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

by Alanna | Sep 21, 2021 | PennNeuroKnow

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 brain^1,4.

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

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).
What are PANS and PANDAS? PANDAS Physicians Network. https://www.pandasppn.org/what-are-pans-pandas/
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).
Swedo SE, Frankovich J, Murphy TK. Overview of Treatment of Pediatric Acute-Onset Neuropsychiatric Syndrome. J Child Adolesc Psychopharmacol. 27, 562-565 (2017).
Dalmau J, Graus F. Antibody-Mediated Encephalitis. N Engl J Med. 9, 840-851 (2018).
Cellucci T, Van Mater H, Graus F, Muscal E, Gallentine W, Klein-Gitelman MS, Benseler SM, Frankovich J, Gorman MP, Van Haren K, Dalmau J, Dale RC. Clinical approach to the diagnosis of autoimmune encephalitis in the pediatric patient. Neurol Neuroimmunol Neuroinflamm. 2, e663 (2020).

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

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why zebra - Aphasia as a Symptom of Autoimmune Encephalitis

Autoimmune Encephalitis and Eating Disorders

by Alanna | Sep 8, 2021 | PennNeuroKnow

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 encephalitis^10–12. 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 behavior^14,15. 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 men^1,13. 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

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).
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).
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).
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).
NIMH » Eating Disorders. https://www.nimh.nih.gov/health/topics/eating-disorders/.
Willcox, M. & Sattler, D. N. The Relationship Between Eating Disorders and Depression. J. Soc. Psychol. 136, 269–271 (1996).
Strother, E., Lemberg, R., Stanford, S. C. & Turberville, D. Eating Disorders in Men: Underdiagnosed, Undertreated, and Misunderstood. Eat. Disord. 20, 346–355 (2012).
Schmidt, U. et al. Eating disorders: the big issue. Lancet Psychiatry 3, 313–315 (2016).
Zerwas, S. et al. Eating Disorders, Autoimmune, and Autoinflammatory Disease. Pediatrics 140, e20162089 (2017).
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).
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).
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).
Hughes, E. G. et al. Cellular and Synaptic Mechanisms of Anti-NMDA Receptor Encephalitis. J. Neurosci. 30, 5866–5875 (2010).
Bednar, I. et al. Glutamate Inhibits Ingestive Behaviour. J. Neuroendocrinol. 6, 403–408 (1994).
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).
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).
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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A Detailed Look Inside The Human Brain

by Alanna | Jul 27, 2021 | PennNeuroKnow

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.

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

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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Creativity in the Brain

by Alanna | Jun 23, 2021 | PennNeuroKnow

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:

Matheson, H. E., & Kenett, Y. N. (2020). The role of the motor system in generating creative thoughts. NeuroImage, 213, 116697.
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 psychology, 9, 1758.
Jung, R. E., Mead, B. S., Carrasco, J., & Flores, R. A. (2013). The structure of creative cognition in the human brain. Frontiers in human neuroscience, 7, 330.
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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Brain Beats

by Alanna | May 25, 2021 | PennNeuroKnow

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 ear^2-3.

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 tone^3,6. 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 ( 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 tone^3,4,6!

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 focus^1,4,610. 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 brainwaves^1-10. 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 concentrated^4,10. Other brain waves at a slower frequency like “delta” and/or “theta” states are associated with sleep and relaxation^4,10. In between, are “alpha” states which are associated with reducing stress and positive thinking^4,10. Interestingly, some scientists believe that the frequency of sounds that the auditory cortex is processing can affect the frequency of your brain waves^4,6,8,10. 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:

Oster, G. (1973). Auditory beats in the brain. Scientific American, 229(4), 94-103.
Lane, J. D., Kasian, S. J., Owens, J. E., & Marsh, G. R. (1998). Binaural auditory beats affect vigilance performance and mood. Physiology & behavior, 63(2), 249-252.
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 Research, 83(2), 357-372.
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
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 Neuroscience, 8, 641.
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 Psychophysiology, 94(3), 399-406.
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 Surgery, 55(6), 571-574.
Solca, M., Mottaz, A., & Guggisberg, A. G. (2016). Binaural beats increase interhemispheric alpha-band coherence between auditory cortices. Hearing research, 332, 233-237.
Garcia-Argibay, M., Santed, M. A., & Reales, J. M. (2019). Binaural auditory beats affect long-term memory. Psychological research, 83(6), 1124-1136
Buskila, Y., Bellot-Saez, A., & Morley, J. W. (2019). Generating brain waves, the power of astrocytes. Frontiers in neuroscience, 13, 1125.

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Depression in Autoimmune Encephalitis

by Alanna | Apr 13, 2021 | PennNeuroKnow

April 14, 2021 | Sarah Reitz, PennNeuroKnow

Major depressive disorder, commonly called depression, is a disorder that affects more than 168 million people worldwide^1,2. 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 disorders^5,6. 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 cytokines^16-19. 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 common^23,24. 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.

References

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
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
American Psychiatric Association. Diagnostic and statistical manual of mental disorders (5^th ed.) (2013). doi: 10.1176/appi.books.9780890425596
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
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
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
Patten SB, Marrie RA, Carta MG. Depression in multiple sclerosis. Int Rev Psychiatry (2017) 29(5):463–72. doi: 10.1080/09540261.2017.1322555
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.
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
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
Kelley, K. W. et al. Cytokine-induced sickness behavior. Brain Behav. Immun. (2003) 17(Suppl. 1):112–118
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
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
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
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
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
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
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
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
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
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
Hansen N and Timaus C. Autoimmune encephalitis with psychiatric features in adults: historical evolution and prospective challenge. J. Neural Transm. (2021) 128:1-14
Kruse JL et al. Psychiatric autoimmunity: N-methyl-D-aspartate receptor IgG and beyond. Psychosomatics. (2015) 56(3)227-241
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
Planaguma J et al. Human N-methyl-D-aspartate receptor antibodies alter memory and behaviour in mice. Brain 138(1):94-109
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
Dalmau J et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol., (2008) 1091-1098.
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.
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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Cytokine Storm: A Detrimental Overreaction

by Alanna | Feb 24, 2021 | PennNeuroKnow

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 organs^2,3. 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

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
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
Fajgenbaum, D. C., & June, C. H. (2020). Cytokine Storm. New England Journal of Medicine, 383(23), 2255–2273. https://doi.org/10.1056/nejmra2026131
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
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
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
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
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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The Neurological Exam

by Alanna | Jan 12, 2021 | PennNeuroKnow

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 diagnosis^4,5. The neurological exam can also be helpful to identify subtle symptoms or track a patient’s progress through treatment.

