PANS/PANDAS, though it can also result from tumors or cancers5. Both conditions are extremely difficult to diagnose and are often misdiagnosed. However, the pathology of AE is better understood than that of PANS/PANDAS, making it easier to test for. In addition, the symptoms and course of PANS/PANDAS distinguishes it from pediatric AE. AE symptoms may include fever, seizures, and cognitive impairment that are not typical in PANS/PANDAS. AE symptoms also progress more slowly, while PANS/PANDAS symptoms appear rapidly, do not necessarily worsen over time, and often retreat rapidly6. Though the symptoms may differ, treatments for AE and PANS are quite similar and include removal of the source of the antibodies either pharmacologically (antibiotics) or surgically (removal of a tumor), suppressing the overactive immune system, and addressing the symptoms (CBT). As research continues and more physicians become aware of acute-onset autoimmune diseases, early diagnosis and treatment will greatly improve the lives of both children and adults that suffer from PANS, AE, and other similar syndromes. 

 References 

  1. Dop D, Marcu IR, Padureanu R, Niculescu CE, Padureanu V. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (Review). Exp Ther Med. 21, 94 (2020).
  2. What are PANS and PANDAS? PANDAS Physicians Network. https://www.pandasppn.org/what-are-pans-pandas/
  3. Lotan D, Benhar I, Alvarez K, Mascaro-Blanco A, Brimberg L, Frenkel D, Cunningham MW, Joel D. Behavioral and neural effects of intra-striatal infusion of anti-streptococcal antibodies in rats. Brain Behav Immun. 38, 249-62 (2014).
  4. Swedo SE, Frankovich J, Murphy TK. Overview of Treatment of Pediatric Acute-Onset Neuropsychiatric Syndrome. J Child Adolesc Psychopharmacol. 27, 562-565 (2017).
  5. Dalmau J, Graus F. Antibody-Mediated Encephalitis. N Engl J Med. 9, 840-851 (2018).
  6. Cellucci T, Van Mater H, Graus F, Muscal E, Gallentine W, Klein-Gitelman MS, Benseler SM, Frankovich J, Gorman MP, Van Haren K, Dalmau J, Dale RC. Clinical approach to the diagnosis of autoimmune encephalitis in the pediatric patient. Neurol Neuroimmunol Neuroinflamm. 2, e663 (2020).

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

 

Become an Advocate by sharing your story. It may result in accurate diagnosis for someone suffering right now who is yet to be correctly identified. Submit your story with two photos to IAES@autoimmune-encephalitis.org  

 

 

International Autoimmune Encephalitis Society (IAES), home of the AEWarrior®, is the only Family/Patient-centered organization that assists members from getting a diagnosis through to recovery and the many challenges experienced in their journey. Your donations are greatly appreciated and are the direct result of IAES’ ability to develop the first product in the world to address the needs of patients, Autoimmune Encephalitis Trivia Playing Cards. Every dollar raised allows us to raise awareness and personally help Patients, Families, and Caregivers through their Journey with AE to ensure that the best outcomes can be reached. Your contribution to our mission will help save lives and improve the quality of life for those impacted by AE.   For this interested in face masks, clothing, mugs, and other merchandise, check out our AE Warrior Store!  This online shop was born out of the desire for the AE patient to express their personal pride in fighting such a traumatic disease and the natural desire to spread awareness. Join our AE family and help us continue our mission to support patients, families and caregivers while they walk this difficult journey.  

