Neuro MythBusters: The truth behind 10 common myths about your brain

by Alanna | Sep 12, 2023 | PennNeuroKnow

September 13, 2023 | by Catrina Hacker, PennNeuroKnow and IAES Collaboration

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Introduction

Many people find neuroscience fascinating because learning about our brains teaches us about ourselves. Unfortunately, popular interest in brain research has led to several pervasive myths that misrepresent how our brains work. Combatting these neuromyths is difficult because the truth is often much more complicated than the myth and buried in intimidating scientific literature. However, correcting misconceptions about how our brains work can have important benefits for our everyday lives. In this post I’ll break down what some of these neuromyths claim, where they came from, whether there’s any truth behind them, and why we should care about correcting them.

Myth #1: Humans only use 10% of our brains.

This is arguably the most common neuromyth¹, inspiring movies like Limitless (2011) and Lucy (2014) in which characters gain superhuman abilities by tapping into the large unused portions of their brains. It’s appealing to think that we all have potential superpowers sitting in our brains waiting to be unleashed, but there’s nothing to support this claim. The reality is that neuroscientists observe activity throughout the entire brain.

While nobody is certain where it came from, some believe that this myth originates from work done by neuroscientist Wilder Penfield in the 1930s¹. Penfield was a neurosurgeon who studied the effects of stimulating the brains of patients undergoing neurosurgery to learn what each part of the brain was responsible for. He found that stimulating a large portion of the brain didn’t cause any noticeable effect², meaning he could not learn what its function might be. However, new and less invasive methods of recording brain activity show that these “silent” parts of the brain are actually active. In fact, a network of brain regions called the default mode network is even active when we are at rest³.

The bottom line: We use 100% of our brains.

Why it matters: The number of drugs and treatments that claim to enhance brain function, collectively called neuroenhancers, is on the rise. While we can always learn and grow, understanding that there is no “hidden” brain waiting to be unlocked can protect you from wasting your money.

Myth #2: Right-brained people are creative while left-brained people are analytical.

The idea that you can be either right-brained or left-brained has captured the attention of people on social media and even teachers in classrooms. It’s tempting to think that people can be categorized so easily and that differences can be attributed to our brains, but the truth isn’t that simple. While people can tend to be more creative than analytical or vice versa, those differences cannot be explained by dominance of one half of the brain over the other⁴.

This myth has been tricky to combat because there is some important truth behind it. There are some differences between the two halves of your brain, but creativity versus logical reasoning isn’t one of them. Your brain has two hemispheres, left and right, that communicate via a bundle of neural connections called the corpus callosum. While almost everything we do involves communication between the two halves of our brain, sometimes one half of the brain contributes a little more than the other. For example, the left hemisphere typically takes the lead in language processing⁵, the right hemisphere seems to play an especially important role in visual attention⁶, and the left and right hemispheres might do slightly different things to aid in face processing⁷. Things like creativity and emotional processing rely on both hemispheres and complicated networks of brain activations^8,9.

The bottom line: Being right-brained or left-brained can’t explain why some people are more creative than others, but there are some differences in what your left and right hemispheres do when it comes to things like language, attention, and face recognition.

Why it matters: Categorizing people as one thing or another (left-brained or right-brained) is restrictive and ultimately harmful. Many “logical” tasks require creativity and “creative” tasks require logic. If teachers, mentors, and bosses make these assumptions about members of their teams or classrooms they risk mischaracterizing people or preventing them from working up to their true potential.

Myth #3: Listening to Mozart makes babies smarter.

This neuromyth, sometimes called the “Mozart effect”, started in 1991 when Alfred Tomatis shared his thoughts about how listening to Mozart could help children with speech and auditory disorders¹⁰. When a group of researchers showed in 1993 that listening to 10 minutes of Mozart’s K. 448 improved college students’ ability to visualize and manipulate mental images¹¹, the media took this result and ran with it. The effects in the original study only lasted 10 to 15 minutes and only impacted mental manipulation of images, but the media wrote about general boosts to intelligence and implied that they lasted much longer. Despite the original study being done with college students, the myth was somehow generalized to include babies. Several studies published since 1993 have provided alternate explanations for the original result or have failed to replicate it while studying the same or different skills¹².

Although listening to Mozart can’t make you smarter, there is some truth behind this myth. Stimulating an infant’s brain helps with their development, but activities like direct interactions with a parent, reading a book, or talking and singing with an infant are much more effective^13,14. When it comes to music, passively listening might not impact development, but learning to play an instrument positively impacts a child’s cognitive abilities and their performance in school¹⁵.

The bottom line: Listening to Mozart doesn’t make babies smarter, but stimulation from things like singing to your child is an important part of their development, and children who learn to play an instrument tend to perform better in school.

Why it matters: Belief in the Mozart effect and similar claims led many people to show their children the popular Baby Einstein videos in the early 2000s. However, in 2007 a study showed that not only did viewing these baby DVDs not improve children’s intelligence, children who watched the videos tended to have a worse vocabulary than other children¹⁶.