References:

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.
Harvey PD. Clinical applications of neuropsychological assessment. Dialogues Clin Neurosci. 2012 Mar;14(1):91-9. PMID: 22577308; PMCID: PMC3341654.
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.
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.
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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The Autonomic Nervous System and Dysautonomia in AE

by Alanna | Nov 10, 2020 | Special Series

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?

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 encephalitis^1,3-6.

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 symptoms^8,9. 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:

Dysautonomia: Symptoms, Causes, Types, & How to Live With. Retrieved October 2, 2020 from https://my.clevelandclinic.org/health/diseases/6004-dysautonomia
Gibbons, CH (2019) Chapter 27: Basics of autonomic nervous system function. In Handbook of Clinical Neurology. Volume 160, pp. 407-418.
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.
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.
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.
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.
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.
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.
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.
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

by Alanna | Sep 26, 2020 | Special Series

September 26, 2020 | Claudia Lopez-Lloreda, PennNeuroKnow

The plastic brain

In 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

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
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
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.
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
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
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
Uscinska, M., Mattiot, A. P., & Bellino, S. (2019). Treatment-Induced Brain Plasticity in Psychiatric Disorders. Behavioral Neuroscience. https://doi.org/10.5772/intechopen.85448
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
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

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Behaviour Change from Autoimmune Encephalitis

by Alanna | Aug 28, 2020 | Special Series

August 29, 2020 | Greer Pettyman, PennNeuroKnow

Autoimmune encephalitis (AE) is a disorder that can be hard to diagnose. Typically, early symptoms are flu-like, making it difficult to distinguish from many other illnesses. Psychiatric symptoms and behavior changes are often among the first signs of autoimmune encephalitis, especially NMDAR encephalitis, and a majority of patients are seen first by psychiatrists upon entering the emergency room¹. Other neurological symptoms of AE, such as seizures and problems with movement and memory typically develop later than the psychiatric symptoms¹. However, AE is not usually diagnosed until the appearance of these neurological symptoms since the early psychiatric symptoms are often misdiagnosed as a psychiatric disorder, which leads to a delay in treatment for AE¹. Understanding the psychiatric symptoms and behavior changes that often signal the onset of AE can lead to quicker detection, earlier treatment, and better outcomes for patients.

One study of AE found that 77% of patients with anti-NMDAR encephalitis initially came to the hospital due to psychiatric symptoms². Usually, the psychiatric symptoms caused by AE include agitation, aggression, irritability, hallucinations, delusions, and depressed mood³. The most common symptom was agitation or irritability, appearing in 59% of adults and 66% of children². Psychotic symptoms such as hallucinations were the second most common². These psychiatric symptoms are often misdiagnosed as a psychiatric disorder rather than being investigated as early symptoms of AE.

An additional challenge in diagnosing AE from psychiatric symptoms is that the pattern of symptoms often differs between adults and children. Adults are more likely than children to experience psychotic symptoms like hallucinations². Children, unlike adults, are likely to have temper tantrums as a symptom⁴. Children also often have some early neurological symptoms like seizures in addition to the behavior changes, while adults usually begin with psychiatric but not neurological symptoms⁶. The differences in type and timeline of symptoms between children and adults could be explained by different underlying causes of AE. For example, in adults AE is often the result of a tumor, but tumors are usually not the cause of AE in kids⁷.

How might AE affect behavior?

While the exact mechanisms by which AE causes behavior changes are not well understood, anti-NMDAR encephalitis research provides some potential insights into processes in the brain that might lead to these symptoms. Anti-NMDAR encephalitis, as the name suggests, involves antibodies against a type of neurotransmitter receptor called NMDARs. These NMDARs bind a neurotransmitter called glutamate. Several conditions must be met for NMDARs to become active: glutamate must bind to the NMDAR and the electrical voltage of the cell must reach a certain level⁸. When NMDARs are active, they allow charged ions to cross the cell membrane, which can then send a signal to other cells. NMDAR activation is involved in processes like learning, memory, and behavior.

In anti-NMDAR encephalitis, antibodies in the immunoglogbulin G (IgG) subclass target the NMDA receptors⁹. These IgG antibodies bind to part of the NMDA receptor and make it so they are not able to signal as usual. Neurons from rats that were treated with IgG from AE patients had a decreased number of NMDARs on the cell surface. When the antibodies were removed, the NMDARs returned back to normal levels¹⁰. This indicates that IgG antibodies can cause removal of NMDARs from the surface of the cell, where they can no longer interact with neurotransmitters. Many NMDARs are found on a type of cell called GABAergic neurons⁹. These neurons typically suppress activation of nearby neurons and help to regulate levels of activity in the brain. The attack on NMDARs in AE may lead to reduced activity of GABAergic neurons, which in turn causes too much activity in other parts of the brain.

