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An overview of N-methyl D-aspartate receptor (NMDAR) antibody-associated encephalitis

An overview of N-methyl D-aspartate receptor (NMDAR) antibody-associated encephalitis

May 11, 2022 | by Seery N, Butzkueven H, O’Brien TJ, Monif M.

A message from IAES Blog Staff:

It is our honor & pleasure to present to all of you an overview of anti-NMDAR Autoimmune Encephalitis by the esteemed team at Monash University in Australia & lead by Dr. Mastura Monif. The International Autoimmune Encephalitis Society is proud to be in collaboration with Dr. Monif and her team in the Australian Autoimmune Encephalitis Consortium Project. Dr. Monif is on the board of directors for IAES and we work closely with them to best support AE patients, caregivers and their families. You can find out more about the team and their efforts to help those with AE and their families via the following link: https://www.monash.edu/medicine/autoimmune-encephalitis

 —-

An overview of N-methyl D-asparate receptor (NMDAR) antibody-associated encephalitis

Contemporary advances in anti-NMDAR antibody (Ab)-mediated encephalitis, Autoimmunity Reviews, April 2022, Volume 21, Issue 4, https://doi.org/10.1016/j.autrev.2022.103057

WHY WE DID THIS WORK:

  • N-methyl D-aspartate receptor (NMDAR) antibody-associated encephalitis, or anti-NMDAR encephalitis is a type of autoimmune encephalitis. Autoimmune encephalitis occurs when parts of the body’s immune system inappropriately attack certain components of nerve cells in the brain. Anti-NMDAR encephalitis is one of the most common defined types of autoimmune encephalitis. Young people who are on average 21 years of age, and females, experience the illness most commonly. But it can occur in older adults (over 45 years) and in young children (less than 12 years), where a relatively higher number of patients are males.
  • To make a diagnosis, doctors record key symptoms (e.g. memory issues, personality change, changes to behaviour alteration, or seizures) and clinical features from tests. The detection of antibodies that bind the receptor (NMDAR) from a patient’s blood or cerebrospinal fluid (fluid that cushions the brain and spinal cord) are also used to confirm the diagnosis of anti-NMDAR encephalitis. Antibodies are proteins produced by the immune system that in normal circumstances have a role in fighting infections. In certain autoimmune diseases, antibodies, along with other parts of the immune system, target normal components of a healthy individual.
  • Anti-NMDAR encephalitis can be treated using medications that selectively reduce components of the immune system, but as the illness is different from person to person, it is challenging to both diagnose and manage. The use of biological markers, or biomarkers (proteins, cells or other characteristics that can generally be detected via a certain test and are association with a particular disease), may be particularly useful for the diagnosis and assessment of how effective treatment is to manage a patient’s illness. Accurate and specific biomarkers for anti-NMDAR encephalitis still do not exist.
  • We did this update to collect the latest research findings from the field to inform researchers and clinicians who manage this condition and have a keen interest.

WHAT WERE THE THINGS WE DISCOVERED?

  • The N-methyl D-aspartate receptor (NMDAR) belongs to a group called glutamate-gated ionotropic receptors. These receptors are mostly located in a region of the brain called the hippocampus more so than other regions, and assist in excitatory transmission of nerve cells. In anti-NMDAR encephalitis, antibodies target a part of the receptor called GluN1.Anti-NMDAR antibodies exist in the serum part of blood and the cerebrospinal fluid.
  • Biomarkers in cerebrospinal fluid that have been identified include B-cell and T-cell chemokines, which are molecules that serve to attract particular white cells to a given part of the body (in particular, CXCL13 and CXCL10), interferon gamma, tumor necrosis factor alpha and interleukins (in particular 6, 7, 10 and 17-A). The levels of certain of these biomarkers were found to also coincide with poor long-term outcomes in patients.

TRIGGERS OF ANTI-NMDAR ENCEPHALITIS:

  • Two known triggers for anti-NMDAR encephalitis are the presence of an ovarian teratoma (an unusual type of tumour that can express nervous tissue) and less commonly, a viral infection of the brain called HSV-encephalitis.
  • Other than these two triggers it is less understood what causes the illness. At a molecular level, patient antibodies induce complex changes to the nerves by disrupting the functioning of the receptor. These findings may explain the variety of symptoms that patients experience, and varying and often impressive degrees of recovery.

CLINICAL FEATURES:

  • The diagnosis of the disease is not always straightforward. Symptoms and other clinical features may overlap with other diseases, and sometimes, at least in the blood, antibodies to the receptor may be seen without the disease itself. A broad range of clinical features exists in anti-NMDAR encephalitis. Patients can experience the following, which may change over time –
      • Changes in behaviour and hallucinations (psychiatric symptoms)
      • Difficulties in mental function (cognitive impairment)
      • Seizures
      • Abnormal movements and
      • Irregularities of the function of the autonomic nervous system (e.g. temperature, heart rate and breathing).
  • Therefore, detection of certain proteins and molecules in the blood or spinal fluid may assist in the diagnosis of the disease, and its management. A variety of candidates have been explored, but so far, generally remain limited in their use in clinical practice.

TREATMENT:

  • The cornerstone of treatment is suppression of the immune system. Research has shown that earlier treatment results in a better long-term outcome.
  • Exciting new treatment options are emerging, but research studies for these treatments are limited to relatively small numbers of patients and their approval for use by government therapeutic agencies is still awaiting. Therefore, we advise clinicians making the decision to use new therapies be made on based on each individual patient’s situation. 

WHAT DO THE FINDINGS MEAN?

  • This research can help clinicians understand how the illness progresses at the cellular and molecular level, its symptoms, the results of supportive tests (e.g. spinal fluid and MRI) and treatment options, and highlight areas of progress and needs in the current research.
  • Most patients will have some degree of recovery in their illness following appropriate treatment, but some symptoms can persist, particularly issues in mental function. Cognitive rehabilitation and follow up with psychiatry and psychology and in some cases antipsychotic medication, anti-depressants and mood stabilizers maybe warranted.

monif group - An overview of N-methyl D-aspartate receptor (NMDAR) antibody-associated encephalitis

2021 Monif group L-R – Paul Sanfilippo, Nabil Seery, Katrina Kan, Robb Wesselingh, William O’Brien, Tiffany Rushen, Mastura Monif (Group Leader), Tracie Tan, Sher Chim Ting, Sarah Griffith, Andrea Muscat.