Myth #4: Everybody has a distinct style in which they learn best.

Many people have memories like mine of being asked if they are a visual, auditory, or kinesthetic learner as a child. You may even have filled out a survey to learn what your learning style is. Even today, many teachers collect this information and personalize their teaching to each student’s supposed learning style. While this seems logical, there is no evidence that each person has a specific learning style in which they learn best^17,18, and some research suggests that teaching to learning styles is more harmful than helpful¹⁹. While it’s true that people vary in ability on different kinds of tasks and that teachers should work with students as individuals to help them succeed, when “visual learners” are tasked with learning through auditory tasks, they do just as well¹⁹.

The bottom line: Everybody has different preferences, but matching teaching to a preferred learning style does not improve learning.

Why it matters: It is a waste of time and resources to focus on tailoring education to preferred learning styles when it has no impact on learning. In fact, teaching based on learning styles might actually harm students by limiting them to certain modalities and subjects that match their learning style and discouraging them from exploring²⁰.

Myth #5: Your handwriting reveals aspects of your personality.

The use of handwriting to learn about someone’s personality is called graphology. Graphology became popular in the late 1800s, with German scientist William Preyer commenting that handwriting is “brain writing”^21,22. Despite its dubious scientific validity, graphology was used to make decisions about a person’s value to society, such as in determining whether a person was trustworthy or a criminal. Fortunately, modern experiments have conclusively shown that handwriting cannot predict a person’s personality. In controlled settings, graphologists are no better at using a person’s handwriting to make judgments about them than if they were guessing²³. However, many people still believe that aspects of a person’s personality can be learned from their handwriting, and some computer scientists are still trying to build computer models that can predict things like criminality and work ethic from handwriting²⁴, repeating the mistakes of the past.

Despite the dubious link between handwriting and personality, there are some reliable links between handwriting and brain health. Our brains control the muscles that move as we write, and some neurological disorders can cause changes in the brain that impact handwriting²¹. For example, one early symptom of Parkinson’s Disease can be small, cramped handwriting²⁵. For this and related disorders, handwriting can act as a window into brain health and an early warning sign that can lead to faster care and better outcomes.

The bottom line: A person’s handwriting cannot reliably predict their personality, but changes to handwriting can be early signs of neurological disorders like Parkinson’s Disease.

Why it matters: Despite there being no connection between a person’s handwriting and their personality, in 2017 then President Donald Trump tweeted about being able to tell from his handwriting that former United States Secretary of the Treasury, Jack Lew, “is secretive”²². Some scientists are still trying to build tools that can determine a person’s personality based on their handwriting to help with hiring decisions²⁴. Without widespread acceptance that handwriting cannot predict personality, we risk repeating the mistakes of the past and using handwriting to unfairly discriminate against certain people.

Myth #6: A common sign of dyslexia is seeing letters backwards.

Dyslexia, characterized by difficulty reading, affects an estimated 20% of the population and is the most common neuro-cognitive disorder²⁶. It is a popular misconception that a common sign of dyslexia is seeing words and letters backwards. People with dyslexia don’t see words and letters backwards, but they do have difficulty naming letters and words (think saying “was” while reading “saw”)²⁷. When it comes to writing, there is some evidence that dyslexic children may be more likely than others to write letters and words backwards, a phenomenon called reversals. However, reversals are common in all children learning to read and write²⁸, and not all children with dyslexia make reversals²⁹.

There are many other reliable indicators that a person may have dyslexia. The signs of dyslexia change throughout a lifetime and range from preschool children who struggle to identify the letters in their names to high school students who struggle to read unfamiliar words³⁰. Visit this fact page from the Yale Center for Dyslexia & Creativity for a full list of signs of dyslexia for all age groups.

The bottom line: Dyslexic children don’t see letters backwards, although they may read and write letters backwards. However, not all dyslexic readers write letters backwards and not all children who write letters backwards are dyslexic.

Why it matters: If parents and educators expect dyslexic children to describe seeing letters backwards or adults think they must see letters backwards to have dyslexia, then many people could go undiagnosed and not get the support they need to succeed.

Myth #7: Human memory works like a camera, perfectly recording what you experience.

As a child, one of my favorite book series starred Cam Jansen, a fifth grader who solves mysteries utilizing her flawless photographic memory. Any time she wanted to remember something she would say “click” and it would be perfectly captured in her memory. As an adult, I’ve watched plenty of TV shows and movies featuring similar characters who can use their perfect memory to save the day. Unfortunately, this kind of memory doesn’t exist outside books and other media.