How does this change in glutamate signaling that is mediated by NMDARs relate to psychiatric symptoms? One theory about the mechanisms underlying schizophrenia, a psychiatric disorder characterized by hallucinations and delusions, also includes reduced availability of NMDARs¹¹. The subsequent deactivation of GABAergic neurons is believed to produce too much activity that leads to many of the psychiatric symptoms of schizophrenia. Drugs that block NMDARs, such as ketamine, are known to cause psychosis, agitation, and difficulties with memory¹¹. All of these are also common symptoms of anti-NMDAR encephalitis. The progressive loss of NMDARs due to antibody attack could create these same psychiatric symptoms in people with AE.

How are psychiatric symptoms addressed?

Getting a better handle on understanding and treating the behavioral symptoms of AE requires improved diagnosis and intervention. When someone arrives in the hospital with significant behavioral changes or psychiatric symptoms, it would be beneficial if doctors could screen for and diagnose AE even before some of the more severe neurological symptoms begin to appear.

Many patients receive medications that target the psychiatric symptoms that are later diagnosed as related to AE¹². These medications include antipsychotics for people who are having symptoms of psychosis. However, in some cases, antipsychotic medications have been shown to cause adverse effects such as catatonia and coma in AE patients, so doctors need to give these medications with care². Earlier diagnosis of AE can prevent patients from getting incorrect diagnoses and psychiatric treatments that can actually worsen their AE. Importantly, while medications may help to manage the psychiatric symptoms, they do not target the underlying causes of AE and patients will still need standard treatments like immunotherapy or tumor removal to treat the AE itself.

Typically, once patients receive immunotherapy, the behavior symptoms of AE begin to go away. Most patients recover fully and no longer have any psychiatric symptoms after recovery. However, approximately 30% of patients may have lasting neuropsychiatric deficits after treatment for AE¹³. In patients who have psychiatric symptoms after immunotherapy, continued use of antipsychotic medications such as clozapine can help to alleviate symptoms¹⁴.

In children who recover from AE, behavioral symptoms may continue and pose particular challenges for parents⁷. Some children were reported to have academic difficulties after recovering from AE¹⁵. Parents and caregivers dealing with bad behavior from a child who had AE can learn behavior management techniques to help address these behavioral difficulties. These strategies, as well as early screening of psychiatric symptoms and behavioral changes, could help to improve diagnosis, treatment, and recovery from AE.

References:

Finke, C. (2019). A transdiagnostic pattern of psychiatric symptoms in autoimmune encephalitis. The Lancet Psychiatry. 6 191-193.
Sarkis, R. A., Coffey, M. J., Cooper, J. J., Hassan, I., & Lennox, B. (2019). Anti- N -Methyl-D-Aspartate Receptor Encephalitis: A Review of Psychiatric Phenotypes and Management Considerations: A Report of the American Neuropsychiatric Association Committee on Research. The Journal of Neuropsychiatry and Clinical Neurosciences, 31(2), 137–142.
Al-Diwani, A., Handel, A., Townsend, L., Pollak, T., Leite, M. I., Harrison, P. J., … Irani, S. R. (2019). The psychopathology of NMDAR-antibody encephalitis in adults: a systematic review and phenotypic analysis of individual patient data. The Lancet Psychiatry, 6(3), 235–246.
Brenton, J. N., & Goodkin, H. P. (2016). Antibody-mediated autoimmune encephalitis in childhood. Pediatric Neurology. 60 13-23.
Suthar, R., Saini, A. G., Sankhyan, N., Sahu, J. K., & Singhi, P. (2016). Childhood Anti-NMDA Receptor Encephalitis. Indian Journal of Pediatrics, 83(7), 628–633.
Esposito, S., Principi, N., Calabresi, P., & Rigante, D. (2019). An evolving redefinition of autoimmune encephalitis. Autoimmunity Reviews. 18 155-163.
Armangue, T., Petit-Pedrol, M., & Dalmau, J. (2012). Autoimmune encephalitis in children. Journal of Child Neurology. 27(11) 1460-1469.
Husi, H. (2004). NMDA Receptors, Neural Pathways, and Protein Interaction Databases. International Review of Neurobiology, 61, 49–77.
Dalmau, J., Lancaster, E., Martinez-Hernandez, E., Rosenfeld, M. R., & Balice-Gordon, R. (2011). Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. The Lancet Neurology. 10(1) 63-74.
Dalmau, J., Gleichman, A. J., Hughes, E. G., Rossi, J. E., Peng, X., Lai, M., … Lynch, D. R. (2008). Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. The Lancet Neurology, 7(12), 1091–1098.
Uno, Y., & Coyle, J. T. (2019). Glutamate hypothesis in schizophrenia. Psychiatry and Clinical Neurosciences, 73(5), 204–215.
Kuppuswamy, P. S., Takala, C. R., & Sola, C. L. (2014). Management of psychiatric symptoms in anti-NMDAR encephalitis: A case series, literature review and future directions. General Hospital Psychiatry, 36(4), 388–391.
Liu, X., Zhang, L., Chen, C., Gong, X., Lin, J., An, D., … Hong, Z. (2019). Long‐term cognitive and neuropsychiatric outcomes in patients with anti‐NMDAR encephalitis. Acta Neurologica Scandinavica, 140(6), 414–421.
Yang, P., Li, L., Xia, S., Zhou, B., Zhu, Y., Zhou, G., … Li, F. (2019). Effect of clozapine on anti-N-methyl-D-aspartate receptor encephalitis with psychiatric symptoms: A series of three cases. Frontier 13(315)
Basheer, S., Nagappa, M., Mahadevan, A., Bindu, P. S., Taly, A. B., & Girimaji, S. C. (2017). Neuropsychiatric Manifestations of Pediatric NMDA Receptor Autoimmune Encephalitis. The Primary Care Companion For CNS Disorders, 19(04), 0–0.

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Limbic Encephalitis

by Alanna | Jul 21, 2020 | Special Series

July-22-2020 | Nitsan Goldstein, PennNeuroKnow

What is limbic encephalitis?

