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Treatments for Autoimmune Encephalitis

Treatments for Autoimmune Encephalitis


April 26, 2023 | by Sophie Liebergall
, PennNeuroKnow and IAES Collaboration

A message from IAES Blog Staff:

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

——-

Introduction

 

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

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

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

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

First-Line Treatments

Steroids

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

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

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

glucocorticoid mechanism summary V1 500x358 - Treatments for Autoimmune Encephalitis

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

 

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

Plasma Exchange (PLEX)

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

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

PLEX summary V2 500x279 - Treatments for Autoimmune Encephalitis

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

 

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

Intravenous Immune Globulin (IVIG)

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

IVIG summary V1 500x323 - Treatments for Autoimmune Encephalitis

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

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

Second-Line Treatments

 

Rituximab

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

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

Cyclophosphamide

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

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

Symptomatic Treatment of AE

 

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

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

 

References

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

 All figures made with biorender.com.

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

 

 

Tabitha Orth 300x218 - Treatments for Autoimmune Encephalitis

 

 

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

 

guidestar platinum logo 300x300 1 e1605914935941 - Treatments for Autoimmune Encephalitis

 

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

 

 

International Autoimmune Encephalitis Society (IAES), home of the AEWarrior®, is the only Family/Patient-centered organization that assists members from getting a diagnosis through to recovery and the many challenges experienced in their journey. Your donations are greatly appreciated and are the direct result of IAES’ ability to develop the first product in the world to address the needs of patients, Autoimmune Encephalitis Trivia Playing Cards. Every dollar raised allows us to raise awareness and personally help Patients, Families, and Caregivers through their Journey with AE to ensure that the best outcomes can be reached. Your contribution to our mission will help save lives and improve the quality of life for those impacted by AE.   Trivia Playing cards 3 FB 500x419 - Treatments for Autoimmune Encephalitis For this interested in face masks, clothing, mugs, and other merchandise, check out our AE Warrior Store!  This online shop was born out of the desire for the AE patient to express their personal pride in fighting such a traumatic disease and the natural desire to spread awareness. Join our AE family and help us continue our mission to support patients, families and caregivers while they walk this difficult journey.   AE Warrior Store 300x200 - Treatments for Autoimmune Encephalitis

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

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What is a headache?

What is a headache?


March 8, 2023 | by
 Marissa Maroni, PennNeuroKnow and IAES Collaboration

A message from IAES Blog Staff:

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

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

Introduction

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

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

What kinds of headaches are there?

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

  1. Tension-type headaches

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

  1. Migraines

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

  1. Cluster Headaches

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

How do they start?

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

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

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

Where does the pain come from?

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

headache 2 496x500 - What is a headache?

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

Sensitization of the brain

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

migraine pain 500x177 - What is a headache?

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

Hyperexcitability

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

Neuropeptide release

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

What are some treatment for migraines?

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

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

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

References

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

Cover photo by Robin Higgins from Pixabay

Figures created with BioRender.com.

 

 

 

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

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

 

 

Tabitha Orth 300x218 - What is a headache?

 

 

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

 

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

 

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

 

 

International Autoimmune Encephalitis Society (IAES), home of the AEWarrior®, is the only Family/Patient-centered organization that assists members from getting a diagnosis through to recovery and the many challenges experienced in their journey. Your donations are greatly appreciated and are the direct result of IAES’ ability to develop the first product in the world to address the needs of patients, Autoimmune Encephalitis Trivia Playing Cards. Every dollar raised allows us to raise awareness and personally help Patients, Families, and Caregivers through their Journey with AE to ensure that the best outcomes can be reached. Your contribution to our mission will help save lives and improve the quality of life for those impacted by AE.   Trivia Playing cards 3 FB 500x419 - What is a headache? For this interested in face masks, clothing, mugs, and other merchandise, check out our AE Warrior Store!  This online shop was born out of the desire for the AE patient to express their personal pride in fighting such a traumatic disease and the natural desire to spread awareness. Join our AE family and help us continue our mission to support patients, families and caregivers while they walk this difficult journey.   AE Warrior Store 300x200 - What is a headache?

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

why zebra - Aphasia as a Symptom of Autoimmune Encephalitis
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Why does it feel like we know so little about autoimmune encephalitis?

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

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

A message from IAES Blog Staff:

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

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

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

Introduction

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

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

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

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

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

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

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

Diseases like autoimmune encephalitis can be hard to categorize and diagnose

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

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

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

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

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

Rigorous science can’t be rushed

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

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

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

Concluding Thoughts

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

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

Image Credits

Cover photo: Photo by Ousa Chea on Unsplash.