 

For more information and resources on anti-NMDAr encephalitis, visit this link here. To download a plain language PDF of the paper summarized in this blog, click the button below:

 

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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 - An overview of N-methyl D-aspartate receptor (NMDAR) antibody-associated 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 - An overview of N-methyl D-aspartate receptor (NMDAR) antibody-associated encephalitis

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Blood, Sweat, and Clusterin

Blood, Sweat, and Clusterin

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

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

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

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

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

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

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

 

References

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

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

 

 

 

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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 - Blood, Sweat, and Clusterin 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 - Blood, Sweat, and Clusterin

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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

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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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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 - 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

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

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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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    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 - Brain Beats 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 - Brain Beats

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

    why zebra - Aphasia as a Symptom of Autoimmune Encephalitis
    Depression in Autoimmune Encephalitis

    Depression in Autoimmune Encephalitis

    April 14, 2021 | Sarah Reitz, PennNeuroKnow

    Major depressive disorder, commonly called depression, is a disorder that affects more than 168 million people worldwide1,2. Symptoms include depressed mood, lack of energy, loss of interest/pleasure, sleep disturbances, significant weight changes, and thoughts of suicide3. While depression can occur on its own, which is known as primary depression, it can also be caused by other diseases or medical conditions. This form of depression, called secondary depression, is relatively common in patients diagnosed with chronic illnesses, and is one of the key factors resulting in an impaired quality of life experienced by patients with chronic diseases4.

    Research has shown that patients with autoimmune diseases involving the brain and spinal cord, such as multiple sclerosis (MS), Hashimoto encephalopathy, and autoimmune encephalitis (AE), are at increased risk for depression and other mood disorders5,6. One study found that depressive symptoms occur in up to half of all patients with MS7, and another showed that prior hospitalization for an autoimmune disease increases the risk of developing a major mood disorder by 45%8. Some of this increase is likely a reaction to the diagnosis itself and the impairments caused by the disease. However, increased rates of depression are seen in MS patients up to 2 years before they are diagnosed with MS. These findings suggest that there is a biological link between autoimmune disease and depression that increases the risk of developing depression, independent of any reaction to the diagnosis or resulting lifestyle changes. 9,10. Research over the last 2 decades supports this idea, with increasing evidence linking the immune system and inflammation to a number of psychiatric disorders, including depression.

    A link between the immune system and depression?

    One indicator that the immune system can affect mood and behavior is the phenomenon of cytokine-induced sickness behavior. During an illness, cells in the immune system release small proteins called cytokines to help regulate and synchronize the immune system’s response to an invading bacteria or virus. Some examples of cytokines include interleukins (IL), tumor necrosis factors (TNF), and interferons (IFN). This increase in cytokines leads to specific behaviors many of us have experienced before while sick, including decreased activity, loss of energy, and even depressed mood11.

    Based on the observation that increased cytokines during sickness can lead to depression-like symptoms, researchers began to examine cytokine levels in patients diagnosed with depression and other psychiatric disorders. Many studies have found that patients with depression, who were otherwise medically healthy, showed signs of immune system activation, with increased levels of IL-6 and, in some cases, TNF-alpha12. Another study examined brain tissue from patients diagnosed with depression and found increased levels of many types of interleukins as well as IFN-gamma13. Additionally, mice treated with cytokines or drugs that increase levels of cytokines show depression-like behaviors, further linking the immune system and inflammatory response to depression14. This effect is also seen in humans, with one study finding that 17% of patients treated with IFN-alpha developed psychiatric side effects, including depression, and that these side effects improve once the cytokine treatment is stopped15.

    Just as increases in cytokine levels are linked to an increased risk of depression, research suggests that decreasing cytokines and inflammation can improve depression symptoms. A number of antidepressant therapies, including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, and even psychotherapy have anti-inflammatory effects, lowering levels of certain pro-inflammatory cytokines16-19. Taking this even further, there is evidence that anti-inflammatory drugs can improve depression symptoms20. However, anti-inflammatory treatments can sometimes interfere with the anti-depressant effects of SSRIs, so adding an anti-inflammatory drug (including drugs such as aspirin or ibuprofen) to a depression treatment plan should only be done after careful discussion with your doctor21.

    Depression in autoimmune encephalitis

    Given this link between immune system activation and depression, it is not altogether surprising that depression and other psychiatric symptoms are common in AE and other autoimmune disorders. For reasons that are still not understood, patients with autoimmune encephalitis with antibodies directed against cell surface antigens (especially anti-NMDA receptor encephalitis) are more likely to experience psychiatric symptoms compared to patients with antibodies directed against intracellular antigens (such as anti-Hu or anti-Ma encephalitis)22. In fact, between 65-80% of patients with anti-NMDA receptor encephalitis experience psychiatric symptoms, with depression being among the most common23,24. This has also been demonstrated in a mouse model of AE, where mice received infusions of cerebrospinal fluid into their brains containing antibodies from patients with NMDA receptor encephalitis. As the anti-NMDA receptor antibodies attacked their NMDA receptors, the mice developed depressive-like behaviors and lost interest in things they had previously found pleasurable (in this case, a sugary drink). Once the infusions stopped and the NMDA receptor levels returned to normal, these depressive-like behaviors improved25.

    In NMDA receptor encephalitis, psychiatric symptoms often appear before any neurologic symptoms26. As a result, it can be difficult to distinguish the initial phases of the disease from psychiatric disorders such as depression or schizophrenia. This leads many patients to assume they have a purely psychiatric disorder and to seek help from a psychiatrist first. One study found that this occurred in 76% of patients ultimately diagnosed with NMDA receptor encephalitis27!

    This becomes problematic when psychiatrists are not aware that early stages of autoimmune encephalitis can mimic psychiatric disorders. Rather than ordering antibody tests to examine a potential autoimmune disorder, they may assume the patient has major depressive disorder or another psychiatric disorder. Based on this assumption, they may attempt to treat the patient with anti-depressant therapies rather than treatments aimed at the underlying autoimmune condition. This is unfortunately not a hypothetical scenario. In a study examining a group of 464 people with NMDA receptor encephalitis, nearly 10% were initially diagnosed with a psychiatric disorder, including depression, before the correct diagnosis of NMDA receptor encephalitis was reached6.

    A timely diagnosis is critical in treating autoimmune encephalitis, since earlier administration of immunotherapies is associated with better patient outcomes28. A delay in a correct diagnosis and treatment plan can be especially harmful given that an estimated 10% of patients with NMDA receptor encephalitis experience suicidal thoughts29. Luckily, as more is learned about AE, psychiatrists are becoming increasingly educated and aware of the psychiatric symptoms of the disease. An improved awareness of AE will allow for faster and more accurate diagnoses, leading to faster treatment and improved outcomes for patients suffering from this disease.