Limbic encephalitis is a type of autoimmune encephalitis (AE) that targets the brain’s limbic system. The limbic system is a group of brain structures that underlie memory and emotion (Fig. 1). The term limbic encephalitis is slightly misleading, however. The disease does not affect all areas of the limbic system and frequently involves non-limbic regions as well¹. The classification, however, can be useful to categorize several specific types of encephalitides that target similar regions of the brain and thus result in common symptoms, even though they may arise from different antibodies and underlying causes. Some of the more common types of AE that fall into this category are caused by antibodies against LGI1, the GABA_B receptor, and the AMPA receptor.

The major brain structures of the limbic system include the amygdala and the hippocampus (Fig. 1). The amygdala is critical in regulating emotion while the hippocampus is primarily responsible for creating new memories. Regardless of the root cause, the different types of limbic encephalitides disproportionally affect these regions¹. This is likely because these regions contain higher levels of the proteins that the antibodies target. Even when doctors cannot identify the antibody that is causing encephalitis, scientists can determine which areas of the brain have high levels of antibody activity. By exposing rodent brains to the cerebrospinal fluid (CSF) from patients containing the antibody, the scientists see that binding of the antibody to neurons is much higher in the hippocampus, for example, than other areas¹.

Figure 1. The Limbic System. The temporal lobes (green, left) are located on the sides of the head, behind the ears. The image to the right shows the inside of the brain. The temporal lobe houses the hippocampus (blue, right), and the amygdala (purple, right) which are two of the major brain structures that make up the limbic system.

While the symptoms and progression of limbic encephalitis vary widely, there are several commonly experienced symptoms due to the similarities in affected brain regions. Patients typically become irritable, depressed, and have trouble sleeping. These signs may rapidly give way to seizures, hallucination, and severe short-term memory loss¹. As the disease progresses and begins to involve other parts of the nervous system, symptoms vary even more widely based on which antibody is present. For example, patients with antibodies against an intracellular protein called Hu experience loss of sensation and even loss of reflexes due to spinal cord neuron damage².

What causes limbic encephalitis?

There are two main causes of limbic encephalitis: viruses and an autoimmune response. An infection with a virus such as the herpes-simplex virus (HSV) can cause a disease called viral encephalitis^1,3. In this case, it is the virus itself that attacks the cells in the limbic system. Thus, while it is a type of limbic encephalitis, it is not an autoimmune disease since it is a foreign agent that is attacking the brain rather than the body’s own antibodies. Viral infections can, however, trigger a patient’s own immune system to attack the brain, resulting in autoimmune encephalitis³.

Non-viral causes result from an autoimmune response involving either cytotoxic T-cells or antibodies. Cytotoxic T-cells arise as a result of a cancerous tumor. In limbic encephalitis, these T-cells target proteins inside neurons (common proteins targeted are Hu and Ma2)^2,4. In contrast, limbic encephalitis caused by antibodies rather than cytotoxic T-cells may develop in response to cancerous tumors or benign tumors. In fact, many cases of limbic encephalitis are not associated with tumors at all⁵. These antibodies target proteins on the surface of neurons like the GABA_B receptor, the AMPA receptor or, in the case of LGI1 limbic encephalitis, the voltage gated potassium channel complex⁵. In either case, neuronal damage is found in limbic regions, explaining why similar symptoms may be observed with these seemingly distinct diseases^1,5.

Diagnosis and treatment

When patients present with symptoms indicating a possible diagnosis of limbic encephalitis, there are several diagnostic tests that are typically performed to confirm the diagnosis. An electroencephalogram (EEG) is administered to measure electrical brain activity. EEG electrodes are placed throughout the scalp, allowing doctors to pick up seizure-like activity in the brain and often isolate where in the brain the seizures originate. EEGs from patients with limbic encephalitis frequently suggest involvement of the temporal lobe¹. The temporal lobe houses the amygdala and hippocampus and is therefore often the source of seizures in limbic encephalitis. A magnetic resonance imaging (MRI) scan is also performed which gives doctors an image of the brain. Differences in contrast can indicate that the blood brain barrier is compromised in the temporal lobe, giving the antibodies access to neural tissue¹. Finally, doctors can take samples of patients’ CSF, which may have increased immune cells and other markers of inflammation¹. However, the findings of any one of these diagnostic tests can be normal which can make diagnosis challenging. Therefore, the results from all tests are considered when making a diagnosis.

Despite the devastating effects autoimmune limbic encephalitis may have on patients, many people are able to fully recover following treatment, though long-term recovery depends on the specific type of encephalitis^1,5. The treatment involves removal of the tumor or other growths that initiated the antibody or T-cell production. In cases where antibodies against cell-surface proteins were present, removing the root cause along with a course of steroids and immunotherapy to restore the immune system can be an extremely successful treatment. In cases where cytotoxic T-cells attack intracellular proteins, patients often continue to experience symptoms even after removal of the tumor². A variety of T-cell therapies can be tested to see if any lead to improvement in individual patients¹. The hope is that future and ongoing research on treatment-resistant types of limbic encephalitis will guide individualized care and improve patient outcomes.

References:

Erdem, T. & Dalmau, J. Limbic Encephalitis and Variants: Classification, Diagnosis and Treatment. The Neurologist 13, 261-271 (2007).
Dalmau, J., Graus, F., Rosenblum, M.K., & Posner, J.B. Anti-Hu–associated Paraneoplastic Encephalomyelitis/Sensory Neuronopathy. A Clinical Study of 71 Patients. Medicine (Baltimore) 72, 59‐72 (1992).
Venkatesan, A. & Murphy, O.C. Viral Encephalitis. Neurol Clin. 36, 705-724 (2018).
Ortega Suero, G., Sola-Vallsm, N., Escudero, D., Saiz, A., & Graus, F. Anti-Ma and anti-Ma2-associated paraneoplastic neurological syndromes. Neurologia 33, 18‐27 (2018).
Dalmau, J. & Graus, F. Antibody-Mediated Encephalitis. N Engl J Med. 378, 840-851 (2018).