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

 

 

 

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

 

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

 

 

International Autoimmune Encephalitis Society (IAES), home of the AEWarrior®, is the only Family/Patient-centered organization that assists members from getting a diagnosis through to recovery and the many challenges experienced in their journey. Your donations are greatly appreciated and are the direct result of IAES’ ability to develop the first product in the world to address the needs of patients, Autoimmune Encephalitis Trivia Playing Cards. Every dollar raised allows us to raise awareness and personally help Patients, Families, and Caregivers through their Journey with AE to ensure that the best outcomes can be reached. Your contribution to our mission will help save lives and improve the quality of life for those impacted by AE.   Trivia Playing cards 3 FB 500x419 - Why does it feel like we know so little about autoimmune encephalitis? For this interested in face masks, clothing, mugs, and other merchandise, check out our AE Warrior Store!  This online shop was born out of the desire for the AE patient to express their personal pride in fighting such a traumatic disease and the natural desire to spread awareness. Join our AE family and help us continue our mission to support patients, families and caregivers while they walk this difficult journey.   AE Warrior Store 300x200 - Why does it feel like we know so little about autoimmune encephalitis?

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What are the different types of autoimmune encephalitis?

What are the different types of autoimmune encephalitis?

December 28, 2022 | by Sophie Liebergall, PennNeuroKnow and IAES Collaboration

A message from IAES Blog Staff:

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

——

Introduction

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

What is autoimmune encephalitis?

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

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

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

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

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

What part of the brain is affected by autoimmune encephalitis?

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

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

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

Is autoimmune encephalitis caused by a tumor?

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

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

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

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

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

Antibody

% of Cases with Presence of Tumor

Common symptoms

Anti-NMDAR

40% (varies)

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

Anti-AMPAR

70%

Limbic encephalitis

Anti-GABAA

 

Severe, prolonged seizures

Anti-GABAB

70%

Limbic encephalitis, frequent seizures

Anti-Caspr2

40%

Limbic encephalitis, confusion, abnormal muscle tone

Anti-LGI1

<10%

Limbic encephalitis, seizures

Anti-Hu

>90%

Limbic encephalitis, problems with cognition

Anti-Ma2

>90%

Limbic encephalitis, brainstem encephalitis

Anti-CV2/CRMP5

>90%

Limbic encephalitis

Anti-Amphiphysin

>90%

Limbic encephalitis, widespread paralysis

 

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

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

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

References:

  1. Dalmau, J. & Rosenfeld, M. R. Paraneoplastic and autoimmune encephalitis.
  2. Chen, L. et al. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget 9, 7204–7218 (2017).
  3. Janeway, C. A., Travers, P., Walport, M. & Shlomchik, M. J. Immunobiology. (Garland Science, 2001).
  4. Abboud, H. et al. Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management. J Neurol Neurosurg Psychiatry 92, 757–768 (2021).
  5. Lancaster, E. The Diagnosis and Treatment of Autoimmune Encephalitis. J Clin Neurol 12, 1–13 (2016).
  6. Gultekin, S. H. et al. Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients. Brain 123 ( Pt 7), 1481–1494 (2000).
  7. Tan, I. L. et al. Brainstem encephalitis: etiologies, treatment, and predictors of outcome. J Neurol 260, 2312–2319 (2013).
  8. Dalmau, J., Graus, F., Rosenblum, M. K. & Posner, J. B. Anti-Hu–associated paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical study of 71 patients. Medicine (Baltimore) 71, 59–72 (1992).
  9. Dalmau, J. & Graus, F. Antibody-Mediated Encephalitis. N Engl J Med 378, 840–851 (2018).
  10. Barry, H., Byrne, S., Barrett, E., Murphy, K. C. & Cotter, D. R. Anti-N-methyl-d-aspartate receptor encephalitis: review of clinical presentation, diagnosis and treatment. BJPsych Bull 39, 19–23 (2015).
  11. Davis, R. & Dalmau, J. Autoimmunity, Seizures, and Status Epilepticus. Epilepsia 54, 46–49 (2013).
  12. Lee, W. J. et al. Seronegative autoimmune encephalitis: clinical characteristics and factors associated with outcomes. Brain awac166 (2022) doi:10.1093/brain/awac166.
  13. Rees, J H. “Paraneoplastic Syndromes: When to Suspect, How to Confirm, and How to Manage.” Journal of Neurology, Neurosurgery & Psychiatry 75, (June 1, 2004): ii43–50. https://doi.org/10.1136/jnnp.2004.040378.