For the rest of us here on earth, our brains forget and fill in details of our memories, even when we feel certain we remember things perfectly. A great example of this is the visual Mandela effect, wherein people consistently report strong false memories of things like whether Curious George has a tail or the Monopoly man wears a monocle (neither is true, but people consistently believe that they are)³¹. In general, it’s a good thing that our brains work in this imperfect way. We don’t want to get bogged down with irrelevant details of memories, so our brains act as a filter, prioritizing memory for the things that matter most and filling in the details and moments that are less important.

If our memory is so imperfect, where does the idea of photographic memory come from? This myth might have started after psychologist Ralph Haber noticed that a small percentage of children seemed to be able to hold pictures in their mind’s eye for seconds or minutes after they were removed from sight³². He called this kind of memory eidetic memory (often used interchangeably with “photographic memory” in popular media). However, these studies only looked at memory for short periods of time, and later research demonstrated that this “memory” is far from perfect³³.

The bottom line: Some people can remember things better or longer than others, but nobody’s memory works like a camera.

Why it matters: Our criminal justice system still relies heavily on eyewitness reports. If police officers, lawyers, and jurors don’t realize that memory is flawed, they risk inflating the value of this kind of testimony and incarcerating innocent people³⁴.

Myth #8: People with bigger brains are smarter.

We’ve all heard or used the term “big-brained” to describe someone who does something smart, but the size of their brain has nothing to do with their intellect. If size was all that mattered, then elephants, whose brains are 3x heavier than ours, would be 3x smarter than us³⁵. Even if we’re just looking at human brains, Albert Einstein’s brain was no bigger than average, and despite years of studying his brain, neuroscientists haven’t found any clear differences in its structure compared to other human brains³⁶.

The myth that smarter people have bigger brains has a particularly harmful history. In the 1800s, scientists measured the skulls of people of different races and genders as an estimate of brain size to provide “scientific” evidence that Caucasian men were superior to women and other races. There are many reasons this approach was flawed, not least of which is that correcting for body size can account for many of the reported differences³⁷. In 1898, a woman named Alice Lee challenged this idea by storming into the all-male meeting of the Anatomical Society at Trinity College Dublin, measuring the skulls of several prominent men in the audience, and demonstrating that many of these supposedly intelligent men had rather small skulls³⁸.

Read my previous post, “The Problem of Brain Size”, for a more detailed look at this myth.

The bottom line: Brain size has nothing to do with intelligence.

Why it matters: Flawed measurements of brain size have historically been used as scientific “proof” that women and racial minorities are not as intelligent as Caucasian men. Dispelling this myth is critical to reverse the harm done by the claims made in these studies and to prevent making the same mistakes in the future.

Myth #9: Playing brain games makes you smarter.

We’ve all seen ads for games that claim to train your brain to make you smarter, or measure your IQ. However, these claims are misleading and overinflated. One study conclusively proved this by having over 11,000 people play online brain games for six weeks. At the end of the six weeks, people had gotten a little better at the specific games that they played, but they were no better at any other tests³⁹. In other words, playing one memory game could make people better at that game, but it didn’t improve their memory overall.

In 2016, the brain game company Lumosity paid a $2 million settlement to the Federal Trade Commission (FTC) who filed false advertising charges against them⁴⁰. The FTC asserted that Lumosity’s claims that playing their games could improve performance on everyday tasks, delay age-related cognitive decline, and reduce the effects of brain injuries like stroke were unfounded. Since the settlement, Lumosity has been forced to alter their claims so that they do not mislead consumers.

The bottom line: Playing brain games makes you better at those particular games, but not any smarter overall.

Why it matters: Before investing time and money into products that claim to improve brain function by playing fun brain training games, it’s important to understand that these effects are often small and improve performance on specific tasks, but don’t generalize.

Myth #10: Different regions of your tongue are specialized for different kinds of tastes.

There are five basic tastes: bitter, salty, sour, sweet, and umami⁴¹. The myth goes that there are different parts of your tongue that are specialized to sense different tastes, so sweet and salty tastes are sensed on the tip of your tongue, while bitter tastes are sensed toward the back. I remember learning this myth for the first time at a girl scout meeting where we tasted different foods by placing them on different parts of our tongue. Since then, I heard it repeated many times in school and even in some of my neuroscience classes as an undergrad. In fact, many textbooks that are still being used today include this false claim. However, the truth is that although some parts of the tongue might be more sensitive to one taste or another, all five basic tastes are sensed across the entire tongue⁴².

The tongue map myth started with a 1901 paper in which German scientist David Hänig measured how much taste sensitivities changed across the tongue. He noticed that some parts of the tongue were more sensitive to a particular taste than others, and he drew some graphs to show how those sensitivities changed across the tongue. In 1940, another scientist adapted these graphs for a book about the different senses. In his adaptation, he simplified things by showing a single taste that was most sensitive on each part of the tongue rather than the relative sensitivities of each taste. This gave the false impression that each region of the tongue could sense just one taste, and this oversimplified figure has been copied thousands of times into science textbooks to teach the neuroscience of taste.