Figure 1 created using BioRender

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Treatments for Autoimmune Encephalitis

by Alanna | Jun 23, 2020 | Special Series

June-24-2020 | Carolyn Keating, PennNeuroKnow

As the name suggests, autoimmune encephalitis (AE) is a group of diseases in which the body’s immune system attacks the brain. To treat it, there are a variety of therapies that target different aspects of the immune system. The goal of these immunotherapies is to reduce brain inflammation and the resulting symptoms, as well as maintain these improvements by preventing relapses¹.

Immunotherapy is most successful in patients with antibodies against cell-surface proteins (such as NMDR, LGI1, and Caspr2). These diseases tend to be caused by B cells and autoantibodies. In contrast, when antibodies are directed against molecules inside of cells (such as Hu, Ma, or GAD65) the disease is usually mediated by T cells, and these patients typically do not respond as well to immunotherapy. It should also be noted that removal of any disease-associated tumors, such as the ovarian teratomas frequently seen in NMDAR encephalitis or tumors seen in patients with intracellular antigens, should be an early treatment priority as removal quickly produces improvements². However, there are currently no standardized treatment guidelines; at present, different regimens are used based on the patient’s particular condition and clinical status, as well as the opinion of their doctor.

First-line Treatments

The first treatment for most patients is typically steroids, also calledcorticosteroids. Corticosteroids act to broadly inhibit inflammation in multiple ways, which results in the depletion of mainly T cells. They offer the additional benefit of restoring the blood-brain barrier (BBB), which can be impaired in

AE. However, corticosteroids aren’t perfect. They have many side effects, and can aggravate or even induce psychiatric symptoms associated with AE such as depression, insomnia, agitation, and psychosis. What’s more, corticosteroids do not target B cells, the cells that go on to produce the antibodies that cause many of the symptoms of AE³.

Two other first-line therapies do target autoantibodies. One is administration of intravenous immunoglobulin (IVIg). IVIg is a blood product prepared from the serum of more than 1,000 donors that contains a broad range of antibodies. Some of these antibodies target a patient’s autoantibodies and neutralize them, along with other pro-inflammatory aspects of the immune system³. The other first-line treatment targeting autoantibodies is plasma exchange (PLEX, also called plasmapheresis). PLEX “cleans” the blood of autoantibodies by replacing the liquid plasma portion of a patient’s blood with that of a donor. PLEX also changes T and B cells in favorable ways. A more refined form of PLEX called immunoadsorption has also been used to treat AE, and selectively removes antibodies from the blood, instead of all the other components that are also in the plasma³. However, both PLEX and immunoadsorption only remove antibodies from the blood, not from the brain; although decreasing antibodies in the blood can lead to a decrease in the brain⁴. Furthermore, all first-line treatments but especially PLEX require a good deal of patient compliance, which can limit their use if the patient is agitated or displays other behavioral problems⁵.

Different subtypes of AE respond differently to treatment. For instance, patients with LGI1 antibodies who are diagnosed early are often responsive to corticosteroids alone. In contrast, only about 50% of patients with NMDAR antibodies are responsive to first-line treatments, and the remaining require second-line therapies⁶.

Second-line Treatments

There are two main second-line immunotherapies for AE. The first is a drug that destroys B cells called rituximab. Rituximab is actually an antibody that targets B cells, which normally go on to become antibody-producing cells. It is expected to work particularly well in patients with LGI1 and Caspr2 autoantibodies. However, because B cells can cross into the brain and become antibody-producing cells, but rituximab cannot cross the BBB, its effects may be limited³.

The other second-line treatment is a chemotherapy drug called cyclophosphamide. Cyclophosphamide directly prevents T and B cells from multiplying, but it affects the ability of many other cells to multiply as well. For that reason, it has some potentially serious side effects including infertility, and instead rituximab is usually the preferred second-line therapy³.

Alternative Treatments

Sometimes second-line treatments are also not effective at treating AE. When that happens, options include re-administration of first-line therapies, extended use of second-line therapies, or use of other non-steroid (steroid-sparing) drugs to suppress the immune system. For instance, the steroid-sparing drug mycophenolate mofetil prevents T and B cells from multiplying and has a better side-effect profile than cyclophosphamide³.

Other alternative treatments are also available. One option interrupts the inflammatory effects of a molecule called interleukin-6 (IL-6). Normally, when IL-6 binds to its receptors on immune cells, it causes B cells to multiply and mature into antibody-producing cells, and causes pro-inflammatory T cells to mature. The antibody drug tocilizumab targets the IL-6 receptor and prevents these inflammatory processes. A molecule related to IL-6, IL-2, is also a target. Instead of inhibiting this molecule, giving patients low doses of IL-2 activates a “good” type of T cell called regulatory T cells that help the body shut down autoimmune responses. Another option, bortezomib, directly targets antibody-producing cells, instead of their immature B cell precursors³.

Maintenance Treatments

Even if AE is successfully treated, sometimes the disease can relapse. Relapses could be caused by some antibody-producing cells that can survive for many months, which are not targeted by treatments. Many of the therapies described above, including the first-line treatments, steroid-sparing agents, and rituximab, have been used as maintenance therapy to try and prevent this from occurring. However, the length of time patients should continue to receive treatment is unknown, and can range from 6 months to several years depending on the patient’s condition and doctor’s opinion³.