 

 

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

 

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

 

 

International Autoimmune Encephalitis Society (IAES), home of the AEWarrior®, is the only Family/Patient-centered organization that assists members from getting a diagnosis through to recovery and the many challenges experienced in their journey. Your donations are greatly appreciated and are the direct result of IAES’ ability to develop the first product in the world to address the needs of patients, Autoimmune Encephalitis Trivia Playing Cards. Every dollar raised allows us to raise awareness and personally help Patients, Families, and Caregivers through their Journey with AE to ensure that the best outcomes can be reached. Your contribution to our mission will help save lives and improve the quality of life for those impacted by AE.   Trivia Playing cards 3 FB 500x419 - What are the different types of autoimmune encephalitis? For this interested in face masks, clothing, mugs, and other merchandise, check out our AE Warrior Store!  This online shop was born out of the desire for the AE patient to express their personal pride in fighting such a traumatic disease and the natural desire to spread awareness. Join our AE family and help us continue our mission to support patients, families and caregivers while they walk this difficult journey.   AE Warrior Store 300x200 - What are the different types of autoimmune encephalitis?

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

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

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

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

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

 

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

 

 

International Autoimmune Encephalitis Society (IAES), home of the AEWarrior®, is the only Family/Patient-centered organization that assists members from getting a diagnosis through to recovery and the many challenges experienced in their journey. Your donations are greatly appreciated and are the direct result of IAES’ ability to develop the first product in the world to address the needs of patients, Autoimmune Encephalitis Trivia Playing Cards. Every dollar raised allows us to raise awareness and personally help Patients, Families, and Caregivers through their Journey with AE to ensure that the best outcomes can be reached. Your contribution to our mission will help save lives and improve the quality of life for those impacted by AE.   Trivia Playing cards 3 FB 500x419 - How does the brain heal from autoimmune encephalitis and why is there so much variability in the healing process? 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 - How does the brain heal from autoimmune encephalitis and why is there so much variability in the healing process?

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Fatigue and Autoimmune Encephalitis: You’re Not Alone

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.

Photo by Zohre Nemati on Unsplash

 

Check out some yoga TikToks (#yogaTok) that you can do in the comfort of your own home!

 

 

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

 

guidestar platinum logo 300x300 1 e1605914935941 - Fatigue and Autoimmune Encephalitis: You're Not Alone

 

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

 

 

International Autoimmune Encephalitis Society (IAES), home of the AEWarrior®, is the only Family/Patient-centered organization that assists members from getting a diagnosis through to recovery and the many challenges experienced in their journey. Your donations are greatly appreciated and are the direct result of IAES’ ability to develop the first product in the world to address the needs of patients, Autoimmune Encephalitis Trivia Playing Cards. Every dollar raised allows us to raise awareness and personally help Patients, Families, and Caregivers through their Journey with AE to ensure that the best outcomes can be reached. Your contribution to our mission will help save lives and improve the quality of life for those impacted by AE.   Trivia Playing cards 3 FB 500x419 - Fatigue and Autoimmune Encephalitis: You're Not Alone 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 - Fatigue and Autoimmune Encephalitis: You're Not Alone

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

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Movement disorders as a window into the diversity of autoimmune encephalitis

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

 

guidestar platinum logo 300x300 1 e1605914935941 - Movement disorders as a window into the diversity of autoimmune encephalitis

 

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

 

 

International Autoimmune Encephalitis Society (IAES), home of the AEWarrior®, is the only Family/Patient-centered organization that assists members from getting a diagnosis through to recovery and the many challenges experienced in their journey. Your donations are greatly appreciated and are the direct result of IAES’ ability to develop the first product in the world to address the needs of patients, Autoimmune Encephalitis Trivia Playing Cards. Every dollar raised allows us to raise awareness and personally help Patients, Families, and Caregivers through their Journey with AE to ensure that the best outcomes can be reached. Your contribution to our mission will help save lives and improve the quality of life for those impacted by AE.   Trivia Playing cards 3 FB 500x419 - Movement disorders as a window into the diversity 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 - Movement disorders as a window into the diversity of autoimmune encephalitis

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

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Genetic Predisposition for Autoimmune Encephalitis

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.