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    References

    1. Kessler RC, Bromet EJ. The epidemiology of depression across cultures. Annu Rev Public Health. (2013) 34:119–38. doi: 10.1146/annurev-publhealth-031912-114409
    2. Abajobir AA, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. (2017) 390:1211–59. doi: 10.1016/S0140-6736(17)32154-2
    3. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (5th ed.) (2013). doi: 10.1176/appi.books.9780890425596
    4. Moussavi S, Chatterji S, Verdes E, Tandon A, Patel V, Ustun B. Depression, chronic diseases, and decrements in health: results from the World Health Surveys. Lancet. (2007) 370:851–8. doi: 10.1016/S0140-6736(07)61415-9
    5. Pape K, Tamouza R, Leboyer M, Zipp F. Immunoneuropsychiatry – novel perspectives on brain disorders. Nat Rev Neurol (2019) 15(6):317–28. doi: 10.1038/s41582-019-0174-4
    6. Al-Diwani A et al. The psychopathology of NMDAR-antibody encephalitis in adults: a systematic review and phenotypic analysis of individual patient data. Lancet Psychiatry (2019) 6(3):235–46. doi: 10.1016/S2215-0366(19)30001
    7. Patten SB, Marrie RA, Carta MG. Depression in multiple sclerosis. Int Rev Psychiatry (2017) 29(5):463–72. doi: 10.1080/09540261.2017.1322555
    8. Benros, M. E. et al. Autoimmune diseases and severe infections as risk factors for schizophrenia: a 30-year population-based register study. Am. J. Psychiatry (2011)168, 1303–1310.
    9. Hoang H, Laursen B, Stenager EN, Stenager E. Psychiatric co-morbidity in multiple sclerosis: The risk of depression and anxiety before and after MS diagnosis. Mult Scler J. (2016) 22:347–53. doi: 10.1177/1352458515588973
    10. Marrie RA et al. Rising incidence of psychiatric disorders before diagnosis of immune-mediated inflammatory disease. Epidemiol Psychiatr Sci. (2017) 28:333–42. doi: 10.1017/S2045796017000579
    11. Kelley, K. W. et al. Cytokine-induced sickness behavior. Brain Behav. Immun. (2003) 17(Suppl. 1):112–118
    12. Haapakoski, R., Mathieu, J., Ebmeier, K. P., Alenius, H. & Kivimaki, M. Cumulative meta-analysis of interleukins 6 and 1β, tumour necrosis factor α and C-reactive protein in patients with major depressive disorder. Brain Behav. Immun. (2015) 49, 206–215
    13. Shelton RC, Claiborne J, Sidoryk-Wegrzynowicz M, Reddy R, Aschner M, Lewis DA, Mirnics K. Altered expression of genes involved in inflammation and apoptosis in frontal cortex in major depression. Mol Psychiatry (2011) 16:751–762
    14. Fu X, Zunich SM, O’Connor JC, Kavelaars A, Dantzer R, Kelley KW. Central administration of lipopolysaccharide induces depressive-like behavior in vivo and activates brain indoleamine 2,3 dioxygenase in murine organotypic hippocampal slice cultures. J Neuroinflammation(2010) 7(43):1–12
    15. Renault PF et al. Psychiatric complications of long-term interferon alfa therapy. Arch Intern Med. (1987) 147:1577–80. doi: 10.1001/archinte.1987.00370090055011
    16. Mohr DC, Goodkin DE, Islar J, Hauser SL, Genain CP. Treatment of depression is associated with suppression of nonspecific and antigen-specific TH1 responses in multiple sclerosis. Arch Neurol. (2001) 58:1081. doi: 10.1001/archneur.58.7.1081
    17. Ohgi Y, Futamura T, Kikuchi T, Hashimoto K. Effects of antidepressants on alternations in serum cytokines and depressive-like behavior in mice after lipopolysaccharide administration. Pharmacol Biochem Behav. (2013) 103:853–9. doi: 10.1016/j.pbb.2012.12.003
    18. Hannestad J, Dellagioia N, Bloch M. The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis. Neuropsychopharmacology. (2011) 36:2452–9. doi: 10.1038/npp.2011.132
    19. Ramirez K, Shea DT, Mckim DB, Reader BF, Sheridan JF. Imipramine attenuates neuroinflammatory signaling and reverses stress-induced social avoidance. Brain Behav Immun. (2015) 46:212–20. doi: 10.1016/j.bbi.2015.01.016
    20. Kohler, O. et al. Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry (2014) 71:1381–1391
    21. Warner-Schmidt JL, Vanover KE, Chen EY, Marshall JJ, Greengard P. Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans. Proc Natl Acad Sci USA. (2011) 108:9262–7. doi: 10.1073/pnas.1104836108
    22. Hansen N and Timaus C. Autoimmune encephalitis with psychiatric features in adults: historical evolution and prospective challenge. J. Neural Transm. (2021) 128:1-14
    23. Kruse JL et al. Psychiatric autoimmunity: N-methyl-D-aspartate receptor IgG and beyond. Psychosomatics. (2015) 56(3)227-241
    24. Wang W, Zhang L, Chi XS, He L, Zhou D, Li JM. Psychiatric symptoms of patients with anti-NMDA receptor encephalitis. Front in Neurol.(2020) doi: 10.3389/fneur.2019.01330
    25. Planaguma J et al. Human N-methyl-D-aspartate receptor antibodies alter memory and behaviour in mice. Brain 138(1):94-109
    26. Dalmau J, Armangué T, Planagumà J, Radosevic M, Mannara F, Leypoldt F, Geis C, Lancaster E, Titulaer MJ, Rosenfeld MR, Graus F (2019) An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models. Lancet Neurol 18:1045–1057
    27. Dalmau J et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol., (2008) 1091-1098.
    28. Titulaer MJ, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol (2013)12:157-165.
    29. Zhang L et al. Suicidality is a common and serious feature of anti-N-methyl-D-aspartate receptor encephalitis. J Neurol. (2017) 264(12):2378-2386.

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

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    Cytokine Storm: A Detrimental Overreaction

    Cytokine Storm: A Detrimental Overreaction

    February 24, 2021 | Claudia Lopez Lloreda, PennNeuroKnow

    When it comes to responses by the body, the immune response is usually a good thing. Your body recognizes an invading pathogen that does not belong there: bacteria, a virus, and other substances. In response to these pathogens, the immune system must react in a regulated manner and then shut off when it has solved the problem. But sometimes this goes awry, creating an overactive reaction that does not turn off and can end up harming the body it is trying to protect.