The bottom line: Sensitivity to each taste varies somewhat across the tongue, but each part of the tongue senses all the basic tastes.

Why it matters: The negative consequences of this myth might not be as harmful as the others, but it’s always worth correcting our understanding of ourselves and our bodies.

Now that you’ve learned the truth behind 10 popular neuromyths, it’s worth asking how so many neuromyths have leaked into popular press and what we can do to prevent them in the future. Preventing the spread of disinformation about the brain starts at all levels. Scientists should be careful not to overgeneralize or oversimplify their findings and to always consider alternative explanations and how their work might be misinterpreted. Journalists and science communicators should carefully report the results of scientific studies and not overstate what a given experiment shows. Non-scientists should think critically about what they read, and fact check things they read from unknown sources on social media. And most importantly, now that you know the truth behind the myth, the best thing you can do is to teach it to others who still believe in these popular neuromyths.

References

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8. Amir, O. & Biederman, I. The Neural Correlates of Humor Creativity. Front. Hum. Neurosci. 10, (2016).

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10. Tomatis, Alfred. Pourqoi Mozart? (Diffusion, Hachette, 1991).

11. Rauscher, F. H., Shaw, G. L. & Ky, K. N. Music and spatial task performance. Nature 365, (1993).

12. Cong, A. FROM MOZART TO MYTHS: Dispelling the ‘Mozart Effect’. Young Sci. J. 49–53 (2014).

13. California Childcare Health Program, UCSF School of Nursing. Building Baby’s Intelligence: Why Infant Stimulation Is So Important. (2002).

14. Walker, S. P. et al. Cognitive, psychosocial, and behaviour gains at age 31 years from the Jamaica early childhood stimulation trial. J. Child Psychol. Psychiatry 63, 626–635 (2022).

15. Román-Caballero, R., Vadillo, M. A., Trainor, L. J. & Lupiáñez, J. Please don’t stop the music: A meta-analysis of the cognitive and academic benefits of instrumental musical training in childhood and adolescence. Educ. Res. Rev. 35, 100436 (2022).

16. Zimmerman, F. J., Christakis, D. A. & Meltzoff, A. N. Associations between Media Viewing and Language Development in Children Under Age 2 Years. J. Pediatr. 151, 364–368 (2007).

17. Pashler, H., McDaniel, M., Rohrer, D. & Bjork, R. Learning Styles: Concepts and Evidence. Psychol. Sci. Public Interest 9, 105–119 (2008).

18. Cuevas, J. Is learning styles-based instruction effective? A comprehensive analysis of recent research on learning styles. Theory Res. Educ. 13, 308–333 (2015).

19. Riener, C. & Willingham, D. The Myth of Learning Styles. Change Mag. High. Learn. 42, 32–35 (2010).

20. Newton, P. M. & Salvi, A. How Common Is Belief in the Learning Styles Neuromyth, and Does It Matter? A Pragmatic Systematic Review. Front. Educ. 5, 602451 (2020).

21. The Telltale Hand. Dana Foundation https://www.dana.org/article/the-telltale-hand/.

22. Trubek, A. Sorry, Graphology Isn’t a Real Science. JSTOR Daily https://daily.jstor.org/graphology-isnt-real-science/ (2017).

23. Dazzi, C. & Pedrabissi, L. Graphology and Personality: An Empirical Study on Validity of Handwriting Analysis. Psychol. Rep. 105, 1255–1268 (2009).

24. Bandhu, K. C., Litoriya, R., Khatri, M., Kaul, M. & Soni, P. Integrating graphology and machine learning for accurate prediction of personality: a novel approach. Multimed. Tools Appl. (2023) doi:10.1007/s11042-023-15567-8.

25. Small Handwriting | Parkinson’s Foundation. https://www.parkinson.org/understanding-parkinsons/non-movement-symptoms/small-handwriting.

26. Dyslexia FAQ. Yale Dyslexia https://dyslexia.yale.edu/dyslexia/dyslexia-faq/.

27. Shaywitz, S. E. & Shaywitz, B. A. Dyslexia (Speciﬁc Reading Disability).

28. Cornell, J. M. Spontaneous mirror-writing in children. Can. J. Psychol. Rev. Can. Psychol. 39, 174–179 (1985).

29. Brooks, A. D., Berninger, V. W. & Abbott, R. D. Letter Naming and Letter Writing Reversals in Children With Dyslexia: Momentary Inefficiency in the Phonological and Orthographic Loops of Working Memory. Dev. Neuropsychol. 36, 847–868 (2011).

30. Signs of Dyslexia. Yale Dyslexia https://dyslexia.yale.edu/dyslexia/signs-of-dyslexia/.

31. Prasad, D. & Bainbridge, W. A. The Visual Mandela Effect as Evidence for Shared and Specific False Memories Across People. Psychol. Sci.