genetic predispositions

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.   Trivia Playing cards 3 FB 500x419 - Genetic Predisposition for Autoimmune Encephalitis For this interested in face masks, clothing, mugs, and other merchandise, check out our AE Warrior Store!  This online shop was born out of the desire for the AE patient to express their personal pride in fighting such a traumatic disease and the natural desire to spread awareness. Join our AE family and help us continue our mission to support patients, families and caregivers while they walk this difficult journey.   AE Warrior Store 300x200 - Genetic Predisposition for Autoimmune Encephalitis

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Why getting better at baseball might require just a little sleep

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.   Trivia Playing cards 3 FB 500x419 - Why getting better at baseball might require just a little sleep For this interested in face masks, clothing, mugs, and other merchandise, check out our AE Warrior Store!  This online shop was born out of the desire for the AE patient to express their personal pride in fighting such a traumatic disease and the natural desire to spread awareness. Join our AE family and help us continue our mission to support patients, families and caregivers while they walk this difficult journey.   AE Warrior Store 300x200 - Why getting better at baseball might require just a little sleep

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

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Ataxia and Autoimmune Encephalitis

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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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 - Ataxia and Autoimmune Encephalitis For this interested in face masks, clothing, mugs, and other merchandise, check out our AE Warrior Store!  This online shop was born out of the desire for the AE patient to express their personal pride in fighting such a traumatic disease and the natural desire to spread awareness. Join our AE family and help us continue our mission to support patients, families and caregivers while they walk this difficult journey.   AE Warrior Store 300x200 - Ataxia and Autoimmune Encephalitis

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

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).

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

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Autoimmune Encephalitis and Eating Disorders

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)
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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 - Autoimmune Encephalitis and Eating Disorders 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 - Autoimmune Encephalitis and Eating Disorders

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A Detailed Look Inside The Human Brain

A Detailed Look Inside The Human Brain

July 28, 2021 |  PennNeuroKnow

Scientists reveal the enormous complexity of a millimeter of the human brain

We all appreciate the complexity of the human brain. While our hearts, lungs, and livers are very similar to those of other mammals, our brains are what distinguish us from our primate ancestors. Humans learn, communicate, adapt, and connect with each other like no other species on Earth. But until recently, the true complexity of the human brain was still a mystery. Scientists often use animal models to study the brain because of how difficult it is to gain access to human brains both technically and ethically. If we want to study the human brain, we use non-invasive imaging to get a sense of what the brain looks like and what areas might respond to certain stimuli. Although new imaging technologies lead to major advances in knowledge, little is actually known about how individual neurons in the human brain are connected to each other and to other cells types and brain structures. This is because neurons are tiny; the cell body of a neuron is about one fifth the width of a human hair. Imaging of live human brains doesn’t come close to that kind of resolution, so how can we learn more about neuronal connections in the brain? Scientists at Harvard University and Google Research have combined advances in imaging and computational analysis methods to offer an unprecedented look into the complexities of the human brain at a nanometer scale1.

How were the images collected and analyzed?

Before diving into this study, it’s important to note that the work is published as a preprint, meaning that it has not yet undergone peer review. Experts in the field will review the paper and ensure that the research is sound and the conclusions are valid before it is published in a scientific journal. Since the findings were made available before this process took place, we can think about them as a “first draft” that may change in the coming months.

First, let’s discuss how this dataset was collected. The researchers wanted to image a piece of the human brain at very high resolution and reconstruct it using sophisticated computer programs. Pieces of human brains, as you might imagine, are not easy to get. Many brain sections that are removed surgically are diseased and would therefore not represent a typical human brain. However, neurosurgeons will occasionally remove a piece of healthy human cortex (the outer layer of the brain) in order to gain access to deeper structures when operating on patients with drug-resistant epilepsy. The team of researchers were able to get a cubic millimeter of healthy human cortex and rapidly preserve it. They then treated it with heavy metals, which is important for later imaging. Finally, the brain section was embedded in resin. The block of resin was then cut by a diamond knife into over 5,000 extremely thin sections and mounted on a long strip of tape that was wrapped around a reel, like old film.