In addition to immunotherapy, other important aspects of treatment include supportive care (particularly while in the hospital); treatment of symptoms such as seizures, spasms, and psychiatric issues; and rehabilitation¹. While responses to tumor removal and immunotherapy are often seen within a few weeks, it may take years for patients to return to normal⁷. As more is discovered about which aspects of the immune system are involved in each subtype of AE, hopefully more directed treatments will become available.

Download AE Treatment.pdf

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References

1. López-Chiriboga, A. S. & Flanagan, E. P. Diagnostic and Therapeutic Approach to Autoimmune Neurologic Disorders. Semin. Neurol. 38, 392–402 (2018).

Seki, M. et al. Neurological response to early removal of ovarian teratoma in anti-NMDAR encephalitis. J. Neurol. Neurosurg. Psychiatry 79, 324–326 (2008).
Shin, Y.-W. et al. Treatment strategies for autoimmune encephalitis. Ther. Adv. Neurol. Disord. 11, 1–19 (2018).
Fassbender, C., Klingel, R. & Köhler, W. Immunoadsorption for autoimmune encephalitis. Atheroscler. Suppl. 30, 257–263 (2017).
Damato, V., Balint, B., Kienzler, A. K. & Irani, S. R. The clinical features, underlying immunology, and treatment of autoantibody-mediated movement disorders. Mov. Disord. 33, 1376–1389 (2018).
Varley, J., Taylor, J. & Irani, S. R. Autoantibody-mediated diseases of the CNS: Structure, dysfunction and therapy. Neuropharmacology 132, 71–82 (2018).
Venkatesan, A. & Adatia, K. Anti-NMDA-Receptor Encephalitis: From Bench to Clinic. ACS Chem. Neurosci. 8, 2586–2595 (2017).

The Unique Nature of Seizures in Autoimmune Encephalitis

by tabitha orth | Apr 28, 2020 | Special Series

April-29-2020 | Claudia Lopez Lloreda, PennNeuroKnow

What are seizures?

Seizures can be scary events both for people who suffer from them and for their loved ones. Symptoms of a seizure typically include muscle spasms; loss of consciousness; sudden, rapid eye movements; or sudden mood changes; among other symptoms, and these can last from seconds to minutes¹. These are the most severe seizures, but mild seizures, with more moderate physical and behavioral symptoms — such as stiffness of the muscles, feelings of déjà vu, anxiety, temporary confusion, or nausea — can also happen and may negatively affect health. During seizures, the body parallels what is happening in the brain: uncontrolled movements of the body can result from uncontrolled bursts of electrical activity in the brain.

Seizures are a response to hyperexcitability, meaning increased activity, of neurons in the brain, and hypersynchrony, meaning more neurons fire at the same time than normal. Seizures are very different across and within conditions. They can be generalized, affecting the entire brain from the beginning of the seizure, or focal, affecting one specific area although it may later spread. Frequent, unprovoked seizures called recurrent seizures may indicate that the person has a condition called epilepsy. Epilepsy is a chronic neurological disorder in which seizures can cause periods of unusual behavior, sensations, and negative effects on cognition such as a loss of awareness. However, because abnormal electrical activity can happen in response to other alterations in the brain such as brain injury and in response to medications, seizures can also be seen in other conditions.

One of these conditions is autoimmune encephalitis (AE). In AE, the body attacks the brain by creating antibodies against important neuronal proteins. Because these proteins help neurons communicate, the antibodies alter neuronal activity. Altering neuronal activation can lead to the changes that are seen in seizures (hyperexcitability and hypersynchrony). In fact, research shows that seizures in some patients can be a common symptom during the acute phase (early on in disease) of AE². It is believed that antibodies against the neuronal proteins contribute directly to the disease processes and the development of seizures. It’s also possible that the process of neuroinflammation associated with AE, which increases the amount of toxic inflammatory molecules in the brain, can also contribute to the development of seizures². Even once the inflammation has been resolved, the brain can still be predisposed to seizures or developing epilepsy, especially if the inflammation resulted in neuronal death³. However, whether epilepsy, a chronic disease, is developed in response to AE is not entirely clear. Some studies suggest that the risk of developing chronic epilepsy is low, from 10-15%⁴.

In different types of AE, seizures appear differently. Apart from the well-known tonic-clonic seizures (associated with jerking muscle movements), seizures in AE can also show up as faciobrachial dystonic seizures. These are characterized by abrupt involuntary movements, typically on one half of the face and arm of the same side. The frequency, response to therapies, and symptoms of the seizures themselves can all vary. However, the AE that most frequently manifest with seizures and chronic epilepsy are those mediated by antibodies against the LGI1, GABA_BR, and GABA_AR; all-important proteins involved in neuronal communication⁵.

Are seizures associated with AE treated the same way as in epilepsy?

Antiepileptic drugs are the standard of care for people with epilepsy. Since seizures are a result of uncontrolled electrical activity and an imbalance of excitation and inhibition in the brain, antiepileptic drugs work by trying to restore that balance. For example, the drug clonazepam prevents seizures by increasing the effectiveness of a molecule in the brain called GABA, which helps the brain dampen the uncontrolled brain activity.

Now, although the normal path for people with epilepsy is treatment with antiepileptic drugs, it may not be particularly effective for people with seizures associated with AE. A study looking at a population of AE patients found that resolution of seizures happened even after discontinued antiepileptic drugs therapy⁶. In these young patients with AE who experienced unprovoked seizures at the onset of the disease there was a remission rate of 94%, meaning they stopped suffering from seizures, after they stopped taking antiepileptic drugs. Rather, immunotherapy seemed to be the important factor in controlling seizures. The researchers suggested that “long-term use of antiepileptic drugs appears not to be necessary to control seizures in AE”⁶.