    One of these immune system overreactions has become fairly common in the last few months. After one year of dealing with the COVID-19 pandemic and being bombarded with new information about this disease daily, you may have encountered a term you had never heard before: cytokine storm. Cytokines are molecules released by the immune cells of the body that act as the signals of the immune system1. They perform critical functions during the immune response, such as regulating the immune cells of the body. They can tell certain cells to divide, to create other molecules, or can even signal them to turn off while also controlling other aspects of the body such as blood vessel dilation.

    Cytokines are critical in modulating the immune response, making sure there is an appropriate level of activity. Cytokine release syndrome, also called a cytokine storm, occurs when there is an excessive production of cytokines, which then circulate throughout the body affecting different organs2,3. They then rile up other immune system cells, leading to hyperactivation of the immune system which may damage the body, including the lungs, the brain, and other organs.

    This damage is reflected as a variety of symptoms in patients suffering a cytokine storm. One of the most common manifestations is a high fever due to the high levels of inflammation throughout the body3. Pulmonary (lungs), renal (kidney), neurological (brain), and hepatic (liver) function may also be affected (Figure 1). Treatments are focused on trying to maintain normal functioning of these along with suppressing the overactive immune system. For example, neutralizing the circulating antibodies or dampening the function of immune cells are usually used as treatments to subdue a cytokine storm3.

    cytokine storm 500x352 - Cytokine Storm: A Detrimental Overreaction

    Figure 1. Symptoms associated with different organs in response to a cytokine storm (Adapted from Fajgenbaum & June, 2020).

     

    Cytokine storms can occur in response to viral infection. For example, cytokine storms have been increasingly observed with SARS-CoV-2 infection, the virus that causes COVID-19. When COVID-19 cases started increasing, scientists and doctors were puzzled by a confusing observation: people were succumbing later in the progression of the disease or even after recovery4. Even when people were surviving the initial consequences of the infection, they found that the overactive immune response was leading to severe illness, organ failure, and sometimes death. In these cases, it was not the virus that led to this damage, but rather the exaggerated response of the body against the virus.

    In these patients, doctors found high levels of cytokines such as interleukin 6 (IL-6), a pro-inflammatory cytokine that has been identified as a common driver of cytokine storms5. Cytokines from this family, called the interleukins, and from another family, interferons, are critical components of these storms2.

    In some ways, a cytokine storm can be likened to an autoimmune disease in which there is a faulty immune response. In autoimmune conditions such as autoimmune encephalitis (AE), the immune system mistakenly attacks the body by generating antibodies against important proteins. Similarly, a cytokine storm creates an overabundance of cytokines that can negatively affect bodily functions, although in a more general manner than the targeted antibodies created in AE.

    Unfortunately, people with autoimmune diseases are more susceptible to cytokine storms. Some studies suggest that autoimmune disorders themselves might be a trigger for cytokine storms. For example, studies show that IL-6, the same cytokine increased in COVID-19 patients with cytokine storms, is also increased in autoimmune disorders, including AE6. One study in patients with lupus suggests that people with autoimmune conditions could also be at higher risk of developing a cytokine storm in response to COVID-197.

    Although there are no research studies linking cytokine storms specifically to AE, there have been case studies, in which one patient is observed, that suggest a potential relationship. In one of these case studies, researchers found that one patient diagnosed with COVID-19 had developed antibodies against the NMDA receptor, which led to a diagnosis of NMDA-receptor encephalitis. The patient also had increased levels of IL-6, which suggested that a cytokine storm was occurring8. Further research is needed to delve into the complex interaction between AE, COVID-19, and the development of cytokine storms.

    References

    1. Steinke, J., & Borish, L. (2006). Cytokines and chemokines. Journal of Allergy and Clinical Immunology, 117(2).https://doi.org/10.1016/j.jaci.2005.07.001
    2. Tisoncik, J. R., Korth, M. J., Simmons, C. P., Farrar, J., Martin, T. R., & Katze, M. G. (2012). Into the Eye of the Cytokine Storm. Microbiology and Molecular Biology Reviews, 76(1), 16–32. https://doi.org/10.1128/mmbr.05015-11
    3. Fajgenbaum, D. C., & June, C. H. (2020). Cytokine Storm. New England Journal of Medicine, 383(23), 2255–2273. https://doi.org/10.1056/nejmra2026131
    4. Ye, Q., Wang, B., & Mao, J. (2020). The pathogenesis and treatment of the `Cytokine Storm’ in COVID-19. Journal of Infection, 80(6), 607–613. https://doi.org/10.1016/j.jinf.2020.03.037
    5. Ragab, D., Eldin, H. S., Taeimah, M., Khattab, R., & Salem, R. (2020). The COVID-19 Cytokine Storm; What We Know So Far. Frontiers in Immunology, 11. https://doi.org/10.3389/fimmu.2020.01446
    6. Lee, W.-J., Lee, S.-T., Moon, J., Sunwoo, J.-S., Byun, J.-I., Lim, J.-A., … Chu, K. (2016). Tocilizumab in Autoimmune Encephalitis Refractory to Rituximab: An Institutional Cohort Study. Neurotherapeutics, 13(4), 824–832. https://doi.org/10.1007/s13311-016-0442-6
    7. Sawalha, A. H., Zhao, M., Coit, P., & Lu, Q. (2020). Epigenetic dysregulation of ACE2 and interferon-regulated genes might suggest increased COVID-19 susceptibility and severity in lupus patients. Clinical Immunology, 215, 108410. https://doi.org/10.1016/j.clim.2020.108410
    8. Panariello, A., Bassetti, R., Radice, A., Rossotti, R., Puoti, M., Corradin, M., … Percudani, M. (2020). Anti-NMDA receptor encephalitis in a psychiatric Covid-19 patient: A case report. Brain, Behavior, and Immunity, 87, 179–181. https://doi.org/10.1016/j.bbi.2020.05.054

     

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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 - Cytokine Storm: A Detrimental Overreaction 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 - Cytokine Storm: A Detrimental Overreaction

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    The Neurological Exam

    The Neurological Exam

    January 13, 2021 | Nitsan Goldstein, PennNeuroKnow

    Diagnosing a problem in the brain can be a major challenge. Unlike a broken bone, many neurological problems are extremely hard to see. A computer tomography (CT) scan of the brain, which is similar to an x-ray, can usually only detect obvious damage, such as bleeding in the brain. Even magnetic resonance imaging (MRI) scans, which are expensive and time consuming, can fail to detect the underlying cause of a neurological disease such as autoimmune encephalitis1. There is one characteristic of the brain, however, that can be leveraged to diagnose brain conditions: the fact that the brain and spinal cord control everything else in the body. Using this fact as a guide, the neurological exam is a standard battery of tests performed by physicians to assess a patient’s neurological function. It’s cheap and relatively easy to administer because it involves testing other parts of the body for clues about how the brain is working, instead of having to look into the brain with complicated and expensive techniques. Let’s examine each part of a standard neurological exam, and how it can help uncover abnormalities in brain function.  