32. Haber, R. N. Twenty years of haunting eidetic imagery: where’s the ghost? Behav. Brain Sci. 2, 583–594 (1979).

33. Gray, C. R. & Gummerman, K. The Enigmatic Eidetic Image: A Critical Examination of Methods, Data, and Theories.

34. Report Urges Caution in Handling and Relying Upon Eyewitness Identifications in Criminal Cases, Recommends Best Practices for Law Enforcement and Courts | National Academies. https://www.nationalacademies.org/news/2014/10/report-urges-caution-in-handling-and-relying-upon-eyewitness-identifications-in-criminal-cases-recommends-best-practices-for-law-enforcement-and-courts.

35. Herculano-Houzel, S. et al. The elephant brain in numbers. Front. Neuroanat. 8, (2014).

36. Hines, T. Neuromythology of Einstein’s brain. Brain Cogn. 88, 21–25 (2014).

37. Gould, S. The Mismeasure of Man. (WW Northon & Company, 1996).

38. McNeill, L. The Statistician Who Debunked Sexist Myths About Skull Size and Intelligence. Smithsonian Magazine https://www.smithsonianmag.com/science-nature/alice-lee-statistician-debunked-sexist-myths-skull-size-intelligence-180971241/.

39. Owen, A. M. et al. Putting brain training to the test. Nature 465, 775–778 (2010).

40. Lumosity to Pay $2 Million to Settle FTC Deceptive Advertising Charges for Its “Brain Training” Program. Federal Trade Commission https://www.ftc.gov/news-events/news/press-releases/2016/01/lumosity-pay-2-million-settle-ftc-deceptive-advertising-charges-its-brain-training-program (2016).

41. sarah. Accounting for taste. Curious https://www.science.org.au/curious/people-medicine/accounting-taste (2016).

42. Caballar, R. D. Do Different Parts of the Tongue Taste Different Things? https://www.brainfacts.org:443/thinking-sensing-and-behaving/taste/2018/do-different-parts-of-the-tongue-taste-different-things-010319.

Cover photo made by Catrina Hacker in Biorender.com using image by GraphicMama-team from Pixabay.

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why zebra - Aphasia as a Symptom of Autoimmune Encephalitis

image - Neuro MythBusters: The truth behind 10 common myths about your brain

10 Big Unanswered Questions in Neuroscience Part 1

by Alanna | Aug 29, 2023 | PennNeuroKnow

August 30, 2023 | by Sophie Liebergall, PennNeuroKnow and IAES Collaboration

A message from IAES Blog Staff:

As AE Warriors, caregivers, friends, family, loved ones and medical personnel we have been unwittingly thrown into a world we may or may not have been at all curious about previously. No matter where we are in our individual AE journeys, neurology and neuroscience are terms we all know well. AE may have sent us on this journey deep into the amazing world of neurology, but we all have found out just how interesting and fascinating our brains can be! In the first of a two-part series, Sophie Liebergall has helped us to better understand 10 big unanswered questions in neuroscience! We hope you enjoy this and look forward to Part II.

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Introduction

This past year, astrophysicists used NASA’s James Webb Space telescope to observe a star that is over 33 billion light years away from earth. Back on earth, particle physicists used the Large Hadron Collider in Switzerland to confirm the existence of incomprehensibly tiny subatomic particles. But despite these astounding scientific and technologic advances, we still have a lot to learn about what is going on in the organ inside our own skulls! In part one of what will be a two-part series, we discuss a few of the fundamental questions about the brain that have remained mysterious to neuroscientists.

1. Where do our memories go when we put them in long-term storage?

For a brain to perform complex tasks, such as telling the body to execute a series of movements or being able to recognize and evade a predator, it must be able to recall information that was gathered during previous experiences. Neuroscience researchers divide memory storage into two stages: short-term memory and long-term memory.¹ When the brain senses something in its environment, it can hold that information for a few seconds to minutes as a short-term memory.² Over time, scientists have gathered clues that short-term memories (at least those of conscious facts and events) are stored in the hippocampus, an almond-size region nestled on either side below the brain’s surface on either side.³ But sometimes the brain needs to hold onto information for longer periods of time (up to a lifetime) so that is can be recalled later. We’re fairly certain that long-term memories aren’t stored in the hippocampus; but where exactly these long-term memories go remains a mystery. Several recent studies seem to suggest that, unlike short-term memories, long-term memories may be widely distributed in the cerebral cortex (the large surface of the brain that is used for complex thought), with different features of the memory spread across different regions.^4,5 You can read more about the process of memory formation and how it can go wrong in some diseases here!

2. Why do we need to sleep?

Evolution has shaped the human body into an elegant and efficient machine, with a versatile digestive system, a continuously beating heart, and a thinking brain. However, one of our basic biologic functions, sleep, seems like something that should have been stamped out by evolution many generations ago. When we sleep, we are essentially unconscious for up to one-third of the day. For our ancestors, this is a time when they were particularly vulnerable to predators and unable to gather food. So why, then, has sleep survived the test of natural selection?