Other studies support the idea that immunotherapy is more effective in attacking seizures in AE. One study looked at three different types of autoimmune encephalitis (anti-LGI1, anti-NMDAR, and anti-GABA_BR) and their response to immunotherapy and antiepileptic drugs⁷. They found that seizure freedom was achieved faster and more frequently after the use of immunotherapy than after the use of antiepileptic drugs. However, there may be a specific window in which immunotherapy is effective at controlling seizures.

Importantly, the researchers do mention that differences in seizures characteristics and therefore response to treatment may be due to the specific type of encephalitis. For example, patients with anti-GABA_BR encephalitis had an increased risk of developing seizures, meaning that the development of seizures may depend on the type of encephalitis⁷.

What do these findings mean for people with AE?

These differences in treatment response between AE and epilepsy point to an important trait that needs to be considered: the cause of seizures. In AE, antibodies generated against important neuronal proteins make the brain go awry. Therefore, one of the most effective ways to treat seizures may be attacking the root of the problem with immunotherapy. However, due to the variable nature of AE and the seizures associated with the condition, proper treatment with immunotherapy and/or antiepileptic medication will change from patient to patient.

What to do if someone is having a seizure?

During the most severe seizures, the person may not be able to control their body movements. For this reason, you may help them clear the area around them to prevent possible injury. If possible, place them on their side and provide cushioning for their head. There are additional indications suggested by the Center for Disease Control (become familiar with these here).

Seizures in AE Handout

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References

Epilepsy. (2019, August 10). Retrieved March 6, 2020, from https://www.mayoclinic.org/diseases-conditions/epilepsy/symptoms-causes/syc-20350093
Rana, A., & Musto, A. E. (2018). The role of inflammation in the development of epilepsy. Journal of Neuroinflammation, 15(1). doi: 10.1186/s12974-018-1192-7
Vezzani, A., Fujinami, R. S., White, H. S., Preux, P.-M., Blümcke, I., Sander, J. W., & Löscher, W. (2015). Infections, inflammation and epilepsy. Acta Neuropathologica, 131(2), 211–234. doi: 10.1007/s00401-015-1481-5
Steriade, C., Moosa, A. N., Hantus, S., Prayson, R. A., Alexopoulos, A., & Rae-Grant, A. (2018). Electroclinical features of seizures associated with autoimmune encephalitis. Seizure, 60, 198–204. doi: 10.1016/j.seizure.2018.06.021
Spatola, M., & Dalmau, J. (2017). Seizures and risk of epilepsy in autoimmune and other inflammatory encephalitis. Current Opinion in Neurology, 30(3), 345–353. doi: 10.1097/wco.0000000000000449
Huang, Q., Ma, M., Wei, X., Liao, Y., Qi, H., Wu, Y., & Wu, Y. (2019). Characteristics of Seizure and Antiepileptic Drug Utilization in Outpatients with Autoimmune Encephalitis. Frontiers in Neurology, 9. doi: 10.3389/fneur.2018.01136
Bruijn, M. A. D., Sonderen, A. V., Coevorden-Hameete, M. H. V., Bastiaansen, A. E., Schreurs, M. W., Rouhl, R. P., … Titulaer, M. J. (2019). Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis. Neurology, 92(19). doi: 10.1212/wnl.0000000000007475

Cover Image from Pixabay: https://pixabay.com/illustrations/epilepsy-seizure-stroke-headache-623346/

How does Sleep Affect the Blood-brain Barrier?

by tabitha orth | Dec 10, 2019 | Hot Topics, Special Series

December-11-2019 | Sarah Reitz, PennNeuroKnow

Autoimmune encephalitis (AE) is the name for a group of conditions that occur when the body’s immune system mistakes its own healthy brain cells for invaders, leading to brain inflammation that ultimately triggers a number of other symptoms. Normally, the body’s immune system has only limited access to the brain, as it is protected by the blood-brain barrier (BBB). When this barrier is healthy, it can prevent an immune system attack by blocking immune cells and antibodies targeting brain cells from actually entering the brain. Like any fortress, however, the BBB isn’t completely impenetrable. Given that AE symptoms occur when immune cells or antibodies manage to cross the BBB, researchers think that the weakening of this barrier plays a critical role in AE and may even be a target for future therapies to reduce or prevent AE symptoms. But what causes the BBB to weaken, allowing cells, antibodies, and other molecules to invade the brain?

The blood-brain barrier: gatekeeper of the brain

Before discussing how the BBB becomes impaired, we need to understand how the healthy BBB functions. The BBB is often referred to as a “gateway”, made up of tightly joined endothelial cells that surround the blood vessels in the brain and spinal cord¹. Outside of the brain, the endothelial cells lining blood vessels have small spaces between them, allowing for the exchange of substances between the blood and the surrounding tissue. However, the endothelial cells of the BBB are connected to each other by proteins called tight junction proteins, which squeeze the cells tightly together, blocking larger cells and molecules from freely flowing between the blood supply and the brain (Figure 1).

PNK Sleep and BBB 300x290 - How does Sleep Affect the Blood-brain Barrier?

Figure 1: The blood-brain barrier is made up of endothelial cells that are tightly connected to each other by tight junction proteins (purple). These tight connections prevent unwanted substances from traveling between the blood and the brain. Different types of transporter proteins (yellow & blue) shuttle only certain types of molecules between the blood and brain.

The BBB is selectively permeable, meaning it allows only certain substances to enter and leave the brain. One way that molecules can cross the BBB is by endocytosis, a process where the endothelial cells uses its cell membrane to take in a molecule on one side (say, the side facing the blood) and pass it through to the other side (facing the brain) where it is released¹. The endothelial cells of the BBB also express a variety of transporter proteins, which actively move molecules between the blood and the brain (Figure 1). Additionally, small, fat-soluble molecules can cross the BBB without any help from endocytosis or transporter proteins, giving the brain access to important nutrients and energy sources¹.