The sections were then imaged using an electron microscope. An electron microscope sends a beam of electrons onto a sample. The electrons then scatter off the sample, and the pattern of this scatter is what creates the image. Using electrons instead of light to create an image dramatically increases the resolution that is possible. Electron microscopy can clearly show very small organelles like mitochondria inside cells. Importantly, electron microscopy is extremely useful for imaging synapses, the connections between neurons. Even the tiny vesicles containing neurotransmitters that travel across synapses are visible through an electron microscope. It is also possible to determine whether a synapse is excitatory, meaning that one neuron will be activated by another, or inhibitory, meaning that one neuron will be silenced by another. Electron microscopy, however, is not a fast process, and the team had over 5,000 brain sections to image. To speed things up, the group used a special microscope that simultaneously sent 61 beams to the sample instead of one, which significantly increased the area that can be imaged at once. This allowed the microscope to image up to 190 million pixels per second. Even with the extra beams and fast imaging, acquiring images of all the sections took a total of 326 days! All those thousands of highly detailed images took up about 2.1 petabytes of storage. To store that amount of data on the type of laptop I am using to write this article, I would need about 33,000 of them.

The group now had this enormous amount of imaging data, so how did they analyze it? The goal of their analysis was to align the 2D images in a 3-dimensional stack, basically putting the pictures of the thin brain slices back together in order, and then digitally reconstruct the neurons, other cells, and blood vessels that were in the piece of brain. The level of detail in the images allowed them to precisely map the synapses at each neuron across the cubic millimeter of the cortex. This was done using mostly automated computer programs that could track an individual cell through the various images, and then create a 3D reconstruction of that cell.

What did they find?

After reconstructing the entire section of brain that was collected, the team examined the types of cells they found and how they were connected to each other. Though there is far too much information to describe here, let’s look at some of the more surprising findings. One important conclusion was that the algorithms identified twice as many glial cells as neurons in this segment of the brain. Glial cells are cells in the brain that are not neurons and do not send electrical signals to other cells. They are, however, very important to normal brain function as regulators of neurons and neural transmission. This study highlights the important of studying glial cells and how they might contribute to normal and abnormal brain function.

A second major finding was the sheer density of connections between neurons that were found in the sample. A total of 133.7 million synapses were identified in this cubic millimeter of human brain. Large, excitatory cells in the cortex called pyramidal neurons each received thousands of both excitatory and inhibitory inputs from the axons of other neurons. Almost all axons only formed one synapse with target neurons. Since each synapse has a relatively weak ability to change the activity of the neuron, the signal that is transmitted to the target neuron depends on the combination of these thousands of inputs. However, the group found a few exceptions where a single axon forms several (in one case up to 19!) synapses with a target neuron. This means that some inputs have a much stronger effect on the activity of the target neuron than all the other single-synapse axons (Figure 1). Though multi-synapse inputs were very rare, 30% of neurons studied had at least one input that formed 7 or more synapses. This suggests that even though these multi-synapse inputs were uncommon, many neurons could have at least one input that is significantly stronger than all the others. Discoveries like these can only be made with this kind of technique, where the source of each synapse can be tracked in 3-dimentional space at the high resolution needed to identify individual synapses.

synapse signal - A Detailed Look Inside The Human Brain

Figure 1. Multi-synaptic inputs. The top black neuron is receiving input from many axons that each only form a single synapse on the neuron’s dendrite. To transmit the signal, many of the inputs must carry the signal at the same time. The bottom target neuron has the same single synapse inputs, but also has input from the light blue axon which is forming several synapses on the dendrite. In this case, the input from the light blue neuron has a larger effect on the transmission of the signal that the input from each single-synapse axon.

Explore!

All of these thousands of neurons and millions of connections between them that took almost a year to image and petabytes to store came from a single cubic millimeter of a 45-year-old woman’s brain. An adult brain is about 1200 cubic centimeters, or 1.2 million times the volume of brain that was imaged in this study. It is impossible to imagine (with our brains, I might add) the amount of computation that happens inside our skulls. However, research like this at least gives us an idea of the kind of complexity that makes us human. And now, everyone can explore the data on their own! The website the team created allows you to visualize the neurons, glia, and blood vessels in 3D and even see the electron microscope images that generated the reconstructions. To see the synapses that communicate with a pyramidal neuron, click here. You can double click on cells in the microscope image or 3D image to make them appear or disappear as well as zoom in and out and scroll through the image in all 3 dimensions. Just make sure you don’t have anything urgent to do first!