Sleep is absolutely necessary for all animals (from armadillos, who sleep up to twenty hours each day, to giraffes who need just two hours of sleep a day).⁶ After just a couple days of total sleep deprivation, many people will start to show symptoms of psychosis.⁷ And if the sleep deprivation continues, it can even be deadly. In a study from the 1980s, which would likely be forbidden under contemporary ethical standards, researchers subjected a group of rats to total sleep deprivation. All of the rats died by the 32^nd day of the study.⁸ The ultrarare genetic disease Fatal familial insomnia gives further insight into the danger of insomnia in humans. Patients with Fatal familial insomnia slowly lose their ability to fall and stay asleep.⁹ Tragically, these patients always die soon after they completely lose their ability to sleep.

Sleep is important for a variety of our body and brain’s normal functions: solidifying events that occurred during the day as long term memories,¹⁰ recalibrating the strength of the connections between brain cells,^11,12 balancing the hormones that control our appetites and metabolism,¹³ and clearing the toxic byproducts of brain cell activity.¹⁴ But scientists still do not know what function (or functions) of sleep are the primary reason why it is essential for survival. Read more about the possible hypothesis for why we sleep in this PNK article!

3. Why do we dream?

Even more mysterious than the question of why we sleep is the question of why we dream. Though sleep has been a target of neuroscience research for decades, there are inherent challenges to studying dreaming that prevent us from using some of the traditional tools of neuroscience research. The study of dreams still largely relies on dream reports, when a person wakes up and verbally reports or writes down whether they were dreaming and what their dream was about. Dream reports are often unreliable because of the bias and imperfect memory of the dreamer. This can prevent researchers from making objective scientific conclusions from dream reports. Furthermore, all animals clearly display some form of sleep, but there is no conclusive evidence that other animals have dreams. This makes it challenging or even impossible to study dreaming using laboratory animals, which generally allow us to perform important experiments that would take too long or be too dangerous in humans.

Though we have recently developed more sophisticated tools that allow us to correlate the dream reports of humans with measures of brain activity, many of these studies have only raised more questions. It was once thought that dreaming only occurred during rapid eye movement (REM) sleep, the phase of sleep during which brain waves look most similar to the waking state. But more recent evidence suggests that dreams occur during both REM and non-REM sleep (though dreams that occur during REM sleep do seem to be more vivid than the dreams that occur during non-REM sleep).^15,16

Another strange aspect of dreaming is called the dream-lag effect, which describes a phenomenon in which you’re most likely to dream about real life events that happened 5-7 days ago.¹⁷ And we still don’t have a clue as to why some people are prone to sleepwalking: a state in which individuals are clearly deep in a dream, but somehow are aware of their surroundings enough to navigate a space, consume food, or even drive a motor vehicle.¹⁸ You can learn more about the neuroscience of dreaming here!

4. How do the general anesthesia drugs used during surgery make you unconscious?

General anesthetics, the class of drugs which cause temporary unconsciousness, have made it possible for doctors to perform lifesaving and life-altering surgeries that would otherwise be impossibly painful for patients. General anesthetics are some of the most safe and reliable medications that are administered by doctors. But we still don’t have an understanding of where general anesthetics act in the brain, or of what their ultimate effects are on brain processes. Even though anesthetic drugs all have the same end effect of making a patient unconscious, anesthetics can come in all different shapes and sizes. Some, like xenon gas, have a structure as simple a single atom, whereas others, like alfaxalone, have a complex structure with many branches and rings.^19,20 Some are inhaled as a gas, whereas others are injected into the bloodstream. And, strangely, general anesthetics don’t just sedate animals with complex brains like humans. They also impair the movement and environmental responsiveness of plants and even single-celled organisms!²¹ You can learn more about the possible mechanisms of general anesthetics and their relationship with sleep in this PNK article.

5. How does each area of the brain know what function it is supposed to perform?

In the mid-19^th century, in the early days of modern neuroscience, the French physician Paul Broca learned of a patient with a unique neurologic condition. This patient had lost the ability to generate speech, but had somehow maintained the ability to comprehend speech.²² When this patient died, Broca performed an autopsy, where he discovered that the patient had sustained an injury to a very specific area of their frontal lobe. Broca’s work inspired other physicians of his age to look for injuries to specific areas of their brains in their patients with specific neurologic symptoms. If multiple patients with the same symptoms had an injury in the same region, then it could be assumed that an injury to that region was the cause of the symptom. These studies of localized brain injuries led neurologists to believe that different regions of the brain are responsible for the different functions of the brain. For example, one region of the brain is required for the ability to move a hand, whereas another region of the brain is required to read language.