    Mental Status

    During the mental status evaluation, a physician will assess basic levels of alertness, behavior, and memory. The patient may be asked where they are, what year it is, and if they can remember a series of words. Abnormalities in mental status such as confusion or erratic behavior could indicate a host of problems ranging from intoxication to severe infection to dementia.

    Cranial Nerves

    Anyone who has had a neurological exam has likely had a flashlight shone in their eye. Why do physicians do this? Many of the tests involving the eyes and face are testing the function of cranial nerves, which are nerves that emerge directly out of the bottom surface of the brain.  

    Our eyes, though small, are intricately controlled by our brains via several cranial nerves, which is why most of these tests focus on the eyes. When light shines in your eye, the information travels from cranial nerve 2 (the optic nerve) to the brain, which then sends a signal down cranial nerve 3 (the oculomotor nerve) to tiny muscles around the pupil, causing them to contract. This protects the retina from light damage. If the pupils do not respond, it is an indication that there may be damage to one of the cranial nerves. The doctor will also check to make sure the right and left pupils are dilating and contracting evenly. If they are not, it may help pinpoint where in the brain the damage is located.

    Another common test involves the physician placing a pen or their finger in front of a patient, and asking them to track the movement with their eyes while leaving their head still. This also tests the cranial nerves, since eye movement is controlled by the oculomotor nerve. Failure of the eyes to move in a specific direction can help identify the site of injury in the brain.

    Physicians also frequently access the function of cranial nerve 7, which is the facial nerve. This nerve sends motor information to the muscles in the face. Physicians may simply ask a patient to smile, and watch the muscles to make sure the smile is symmetric. They may also ask patients to puff out their cheeks. Neurological conditions involving the facial nerve may cause weakness that would cause air to leak out. 

    There are many other tests of cranial nerve function that may be performed including assessing smell, hearing, and the gag reflex. These tests help physicians understand whether there are specific injuries to the different cranial nerves, which mediate important functions.  

    Motor Function

    The brain controls movement by sending electrical signals from the brain to the spinal cord, and out to the muscles. If a neurological condition affects any part of this pathway, weakness or abnormalities in muscle tone may occur. A physician will usually ask patients to push their arms or legs against the doctor’s hands, or try to keep their arms or legs still while the physician pushes against them. If patients’ muscles are unusually weak or there are differences in strength between the left and right side, physicians will want to look for conditions affecting motor areas of the brain or motor neurons in the body that control muscles.

    Sensation

    Tests of sensation involve assessing a person’s sense of touch. Again, these are relatively simple tests that involve touching a patient’s skin with a sharp object, like a small needle, and a soft object, like a Q-tip, and asking if they can feel the difference. The physician may also use a tuning fork, which vibrates at certain frequencies and ask the patient if they can feel the vibration. Our skin contains sensory neurons that respond differently to sharp and dull objects and to vibration. The sensory neurons relay this information to the spinal cord and then to the somatosensory cortex in the brain, where the signal is interpreted. Dysfunction in any part of this pathway may result in abnormalities during the sensory portion of a neurological exam.

    Reflexes

    Reflexes are automatic responses that involve sensory neurons in the skin, tendons or muscles, neurons in the spinal cord, and motor neurons that control muscle movement. One example is the famous “hammer on the knee” test, where a physician will tap the tendon below your knee, eliciting an automatic contraction of the quadricep and a kicking motion. These tests check that the basic circuits that sense touch and stretch and those that control muscles are working properly.  

    Balance & Coordination

    Balance and coordination are controlled, in part, by a brain structure called the cerebellum. There are many ways to test balance, including asking patients to stand on one leg with their eyes closed, or walk heel-to-toe in a straight line. A common way to test coordination is to have patients close their eyes, put their arms out in front of them, and touch their nose with their finger. A healthy person’s finger will take a straight route and touch the nose or very close to the nose without relying on sight or touch to know where the nose is. If a person cannot touch their nose it could indicate there is a problem in the cerebellum.  

    Terminology

     A comprehensive neurological exam with every possible test would take a very long time. Therefore, in most cases, only a subset of these tests are performed depending on what symptoms the patient is experiencing or where the doctor suspects there may be damage. Thus, one person’s neurological exam may look very different from another’s. Some exams focus more on cognitive function, especially when the patient’s behavior is altered or memory problems are present. These can be called neuropsychological exams because they focus more on the patient’s mental and cognitive status rather than, for example, problems with movement2. The goal, however, is always the same: to determine whether there is a problem in the nervous system and to try to locate and identify that problem so that it can be treated. 

    Neurological Exam and AE         

    A neurological exam is likely one of the first diagnostic tests to be performed on a patient with autoimmune encephalitis since the initial symptoms typically point to some kind of neurological problem. Anti-NMDAR encephalitis, for example, begins with predominantly psychiatric problems such as agitation and hallucinations3. Limbic encephalitis will cause behavioral changes, confusion, and memory problems3. While brain scans can reveal abnormalities, in many cases they do not1, making the neurological exam even more important. But the exam, as comprehensive as it is, cannot identify the underlying cause of these symptoms. It can, however, rule out other causes such as schizophrenia, which may be crucial in the decision to test for autoantibodies in the blood, which will lead to the correct diagnosis4,5. The neurological exam can also be helpful to identify subtle symptoms or track a patient’s progress through treatment. 

    neuro - The Neurological Exam

    References: 

    1. Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013 Feb;12(2):157-65. doi: 10.1016/S1474-4422(12)70310-1. Epub 2013 Jan 3. PMID: 23290630; PMCID: PMC3563251.
    2. Harvey PD. Clinical applications of neuropsychological assessment. Dialogues Clin Neurosci. 2012 Mar;14(1):91-9. PMID: 22577308; PMCID: PMC3341654.
    3. Leypoldt F, Armangue T, Dalmau J. Autoimmune encephalopathies. Ann N Y Acad Sci. 2015 Mar;1338(1):94-114. doi: 10.1111/nyas.12553. Epub 2014 Oct 14. PMID: 25315420; PMCID: PMC4363225.
    4. Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016 Apr;15(4):391-404. doi: 10.1016/S1474-4422(15)00401-9. Epub 2016 Feb 20. PMID: 26906964; PMCID: PMC5066574.
    5. Hao Q, Wang D, Guo L, Zhang B. Clinical characterization of autoimmune encephalitis and psychosis. Compr Psychiatry. 2017 Apr;74:9-14. doi: 10.1016/j.comppsych.2016.12.006. Epub 2016 Dec 27. PMID: 28081431.