References 

  1. Shapson-Coe, A., et al. A connectomic study of a petascale fragment of human cerebral cortex. bioRxiv 2021.05.29.446289; doi: https://doi.org/10.1101/2021.05.29.446289

Cover photo by Gordon Johnson from Pixabay

 

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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 - A Detailed Look Inside The Human Brain For this interested in face masks, clothing, mugs, and other merchandise, check out our AE Warrior Store!  This online shop was born out of the desire for the AE patient to express their personal pride in fighting such a traumatic disease and the natural desire to spread awareness. Join our AE family and help us continue our mission to support patients, families and caregivers while they walk this difficult journey.   AE Warrior Store 300x200 - A Detailed Look Inside The Human Brain

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Creativity in the Brain

Creativity in the Brain

June 23, 2021 | Sara Taylor, PennNeuroKnow

Creativity can often feel spontaneous and out of our control. It can hit us all at once, seemingly coming out of nowhere. Then there’s writer’s block. The struggling, uninspired artist. The elusive solution. Scientists have long been trying to understand creativity by uncovering its biological basis. What is happening in the brain when we have that lightbulb moment? To tackle that question, we first have to ask: what needs to happen in the brain to switch on the light?

There are several processes that come together in a moment of creativity. Let’s take a challenge that is typical in the days leading up to a grocery store run: what meal can you make out of what you have in your house already? One process that is going to be engaged is memory. It could be helpful to remember meals you’ve made in the past, recipes you’ve read, and what you have left in your pantry. Another process that is engaged is attention. Attention is important to help us filter through the nearly infinite things we could be considering in any moment. When trying to come up with your meal for the night, you want to be focusing on the relevant ingredients and ideas (and not get distracted by the jar of expired olives or the thing for work you still need to finish up). The third process involved in creativity is cognitive control, which helps coordinate memory and attention while holding onto the ultimate goal (in this case tonight’s meal). Its relationship to creativity is a little complicated – you need at least some cognitive control to be able to problem solve, but too much may actually get in the way of creativity.

There are a couple of theories about what is happening in the brain during the creative process. One (called the embodied theory of creativity) is that the motor system is important with helping us generate ideas. This concept is rooted in evolutionary theories – humans have been figuring out how to use tools for a long, long time. Whether it is how to get two rocks to spark a fire or how to play a chord on a guitar, people have consistently engaged with objects to achieve goals in all kinds of contexts. There are regions in the brain that help us plan and carry out motor functions like playing the guitar. Interestingly, studies have shown that these brain regions can be active even without movement. The embodied theory of creativity argues that before we can take a creative action, we first activate these brain regions to simulate possible actions and movements we could take. The same motor systems that allow us to ultimately take the action can run through the different possibilities without us needing to move at all. Studies of creativity have found that motor systems in the brain are active during certain types of creative tasks, like imagining or creating a musical improvisation (1). Even more compellingly, in a study with jazz musicians, researchers altered activity in the brain area that send signals to our muscles to take an action (called primary motor cortex). When this region was stimulated, enhancing its function, the musician’s solos became more creative (1,2). This study suggests that the motor system not only helps us complete actions but also helps us to produce creative actions.

Another theory of creativity is the disinhibition theory. This theory suggests that having less cognitive control leads to greater creativity. Cognitive control is what allows us to complete complex tasks by suppressing action and attention not related to the goal at hand. It also allows for the selection of information that is relevant to the task and the initiation of processes that are necessary to complete it. For example, think about what happens once you finally get to the grocery store to get materials for dinner. Cognitive control is what allows you to ignore the birthday cakes and focus on the food items that you might need for dinner. It also allows you to think about the last time you made this meal, focusing on the ingredients you used and not the other details of making the meal, like whether were you tired from a long day or what music was playing while you cooked.  Disinhibition theory argues that less cognitive control is what allows for creativity. Too much cognitive control can make you rigid and not open to other creative options. For instance, say you are following a recipe but don’t have one of the ingredients – too much cognitive control might get in the way of finding a good substitute as you are so stuck on following the recipe exactly. There is quite of bit of research that backs up this theory, including studies with patients that have damage to their frontal lobes (an area in the front of the brain that is generally responsible for cognitive control) and studies in healthy people. In multiple cases, damage to the frontal lobe area led to greater creativity and interest in art (3). Studies with healthy people without damage found that decreased thickness of the left frontal lobe was associated with more creativity (3). Also, temporarily increasing the activity of the lateral prefrontal cortex, another region involved in cognitive control, decreased how creative and novel people were in completing a task (4). 

Over the past several decades, research on how creativity works in the brain has developed rapidly. Scientists are still learning about how attention, memory, and cognitive control come together to create those magic lightbulb moments. So far, it seems like there may be some unexpected brain areas involved (like those involved in movement) and that a balance of just enough cognitive control may be required. As neuroscientists uncover more about the creative processes in the brain, hopefully we will be able to maximize our chances to solve life’s problems, big and small.