Modern-day neuroscientists and neurologists take the idea that certain regions of the brain are responsible for certain functions for granted. But there is a great deal of complexity to this picture that we have yet to understand. The exact mapping of the functions of the brain can vary between individuals – sometimes in dramatic ways. For example, most people have the speech control area of their brain somewhere on the left side of their brain. But occasionally, in people who are left-handed, the speech control area is instead found on the right side.²³ This variability between individuals suggests that the process of assigning a function to a specific brain region doesn’t follow a simple blueprint. But we still don’t know how the brain knows which functions it needs to perform. And we also don’t know each function is assigned to a particular region of the brain.

Stay tuned for part two with five more big unanswered questions in neuroscience coming this summer!

References

1. Cowan, N. What are the differences between long-term, short-term, and working memory? Prog Brain Res 169, 323–338 (2008).

2. Atkinson, R. C. & Shiffrin, R. M. Human Memory: A Proposed System and its Control Processes11This research was supported by the National Aeronautics and Space Administration, Grant No. NGR-05-020-036. The authors are indebted to W. K. Estes and G. H. Bower who provided many valuable suggestions and comments at various stages of the work. Special credit is due J. W. Brelsford who was instrumental in carrying out the research discussed in Section IV and whose overall contributions are too numerous to report in detail. We should also like to thank those co-workers who carried out a number of the experiments discussed in the latter half of the paper; rather than list them here, each will be acknowledged at the appropriate place. in Psychology of Learning and Motivation (eds. Spence, K. W. & Spence, J. T.) vol. 2 89–195 (Academic Press, 1968).

3. Duff, M. C., Covington, N. V., Hilverman, C. & Cohen, N. J. Semantic Memory and the Hippocampus: Revisiting, Reaffirming, and Extending the Reach of Their Critical Relationship. Frontiers in Human Neuroscience 13, (2020).

4. Yadav, N. et al. Prefrontal feature representations drive memory recall. Nature 608, 153–160 (2022).

5. Roy, D. S. et al. Brain-wide mapping reveals that engrams for a single memory are distributed across multiple brain regions. Nat Commun 13, 1799 (2022).

6. Campbell, S. S. & Tobler, I. Animal sleep: a review of sleep duration across phylogeny. Neurosci Biobehav Rev 8, 269–300 (1984).

7. Waters, F., Chiu, V., Atkinson, A. & Blom, J. D. Severe Sleep Deprivation Causes Hallucinations and a Gradual Progression Toward Psychosis With Increasing Time Awake. Front Psychiatry 9, 303 (2018).

8. Everson, C. A., Bergmann, B. M. & Rechtschaffen, A. Sleep deprivation in the rat: III. Total sleep deprivation. Sleep 12, 13–21 (1989).

9. Fatal Familial Insomnia – Symptoms, Causes, Treatment | NORD. https://rarediseases.org/rare-diseases/fatal-familial-insomnia/.

10. Diekelmann, S. & Born, J. The memory function of sleep. Nat Rev Neurosci 11, 114–126 (2010).

11. Frank, M. G. Erasing Synapses in Sleep: Is It Time to Be SHY? Neural Plast 2012, 264378 (2012).

12. Tononi, G. & Cirelli, C. Sleep function and synaptic homeostasis. Sleep Medicine Reviews 10, 49–62 (2006).

13. Sharma, S. & Kavuru, M. Sleep and Metabolism: An Overview. Int J Endocrinol 2010, 270832 (2010).

14. Xie, L. et al. Sleep Drives Metabolite Clearance from the Adult Brain. Science 342, 10.1126/science.1241224 (2013).

15. Foulkes, W. D. Dream reports from different stages of sleep. J Abnorm Soc Psychol 65, 14–25 (1962).

16. Hobson, J. A., Pace-Schott, E. F. & Stickgold, R. Dreaming and the brain: toward a cognitive neuroscience of conscious states. Behav Brain Sci 23, 793–842; discussion 904-1121 (2000).

17. Eichenlaub, J. et al. The nature of delayed dream incorporation (‘dream‐lag effect’): Personally significant events persist, but not major daily activities or concerns. J Sleep Res 28, e12697 (2019).

18. Cochen De Cock, V. Sleepwalking. Curr Treat Options Neurol 18, 6 (2016).

19. PubChem. Alfaxalone. https://pubchem.ncbi.nlm.nih.gov/compound/104845.

20. PubChem. Xenon. https://pubchem.ncbi.nlm.nih.gov/compound/23991.

21. Kelz, M. B. & Mashour, G. A. The Biology of General Anesthesia from Paramecium to Primate. Current Biology 29, R1199–R1210 (2019).

22. Dronkers, N. F., Plaisant, O., Iba-Zizen, M. T. & Cabanis, E. A. Paul Broca’s historic cases: high resolution MR imaging of the brains of Leborgne and Lelong. Brain 130, 1432–1441 (2007).

23. Packheiser, J. et al. A large-scale estimate on the relationship between language and motor lateralization. Sci Rep 10, 13027 (2020).

Cover photo made with biorender.com.