    Neurological Exam Information Adapted From:

    Goldberg, C. Practical Guide to Clinical Medicine: The Neurological Examination. UC San Diego School of Medicine. https://meded.ucsd.edu/clinicalmed/neuro2.html  

    Johns Hopkins Medicine: Neurological Exam. https://www.hopkinsmedicine.org/health/conditions-and-diseases/neurological-exam

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    seal - The Neurological Exam     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 - The Neurological Exam 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 - The Neurological Exam

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

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    The Autonomic Nervous System and Dysautonomia in AE

    The Autonomic Nervous System and Dysautonomia in AE

    November 11, 2020 | Sarah Reitz, PennNeuroKnow

    Dysautonomia is a collection of disorders that involve dysfunction or impairment of the autonomic nervous system (ANS). It affects more than 70 million people worldwide, and can be caused by a number of disorders, including autoimmune encephalitis (AE)1. To better understand dysautonomia as a symptom of AE and other disorders, it is helpful to first know how the healthy ANS works.

    What is the autonomic nervous system?

    The ANS, as its name might suggest, controls the automatic processes of the body that we do not have to consciously think about. Some of these include regulation of heart rate, blood pressure, body temperature, breathing, kidney function, and digestion. The ANS regulates this huge variety of processes through its 3 branches, or subdivisions: the sympathetic, the parasympathetic, and the enteric nervous system2.

    The sympathetic branch of the ANS is commonly called the “fight or flight” branch and is largely responsible for activating the physiological processes described above, quickly mobilizing the body to respond to changing conditions. This means that activation of the sympathetic nervous system produces effects such as increased heart rate and blood pressure, dilated pupils, decreased digestion, and increased breathing rate2.

    On the other hand, the parasympathetic branch is considered to be a dampening system, generally inhibiting the same processes that are activated by the sympathetic nervous system. It is sometimes called the “rest and digest” system, as it stimulates digestion by increasing blood flow to the intestines and production of saliva, slows heart rate, and constricts the pupils. The third branch of the ANS, the enteric nervous system, also controls the gastrointestinal tract by regulating gut motility as well as the secretion of digestive enzymes and mucus2. 

    These three branches work together to ensure the body responds properly to any given situation, like increasing body temperature when it is cold, or decreasing heart rate and blood pressure when you are relaxed and need to digest a meal. But how do they know when to activate or inhibit specific physiological processes?

    autonomic nervous system PNK e1604088238851 - The Autonomic Nervous System and Dysautonomia in AE

    Two of the main branches of the ANS, the sympathetic and parasympathetic branches, play generally opposing roles in controlling many physiological processes such as heart rate, blood pressure, and digestion.

    The organization of the autonomic nervous system

    The sympathetic and parasympathetic branches of the ANS involve 2 types of neurons (Figure 1). The first type are called preganglionic neurons, and are located in the central nervous system: either the brainstem (for the parasympathetic branch) or the spinal cord (for both sympathetic and parasympathetic branches). These preganglionic neurons project to a specific cluster of neurons—called a ganglion—where they connect to a postganglionic neuron. Preganglionic neurons for both major branches communicate with the postganglionic neuron using a neurotransmitter called acetylcholine2.

    The postganglionic neurons then act as a relay center, passing the message from the brain or spinal cord to the appropriate muscle or organ. While the postganglionic neurons of the parasympathetic nervous system use acetylcholine to communicate with the target tissue, postganglionic neurons in the sympathetic nervous system transmit their messages using a different neurotransmitter, called norepinephrine2. This difference in the chemical signal allows the two branches to produce opposite effects on the muscles and organs. Together, these branches of the ANS work together to integrate signals from the brain and spinal cord to produce the appropriate physiological response to any given situation. 

    Dysautonomia

    Dysautonomia results when the ANS does not function properly. Usually, this means one or more systems or processes controlled by the ANS fail or are impaired, but cases of dysautonomia have also occurred due to an overactive ANS. Dysautonomia can be categorized into two large classes: primary dysautonomia, which occurs on its own without other existing conditions, and secondary dysautonomia, which occurs as a result of another disease such as Parkinson’s, diabetes, lupus, or autoimmune encephalitis1,3-6.

    Because the ANS is so broad and controls such a wide array of systems and responses in the body, the symptoms of dysautonomia are extremely variable from person to person and can be unpredictable. Symptoms can range in severity, and even the severity level can change across time within a single person. For instance, some people find their symptoms get worse during stressful times, but then improve as stress decreases. Others find that dehydration or overexertion can trigger symptoms. Symptoms can be local, only affecting one aspect of the ANS, or a full, global autonomic failure. One common symptom is orthostatic intolerance, meaning it is hard to stand up for a long time without feeling faint or dizzy. Other symptoms that a person with dysautonomia might experience include things such as swings in body temperature, heart rate, or blood pressure, gastrointestinal problems, low blood sugar, dehydration, shortness of breath, and mood swings1 

    How is dysautonomia diagnosed?

    One test that is commonly used to diagnose dysautonomia is called the tilt table test. During this test, the patient is connected to equipment that monitors heart rate, blood pressure, and oxygen levels. They then lie on a table that can be tilted at different angles. As the table is tilted in various directions, the equipment measures how well the body regulates blood pressure, heart rate, and oxygen levels. While a person without dysautonomia will be able to keep those measures constant regardless of their body position, a person with dysautonomia will typically have swings in these measures as their body is tilted in different positions since the ANS cannot regulate them properly. However, since dysautonomia symptoms can vary widely, doctors can also use other, more specific tests of the affected organ systems to help diagnose the disease1.