References:

  1. Matheson, H. E., & Kenett, Y. N. (2020). The role of the motor system in generating creative thoughts. NeuroImage213, 116697.
  2. Anic, A., Olsen, K. N., & Thompson, W. F. (2018). Investigating the role of the primary motor cortex in musical creativity: a transcranial direct current stimulation study. Frontiers in psychology9, 1758.
  3. Jung, R. E., Mead, B. S., Carrasco, J., & Flores, R. A. (2013). The structure of creative cognition in the human brain. Frontiers in human neuroscience7, 330.
  4. Kenett, Y. N., Rosen, D. S., Tamez, E. R., & Thompson-Schill, S. L. (2021). Noninvasive brain stimulation to lateral prefrontal cortex alters the novelty of creative idea generation. Cognitive, Affective, & Behavioral Neuroscience, 1-16.

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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 - Creativity in the Brain For this interested in face masks, clothing, mugs, and other merchandise, check out our AE Warrior Store!  This online shop was born out of the desire for the AE patient to express their personal pride in fighting such a traumatic disease and the natural desire to spread awareness. Join our AE family and help us continue our mission to support patients, families and caregivers while they walk this difficult journey.   AE Warrior Store 300x200 - Creativity in the Brain

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Brain Beats

Brain Beats

May 26, 2021 | Vanessa B. Sanchez, PennNeuroKnow

Have you ever put on music to help you study? Or to calm you down after a stressful day? Maybe you’re scrolling on Youtube right now trying to figure out what to listen to next…Well, have you ever considered listening to binaural beats? 

What are binaural beats?

Binaural beats are a perceptual phenomenon (or illusion) that occurs when two different tones are presented separately to each ear1. When these two tones are presented, you, the listener, perceive the difference between the sound waves entering the left and right ear2-3

For example, if the left ear registers a tone at 400 Hz and the right ear registers one at 410 Hz, what you actually hear is halfway between the two tones: 405 Hz – the binaural beat (Figure 1) 3,6.  Because your brain is trying to interpret these two frequencies, this binaural beat of 405 Hz is considered an illusory tone3,6. Scientists from around the world have shown that in order for a binaural beat to occur, the difference between the two frequencies (e.g., 400 Hz – 410 Hz = 10 Hz) must be small (≤ 30 Hz)7. If the difference is not small (01571ce3 a8cc 4b98 a6dd 7b5573dc113b - Brain Beats 30 Hz), your ears will be able to capture the two tones separately and no binaural beat will be perceived6. Will you perceive a binaural beat if you listen to 10 Hz from both ears? No, because a binaural beat is the difference between the two frequencies, which is why it is considered an auditory phenomenon or illusory tone3,4,6

 
 
 Figure 1: If the left ear registers a tone at 400 Hz and the right ear registers one at 410 Hz, what you actually hear is the halfway between the two tones, 405 Hz – the binaural beat or illusory tone. The difference between 400 Hz and 410 Hz is 10 Hz, which is within the alpha brain wave/state and is associated with relaxation and focus1,4,610. Image was created with BioRender.com

 

 

 

Figure 1: If the left ear registers a tone at 400 Hz and the right ear registers one at 410 Hz, what you actually hear is the halfway between the two tones, 405 Hz – the binaural beat or illusory tone. The difference between 400 Hz and 410 Hz is 10 Hz, which is within the alpha brain wave/state and is associated with relaxation and focus1,4,610. Image was created with BioRender.com

How are binaural beats processed in the brain?

How your brain is processing these binaural beats is still not exactly clear. Some scientists believe the phenomenon of binaural beats is thought to occur through a process called interhemispheric coherence3,9. Your brain can be divided up into two major parts: the left and the right hemisphere. In each hemisphere lies a region called the auditory cortex, which is where and how auditory information (in this case binaural beats) gets processed. Normally, the sounds that your right and left auditory cortices are processing are very similar. When you listen to binaural beats, your auditory cortices become confused because they are trying to process the two different tones9. To solve this binaural puzzle, scientists believe that your auditory cortices communicate with each other more, and therefore become more synchronized9