BBB permeability changes across the day

The permeability of the BBB is not always the same, however. Research has shown that its permeability actually changes depending on the time of day². Like many cells in the body, BBB cells are controlled by circadian rhythms, biological processes that cycle roughly every 24 hours. These rhythms are driven by a molecular “clock” within each cell, and cells across the body are synchronized by the “master clock” located in the brain.

What do these rhythms mean for BBB permeability though? Interestingly, research in both flies and mice shows that the amount of hormones, inflammatory proteins, and other molecules that cross from the blood into the brain fluctuates across the day, with peak BBB permeability occurring at night².

Sleep loss impairs BBB function

Circadian rhythms aren’t the only daily process that affects the integrity of the BBB. Sleep—or more appropriately, lack of sleep—is also known to affect the BBB’s protection of the brain. This relationship between sleep and the BBB is increasingly important as sleep restriction becomes more and more common in our modern society.

Sleep loss is also highly relevant to the AE community. One study found that 73% of AE patients surveyed reported sleep disturbances, including gasping/snoring and insomnia. Even further, patients with AE had decreased total sleep time and increased fragmentation of sleep compared to people without AE³. But how exactly does sleep loss affect the BBB?

Blood Brain Barrier after full sleep 300x71 - How does Sleep Affect the Blood-brain Barrier?

Figure 2: After periods of sleep loss, the blood-brain barrier is negatively affected in many ways (left). Inflammatory signaling caused by TNFα and IL-6 increases, leading to the breakdown of tight junction proteins (purple). This causes gaps between endothelial cells, allowing unwanted immune cells and antibodies to enter the brain. After sleep loss, the endothelial cells also make fewer of the transporter proteins (blue and yellow) that are required to shuttle necessary molecules between the brain and blood.

Multiple studies have now shown that sleep restriction weakens the BBB. One reason is due to the increase in inflammatory signaling that results from extended periods of wakefulness. Increases in inflammatory proteins, like TNFα and IL-6, are known to break down the tight junction proteins that keep the endothelial cells tightly joined together² (Figure 2). Sleep-deprived mice and rats showed decreased numbers of tight junction proteins, leading to increased BBB permeability.

In addition to weakened tight junctions between endothelial cells, sleep loss also increases permeability by enhancing the rate of endocytosis across the BBB², meaning that the endothelial cells shuttle more molecules from the blood into the brain. Relevant to AE, this increased permeability means that more immune cells and antibodies can enter the brain after sleep loss compared to after a full night’s sleep.

While these results are a bit frightening, there is good news. All of the damage to the BBB caused by sleep loss returns to normal after getting enough sleep! One study found that even an extra 1-2 hours of sleep following sleep loss restored BBB function in most brain areas⁴. Given even more time to sleep, the BBB throughout the brain returned to normal function⁵. These results suggest that treating the sleep disorders commonly associated with AE may help strengthen the BBB, increasing the brain’s protection against the immune system’s cells and antibodies and improving long-term outcomes for patients.

The BBB as a treatment target

Given that AE is caused by immune cells and antibodies infiltrating and attacking the brain, researchers are now looking at the BBB as a potential therapeutic target¹. Treatments that strengthen the BBB will hopefully reduce the number of immune cells and antibodies that make it into the brain, and may also increase the effectiveness of some AE medications, such as anti-inflammatory drugs or immune-suppressants. Because these AE medications are specifically designed to cross a healthy BBB and access the brain, strengthening a weakened BBB will protect against molecules that aren’t supposed to be in the brain, while still allowing the necessary medication in.

The known circadian effects on BBB permeability can also be used in determining when to give medication that needs to cross the BBB. Medication can be given at the time of day when BBB permeability is highest to increase the amount of drug that makes it into the brain. In fact, this has already been studied with anti-seizure medication in epilepsy. For instance, in both flies and humans, when medication was given at night during peak BBB permeability, it was most effective at controlling seizures^6,7.

This new strategy of “chronotherapeutic” dosing schedules has the potential to improve the efficacy of medication in many diseases. By administering drugs when it is easiest for them to enter the brain, doctors may be able to see results at lower doses of the drug, potentially reducing the risk of harmful side effects. As we continue to learn more about the BBB, scientists may identify even more ways to improve BBB health in the many disease states where it is compromised.

Free Download for BBB Handout

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Image References: Figure 1 and 2 created with BioRender.com

References:

Platt MP, Agalliu D, Cutforth T (2017) Hello from the other side: How autoantibodies circumvent the blood-brain barrier in autoimmune encephalitis. Front. Immunol. 8:442. doi: 10.3389/fimmu.2017.00442
Cuddapah VA, Zhang SL, Sehgal A (2019) Regulation of the blood-brain barrier by circadian rhythms and sleep. Trends Neurosci 42(7):500-510. doi: 10.1016/j.tins.2019.05.001
Blattner MS, de Bruin GS, Bucelli RC, Day GS (2019) Sleep disturbances are common in patients with autoimmune encephalitis. J Neurol 266(4):1007-1015. doi: 10.1007/s00415-019-09230-2
Gomex-Gonzalez B, et al. (2013) Rem sleep loss and recovery regulates blood-brain barrier function. Curr. Neurovasc. Res. 10, 197-207
He J, Hsuchou H, He Y, Kastin AJ, Wang Y, &Pan W (2014) Sleep restriction impairs blood-brain barrier function. J Neurosci 34(44)14697-14706. doi: 10.1523/jneurosci.2111-14.2014
Zhang SL, Yue Z, Arnold DM, Artiushin G, Sehgal A (2018) A circadian clock in the blood-brain barrier regulates xenobiotic efflux. Cell 173(1):130-139. doi: 10.1016/j.cell.2018.02.017
Yegnanarayan R, et al. (2006) Chronotherapeutic dose schedule of phenytoin and carbamazepine in epoleptic patients. Chronobiol. Int 23, 1035-1046

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