    Treatment for Dysautonomia

    While there is currently no cure for this group of diseases, there are multiple ways to manage the symptoms. Some of these are as simple as standing up slowly, avoiding extreme heat, drinking more water every day or adding extra salt to your diet to help maintain a normal blood pressure. Other treatments include sleeping with your head elevated 6-10 inches above your body, or taking medication to increase blood pressure1. Again, due to the variability of the disorder, symptom management depends on the specific symptoms experienced by each patient. For secondary dysautonomia, such as dysautonomia associated with autoimmune encephalitis, treatment of the underlying disease may improve the dysautonomia symptoms1.

    Dysautonomia in autoimmune encephalitis

    ANS dysfunction is known to occur in various types of autoimmune encephalitis, including anti-GAD653, anti-CASPR-24, and limbic encephalitis5. However, it seems to appear most frequently in anti-NMDAR encephalitis, with one study finding that about 35% of patients under age 12 and 50% of patients over age 12 show ANS-related symptoms6, compared to the roughly 10% of patients with limbic encephalitis who experience ANS-related symptoms5. NMDA receptors are found in both the cholinergic and noradrenergic systems7, which as mentioned earlier are critical in ANS signaling. The decrease in the number of NMDA receptors caused by the autoantibodies directed against them might explain why dysautonomia is more common in this specific type of autoimmune encephalitis.

    Because dysautonomia as a symptom of AE is a type of secondary dysautonomia, treating the source of the encephalitis itself can often help resolve the ANS symptoms8,9. However, severe ANS dysfunction is associated with worse outcomes in AE patients that require ICU treatment10. A study of 500 patients with anti-NMDAR encephalitis found that ANS dysfunction was responsible for the majority of the deaths in the cohort6. Thus, understanding dysautonomia in the context of AE is critically important. Increasing awareness of dysautonomia as a symptom of AE is also crucial, as it may help patients receive a proper diagnosis much faster, allowing more time for treatments to be administered and to be effective before the autonomic symptoms become severe and even life-threatening.  

    Image References:

    Figure 1: Image by Geo-Science-International via Wikimedia Commons, CC0 1.0. https://commons.wikimedia.org/wiki/File:The_Autonomic_Nervous_System.jpg

    References:

    1. Dysautonomia: Symptoms, Causes, Types, & How to Live With. Retrieved October 2, 2020 from https://my.clevelandclinic.org/health/diseases/6004-dysautonomia
    2. Gibbons, CH (2019) Chapter 27: Basics of autonomic nervous system function. In Handbook of Clinical Neurology. Volume 160, pp. 407-418.
    3. Ben Achour N, Ben Younes T, Rebai I, Ben Ahmed M, Kraoua I, Ben Youssef-Turki I (2018) Severe dysautonomia as a main feature of anti-GAD encephalitis: Report of a paediatric case and literature review. Eur J Paediatr Neurol. 22(3):548-551.
    4. Irani SR, Pettingill P, Kleopa KA, Schiza N, Waters P, Mazia C, Zuliani L, Watanabe O, Lang B, Buckley C, Vincent A (2012) Morvan syndrome: clinical and serological observations in 29 cases. Ann Neurol. 72(2):241-255.
    5. Irani SR, Alexander S, Waters P, Kleopa KA, Pettingill P, Zuliani L, Peles E, Buckley C, Lang B, Vincent A (2010) Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan’s syndrome, and acquired neuromyotonia. Brain133:2734-2748.
    6. Titulaer MJ et al. (2013) Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 12(2):157-165.
    7. Maramottom BV & Jacob A (2011) N-methyl D-aspartate receptor encephalitis: a new addition to the spectrum of autoimmune encephalitis. Ann Indian Acad Neurol. 14(3):153-157.
    8. Sansing LH, Tuzun E, Ko MW, Baccon J, Lynch DR, Dalmau J (2007) A patient with encephalitis associated with NMDA receptor antibodies. Nat Clin Pract Neurol. 3(5)291-296.
    9. Ren C, Nai Y, LV W, Liu H, Chen Q, Sun Z-W, Wang J-H, Guan L-N, Gong L, Wang X-T (2019) Focus on autonomic dysfunctions in anti-NMDAR encephalitis: a case report. Eur Rev Med Pharmacol Sci. 23(24)10970-10975.
    10. Schubert J, et al. (2019) Management and prognostic markers in patients with autoimmune encephalitis requiring ICU treatment. Neurol Neuroimmunol Neuroinflamm. 6(1). 

     

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    The Dynamic Brain in Autoimmune Encephalitis

    The Dynamic Brain in Autoimmune Encephalitis

    September 26, 2020 | Claudia Lopez-Lloreda, PennNeuroKnow

    The plastic brain

    Brain plasticity handout image Facebook Post 300x251 - The Dynamic Brain in Autoimmune EncephalitisIn autoimmune encephalitis (AE), the body generates antibodies that mistakenly attack neuronal proteins that are important for brain function. Among the most important proteins targeted in AE are neurotransmitter receptors1. Neurotransmitter receptors function as the “lock” for different neurotransmitters, like dopamine and serotonin, that act as “keys”. Neurotransmitters unlock these receptors and through this allows neurons to communicate with each other.

    One defining feature of the nervous system that neurotransmitters play a key role in is brain plasticity. Brain plasticity, also called neuroplasticity, is the ability of the brain to adapt by changing, re-wiring, or making new connections between neurons. This is important because this plasticity in response to lived experiences is what enables behavioral changes, such as learning new things and forming new memories2. Research and anecdotal evidence show that learning and memory are affected in AE, which makes it important to understand what brain plasticity is and how it is affected in disease.

    Brain plasticity: How does it work?

    At the cellular level, plasticity is seen mainly by the change in strength of the connections between neurons, called synapses. This is known as synaptic plasticity and it can go two ways: synapses can strengthen, known as long-term potentiation (LTP), or they can weaken, known as long-term depression (LTD)2. Importantly, the quantity and function of neurotransmitters and their corresponding receptors are critical for synaptic plasticity. More neurotransmitter molecules and more receptors means that neurons can communicate better and more effectively, which allows for the strengthening of their connection.

    Strengthening usually happens when two neurons synchronize their activity. One famous researcher, Donald Hebb, said it conclusively: “Neurons that fire together, wire together.” This usually happens in our brain in response to different experiences, but it can also be studied in the lab. This process is studied by artificially stimulating connections to induce either LTP or LTD2. Using a baseline, scientists then study how different interventions affect whether the connection strengthens or weakens. By doing this, they can see how different changes, such as a generation of autoantibodies, can change these connections.

    Can autoantibodies affect plasticity?