Some scientists believe that this synchrony is associated with your brainwaves1-10. Brain waves are electrical impulses that reflect how the neurons in your brain are communicating with each other10. These brain waves can occur at certain frequencies and can be either slow or fast. Your brain has five different types of brain waves that each fall within a certain range of frequencies. These types of brain waves represent what is called a brain state. For example, if your brain waves occur at high frequency (or what’s called the “gamma” or “beta” states), you are likely to be learning and deeply concentrated4,10. Other brain waves at a slower frequency like “delta” and/or “theta” states are associated with sleep and relaxation4,10. In between, are “alpha” states which are associated with reducing stress and positive thinking4,10. Interestingly, some scientists believe that the frequency of sounds that the auditory cortex is processing can affect the frequency of your brain waves4,6,8,10. So, if binaural beats are also in these lower frequencies like 4 – 8 Hz (theta state), it is thought that your brain waves will synchronize with these frequencies, which would then make you feel relaxed. 

Is this true?

Dentists think so…

Many of us have experienced the anxiety that comes with getting our wisdom teeth removed. In one study, some patients were lucky enough to be offered a chance to listen to binaural beats before surgery. If they agreed, they listened to binaural beats (9.3 Hz ~ theta waves) through stereo headsets for 10 minutes and during this time they were given a local anesthetic7. Those who chose not to listen were just given the local anesthetic and sat alone, in silence, for 10 minutes. To measure anxiety levels scientists used a visual analog scale (VAS) before and after the 10 minutes (where patients either sat in silence or listened to binaural beats).  You’ve probably seen a VAS at your local dentist’s office; it is just a line that represents a continuum of “no anxiety at all” to “worst anxiety imaginable” and can also be represented as 6 faces that go from a happy face (no anxiety) to a face with tears (worst anxiety)7. What scientists found was that those who chose not to listen to binaural beats leaned towards the right side of the spectrum: worst anxiety. Meanwhile, patients who originally reported high levels of anxiety and then listened to binaural beats (for 10 min) reported that their anxiety levels significantly decreased7. Remember, theta waves are associated with relaxation, so it is not surprisingly if these patients might have felt more relaxed after listening to binaural beats and reported lower anxiety levels. Overall, this interesting study suggests that listening to binaural beats can reduce anxiety levels in a variety of situations.  

Other interesting studies that have been conducted on binaural beats show that they help to improve cognition, focus, motivation, memory, and even confidence!9 With all this in mind, I would encourage you to check them out – you never know unless you try. Curious? My favorite binaural beat to help me focus is here.

References:

  1. Oster, G. (1973). Auditory beats in the brain. Scientific American229(4), 94-103.
  2. Lane, J. D., Kasian, S. J., Owens, J. E., & Marsh, G. R. (1998). Binaural auditory beats affect vigilance performance and mood. Physiology & behavior63(2), 249-252.
  3. Garcia-Argibay, M., Santed, M. A., & Reales, J. M. (2019). Efficacy of binaural auditory beats in cognition, anxiety, and pain perception: a meta-analysis. Psychological Research83(2), 357-372.
  4. Booth, S. (2019, May 14). This Is Your Brain on Binaural Beats. Retrieved March 25, 2021, from https://www.healthline.com/health-news/your-brain-on-binaural-beats
  5. Lentz, J. J., He, Y., & Townsend, J. T. (2014). A new perspective on binaural integration using response time methodology: super capacity revealed in conditions of binaural masking release. Frontiers in Human Neuroscience8, 641.
  6. Gao, X., Cao, H., Ming, D., Qi, H., Wang, X., Wang, X., … & Zhou, P. (2014). Analysis of EEG activity in response to binaural beats with different frequencies. International Journal of Psychophysiology94(3), 399-406.
  7. Isik, B. K., Esen, A., Büyükerkmen, B., Kilinc, A., & Menziletoglu, D. (2017). Effectiveness of binaural beats in reducing preoperative dental anxiety. British Journal of Oral and Maxillofacial Surgery55(6), 571-574.
  8. Solca, M., Mottaz, A., & Guggisberg, A. G. (2016). Binaural beats increase interhemispheric alpha-band coherence between auditory cortices. Hearing research332, 233-237.
  9. Garcia-Argibay, M., Santed, M. A., & Reales, J. M. (2019). Binaural auditory beats affect long-term memory. Psychological research83(6), 1124-1136
  10. Buskila, Y., Bellot-Saez, A., & Morley, J. W. (2019). Generating brain waves, the power of astrocytes. Frontiers in neuroscience13, 1125.

Cover image: Photo by Andrea Piacquadio from Pexels

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