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

Autoimmune Encephalitis and Eating Disorders

September 8, 2021 |  Catrina Hacker, PennNeuroKnow

 

Content Warning: Eating Disorders

Eating disorders impact the lives of millions of people around the world, with negative effects on the physical and mental health of people with these disorders as well as their families and friends. In 2018, the estimated prevalence of eating disorders in the United States was 4.6%1. Caretakers of relatives with eating disorders also report impaired mental health with feelings of anxiety, powerlessness, sadness, and desperation2. In the US, eating disorders cost an estimated $64.7 billion, or $11,808 per affected person between 2018 and 20193. Public awareness of these disorders is essential as early identification and treatment can be one of the best predictors of successful outcomes4

Eating disorders are typically characterized by disturbances in eating behavior and body weight that impact a person’s mental and physical health. There are three common eating disorders: anorexia nervosa, bulimia nervosa, and binge-eating disorder. Anorexia nervosa is characterized by restricted eating and a fixation on thinness. Bulimia nervosa involves episodes of overeating followed by behaviors that compensate such as vomiting, fasting, or excessive exercising. Binge-eating disorder is the most common eating disorder in the United States and is characterized by periods of uncontrolled overeating5. Eating disorders not only have negative impacts on physical health, but have been associated with several other disorders including depression6

Two well-established risk factors for eating disorders are age and sex. Prevalence is much higher in women than men, with 8.4% of women experiencing an eating disorder in their lifetime compared to 2.2% of men1, although eating disorders in men are likely underdiagnosed7. Age is also an important risk factor, with peak onset between the ages of 15 and 258.

While risk factors like age and sex are well established, recent work has pointed to autoimmune disorders as an additional risk factor for developing an eating disorder. Autoimmune diseases have already been linked to several psychiatric disorders9, and several recent case studies have reported that some patients suffering from a type of autoimmune disease called anti-NMDAR encephalitis first presented with eating disorders. Four such cases involved teenage girls who were first admitted to eating disorder clinics with diagnoses of anorexia nervosa. All four patients eventually developed seizures and other symptoms that led to a diagnosis of autoimmune encephalitis10–12. Following treatment of their autoimmune encephalitis, the patients returned to pre-illness eating patterns. 

One possibility for how autoimmune encephalitis and eating disorders are linked has to do with a receptor in the brain called an NMDA (N-methyl-D-aspartate) receptor. Anti-NMDAR encephalitis causes patients to have fewer NMDA receptors than healthy people13. NMDA receptors have many functions in the human brain, and studies in rats have shown that they play an important role in feeding behavior14,15. Researchers have been able to both increase16 and decrease17 an animal’s eating by modulating activity of NMDA receptors in the brain. Cases of anti-NMDAR encephalitis that present as eating disorders provide compelling evidence that NMDA receptors also play an important role in eating behavior in humans. 

The growing evidence that autoimmune encephalitis cases can present first as eating disorders highlights the importance of recognizing diagnoses of eating disorders as possible early signs of autoimmune encephalitis. This is especially important given that both autoimmune encephalitis and eating disorders are often diagnosed in the same populations of people. The average onset of anti-NMDAR autoimmune encephalitis is 21 years11, which coincides with the peak onset of eating disorders between 15 and 25 years of age8. Similarly, both autoimmune encephalitis and eating disorders are more prevalent in women than in men1,13. Awareness of the relationship between these two diagnoses can help lead to earlier diagnosis and treatment of autoimmune encephalitis11 which hopefully leads to better outcomes. 

If you think that you or someone you know may be dealing with an eating disorder, these resources are available to help: National Eating Disorders Association, Mayo Clinic