    Since we know that AE is characterized by autoantibodies against important neuronal proteins—specifically neurotransmitter receptors—scientists wondered whether these autoantibodies could affect synaptic plasticity. One study looked at this by treating mice with antibodies against one specific subunit of the AMPA receptor derived from AE patients3. The AMPA receptor is one of the locks for the neurotransmitter glutamate, which is important in excitatory transmission, the type of communication where neurons activate other neurons. The researchers found that treating mice with autoantibodies led to internalization of the receptor, meaning the cells took the receptor away from its normal location on the outside of the neuron. Inside the neuron, the receptor could no longer exert its function and the neurotransmitter lost its effect.

    The mice treated with these human antibodies against AMPA receptors had impaired LTP in a specific pathway of the hippocampus, an area that is critical for the formation of memories3. This means that with autoantibody treatment from AE patients, the strengthening of the synapses did not occur as well as it did when mice were not treated with the antibodies. As a consequence, treating mice with these antibodies affected their learning and memory. The researchers saw that the impairments that mice developed with antibody treatment paralleled the strong memory impairments seen in disease.

    Similarly, a group of researchers treated brain slices from mice with fluid derived from the brains of patients with AE4. This fluid had autoantibodies specifically against an important neurotransmitter receptor called the NMDA receptor (NMDAR), another lock for the same neurotransmitter glutamate. Once again, the antibody-rich fluid derived from AE patients impaired LTP4. Injecting fluid from patients with NMDAR encephalitis straight into the brains of live mice also blunted the ability of connections to strengthen5.

    However, these studies were done in animals. In humans, studying brain plasticity is a bit trickier, since neurons are deep inside the human brain in humans and artificially activating them is not an easy task. One way it can be done is by pairing two activations. The first activation, called peripheral electrical stimulation, is done by giving a jolt of electrical pulses to peripheral nerves such as those in the hand. At the same time, the researchers non-invasively stimulate the area in the brain that connects with the peripheral nerve by using a technique called transcranial magnetic stimulation. By doing this, they can “look” at what is happening in the brain to see how this artificial paired activation leads to changes in synaptic plasticity.

    Studies show that this type of stimulation in humans produces something similar to the plasticity seen in mice and in tissue slices6. One study applied transcranial magnetic stimulation to patients with NMDA encephalitis and found that plasticity was impaired when compared to healthy individuals6. Strikingly, the degree of impairment in synaptic plasticity was associated with disease severity. These studies suggest that the autoantibodies generated in AE can be detrimental to the important function of synaptic plasticity in the brain. Further, impairments in synaptic plasticity could be a contributing factor to the symptoms seen with disease.

    What does this mean for recovery?

    Brain plasticity is also a mechanism that the brain uses to recover from damage. After injury, the brain can try to find new ways to do things. For example, if an area that controls understanding speech is damaged, the brain can reorganize to change where it gets different speech information from. In this case, the rearrangement of synapses and the alteration of synapse strength could be a way the brain tries to respond to the injury mediated by autoantibodies in AE. As a treatment, activating plasticity has been considered for psychiatric disorders7. Different strategies include medication8 and even exercise, which has been shown to enhance plasticity9. Therefore, it is possible that plasticity could be activated to help patients with AE. However, more research has to be done to further understand how exactly these interventions could change brain plasticity in AE and potentially help people recover from the debilitating symptoms.

    References

    1. Lancaster, E. (2016). The Diagnosis and Treatment of Autoimmune Encephalitis. Journal of Clinical Neurology, 12(1), 1. https://doi.org/10.3988/jcn.2016.12.1.1
    2. Amtul, Z., & Atta-Ur-Rahman. (2015). Neural plasticity and memory: molecular mechanism. Reviews in the Neurosciences, 26(3). https://doi.org/10.1515/revneuro-2014-0075
    3. Haselmann, H., Mannara, F., Werner, C., Planagumà, J., Miguez-Cabello, F., Schmidl, L., … Geis, C. (2018). Human Autoantibodies against the AMPA Receptor Subunit GluA2 Induce Receptor Reorganization and Memory Dysfunction. Neuron, 100(1). https://doi.org/10.1016/j.neuron.2018.07.048.
    4. Zhang, Q., Tanaka, K., Sun, P., Nakata, M., Yamamoto, R., Sakimura, K., … Kato, N. (2012). Suppression of synaptic plasticity by cerebrospinal fluid from anti-NMDA receptor encephalitis patients. Neurobiology of Disease, 45(1), 610–615. https://doi.org/10.1016/j.nbd.2011.09.019
    5. Würdemann, T., Kersten, M., Tokay, T., Guli, X., Kober, M., Rohde, M., … Kirschstein, T. (2016). Stereotactic injection of cerebrospinal fluid from anti-NMDA receptor encephalitis into rat dentate gyrus impairs NMDA receptor function. Brain Research, 1633, 10–18. https://doi.org/10.1016/j.brainres.2015.12.027
    6. Volz, M. S., Finke, C., Harms, L., Jurek, B., Paul, F., Flöel, A., & Prüss, H. (2016). Altered paired associative stimulation-induced plasticity in NMDAR encephalitis. Annals of Clinical and Translational Neurology, 3(2), 101–113.https://doi.org/10.1002/acn3.277
    7. Uscinska, M., Mattiot, A. P., & Bellino, S. (2019). Treatment-Induced Brain Plasticity in Psychiatric Disorders. Behavioral Neuroscience. https://doi.org/10.5772/intechopen.85448
    8. Nitsche, M. A., Müller-Dahlhaus, F., Paulus, W., & Ziemann, U. (2012). The pharmacology of neuroplasticity induced by non-invasive brain stimulation: building models for the clinical use of CNS active drugs. The Journal of Physiology, 590(19), 4641–4662. https://doi.org/10.1113/jphysiol.2012.232975
    9. Erickson, K. I., Miller, D. L., Weinstein, A. M., Akl, S. L., & Banducci, S. (2012). Physical activity and brain plasticity in late adulthood: a conceptual and comprehensive review. Ageing Research, 3(1), 6. https://doi.org/10.4081/ar.2012.e6

     

     

    IAES PNK Partnership logo 500x419 - The Dynamic Brain in Autoimmune Encephalitis

     

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

    seal - The Dynamic Brain in 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 - The Dynamic Brain in Autoimmune Encephalitis

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

     

    AE Warrior Store 300x200 - The Dynamic Brain in Autoimmune Encephalitis

     

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

     

    why zebra - Aphasia as a Symptom of Autoimmune Encephalitis

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


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