References

  1. Galmiche, M., Déchelotte, P., Lambert, G. & Tavolacci, M. P. Prevalence of eating disorders over the 2000–2018 period: a systematic literature review. Am. J. Clin. Nutr. 109, 1402–1413 (2019).
  2. De LA Rie, S. M., Van furth, E. F., De Koning, A., Noordenbos, G. & Donker, M. C. H. The Quality of Life of Family Caregivers of Eating Disorder Patients. Eat. Disord. 13, 345–351 (2005).
  3. Streatfeild, J. et al. Social and economic cost of eating disorders in the United States: Evidence to inform policy action. Int. J. Eat. Disord. 54, 851–868 (2021).
  4. Chang, P. G. R. Y., Delgadillo, J. & Waller, G. Early response to psychological treatment for eating disorders: A systematic review and meta-analysis. Clin. Psychol. Rev. 86, 102032 (2021).
  5. NIMH » Eating Disorders. https://www.nimh.nih.gov/health/topics/eating-disorders/.
  6. Willcox, M. & Sattler, D. N. The Relationship Between Eating Disorders and Depression. J. Soc. Psychol. 136, 269–271 (1996).
  7. Strother, E., Lemberg, R., Stanford, S. C. & Turberville, D. Eating Disorders in Men: Underdiagnosed, Undertreated, and Misunderstood. Eat. Disord. 20, 346–355 (2012).
  8. Schmidt, U. et al. Eating disorders: the big issue. Lancet Psychiatry 3, 313–315 (2016).
  9. Zerwas, S. et al. Eating Disorders, Autoimmune, and Autoinflammatory Disease. Pediatrics 140, e20162089 (2017).
  10. Virupakshaiah, A., Consolini, D., Bean, C. & Elia, J. When Autoimmune Encephalitis masquerades as an Eating Disorder, two case reports on unique presentation of anti – NMDAR Encephalitis. (P2.2-016). Neurology 92, P2.2-016 (2019).
  11. Mechelhoff, D. et al. Anti-NMDA receptor encephalitis presenting as atypical anorexia nervosa: an adolescent case report. Eur. Child Adolesc. Psychiatry 24, 1321–1324 (2015).
  12. Perogamvros, L., Schnider, A. & Leemann, B. The Role of NMDA Receptors in Human Eating Behavior: Evidence From a Case of Anti-NMDA Receptor Encephalitis. Cogn Behav Neurol 25, 5 (2012).
  13. Hughes, E. G. et al. Cellular and Synaptic Mechanisms of Anti-NMDA Receptor Encephalitis. J. Neurosci. 30, 5866–5875 (2010).
  14. Bednar, I. et al. Glutamate Inhibits Ingestive Behaviour. J. Neuroendocrinol. 6, 403–408 (1994).
  15. Stanley, B. G., Urstadt, K. R., Charles, J. R. & Kee, T. Glutamate and GABA in lateral hypothalamic mechanisms controlling food intake. Physiol. Behav. 104, 40–46 (2011).
  16. Hung, C.-Y., Covasa, M., Ritter, R. C. & Burns, G. A. Hindbrain administration of NMDA receptor antagonist AP-5 increases food intake in the rat. Am. J. Physiol.-Regul. Integr. Comp. Physiol. 290, R642–R651 (2006).
  17. Lee, S. W. & Stanley, B. G. NMDA receptors mediate feeding elicited by neuropeptide Y in the lateral and perifornical hypothalamus. Brain Res. 1063, 1–8 (2005)

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

 

Become an Advocate by sharing your story. It may result in accurate diagnosis for someone suffering right now who is yet to be correctly identified. Submit your story with two photos to IAES@autoimmune-encephalitis.org  

 

 

International Autoimmune Encephalitis Society (IAES), home of the AEWarrior®, is the only Family/Patient-centered organization that assists members from getting a diagnosis through to recovery and the many challenges experienced in their journey. Your donations are greatly appreciated and are the direct result of IAES’ ability to develop the first product in the world to address the needs of patients, Autoimmune Encephalitis Trivia Playing Cards. Every dollar raised allows us to raise awareness and personally help Patients, Families, and Caregivers through their Journey with AE to ensure that the best outcomes can be reached. Your contribution to our mission will help save lives and improve the quality of life for those impacted by AE.   For this interested in face masks, clothing, mugs, and other merchandise, check out our AE Warrior Store!  This online shop was born out of the desire for the AE patient to express their personal pride in fighting such a traumatic disease and the natural desire to spread awareness. Join our AE family and help us continue our mission to support patients, families and caregivers while they walk this difficult journey.  

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

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.

CONTACT US


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IAES@AUTOIMMUNE-ENCEPHALITIS.ORG

Autoimmune Encephalitis Trivia Playing Cards

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