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A link between COVID-19 and autoimmune encephalitis?

by Alanna | Aug 22, 2023 | PennNeuroKnow

August 23, 2023 | by Kara McGaughey, PennNeuroKnow and IAES Collaboration

A message from IAES Blog Staff:

——-

Introduction

The Covid 19 pandemic spread its insidious tentacles all over the world. Scientific papers, chapters of books and entire university courses can be counted on to outline and delve deep into the wide spread effects on all levels of society that Covid has caused. For the AE community we are not only affected by the general Covid effects but possibly, also, in relation to our own ongoing AE journeys. How does the Covid virus affect AE? Is there a link between Covid 19 and AE? Kara McGaughey from the PNK team has done a wonderful job helping us all better understand what can be understood about this possible relationship at this time and what it may mean for the future of AE research.

Coronavirus Disease (COVID-19) is an ongoing global health crisis with more than 760 million confirmed cases and nearly 7 million deaths reported by the World Health Organization as of June 2023.¹ However, as we enter into the fourth year of the pandemic, we’re beginning to understand that knowing the number of active cases of COVID-19 isn’t the whole story.

In this post, we will dive into the long-term consequences of COVID-19, with a focus on the potential link between COVID-19 and autoimmune encephalitis (AE). We will explore why scientists think these diseases might be connected as well as what implications these new, post-COVID cases can have for AE research.

What is the connection between COVID-19 and AE?

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a newly-emerged virus that causes Coronavirus Disease 2019 (COVID-19). SARS-CoV-2 infection results in various systemic and respiratory symptoms such as fever, fatigue, cough, and difficulty breathing. In cases of severe disease, these symptoms can cause heart and lung failure, requiring hospitalization. However, the struggle isn’t always over once infection has subsided. Around 15% of patients have persistent symptoms for months after testing positive.^2-3These symptoms, often including fatigue and brain fog, can be debilitating. In many cases, a patient’s ability to carry out normal, everyday activities is profoundly affected. In a much, much smaller percentage of cases, the SARS-CoV-2 virus can also function as a trigger for some autoimmune diseases, like Guillain-Barré Syndrome (GBS), rheumatoid arthritis, and even autoimmune encephalitis (AE).^4-5

AE refers to a group of conditions that occur when the body’s immune system mistakenly attacks healthy brain tissue.⁵ The cause of AE is often unknown. However, experts say that, in some cases, exposure to certain bacteria or viruses may increase someone’s risk of AE. For example, infection with herpes simplex virus 1 (HSV-1) has been linked to later development of AE, particularly the anti-NMDA AE subtype.⁷

We are seeing something similar happening now with SARS-CoV-2 viral infections (and re-infections) leading to an uptick in the number of AE diagnoses. Case reports of this so-called “post-COVID AE” have come from all over the world — Iran, Canada, France, Italy, the United Kingdom, China, Sweden, India, Mexico, and the United States — and describe patients across a wide range of ages from 2 to 88.^4,8-9 A majority of these post-COVID AE diagnoses are for either limbic or anti-NMDA AE subtypes with patients experiencing headache, cognitive impairment, and seizures.⁴ Fortunately, a majority of patients respond well to treatment.⁴

How can SARS-CoV-2 infection lead to AE?

How exactly AE develops from SARS-CoV-2 infections is not yet fully understood. However, scientists do have some theories.

The “cytokine storm” and inflammatory cytokines:

Cytokines are small proteins that are crucial for controlling the immune system’s activity.¹⁰ Inflammatory cytokinesact as signals that tell the immune system to turn on, enabling the body to recognize and destroy foreign invaders (like the SARS-CoV-2 virus). Anti-inflammatory cytokines are responsible for dialing immune system activity back down once the threat has been neutralized. During the pandemic, you may have heard about COVID-19 causing the overproduction of inflammatory cytokines, known as a “cytokine storm.” With too many of these cytokines released in the body, immune system activity and inflammation can spiral out of control, leading to, in the worst cases, multi-organ failure.^4-6,11

Scientists think that one link between COVID-19 and AE is a particular inflammatory cytokine, IL-6, released during this storm.^5,12 Elevated levels of IL-6 are often found in patients with anti-NMDA AE.^11,13-14 In fact, they are considered a characteristic feature of this AE subtype.¹³ Given that many post-COVID AE cases are anti-NMDA, it is possible that high levels of IL-6 as a result of SARS-CoV-2 viral infection could be one reason for the increased risk of developing AE after COVID-19.

Accidental autoimmunity:

While we want an immune system that can recognize and react to foreign invaders (e.g., SARS-CoV-2, tumor cells, etc.), it is just as important that our own cells don’t get caught up in the crossfire. Fortunately, our immune system has evolved to both quickly and accurately distinguish outsiders from the body itself. However, sometimes in the face of viral infections that cause extreme inflammation, this protective, self-recognition feature goes awry and the body begins to produce antibodies that accidentally target its own tissue (“autoantibodies”). This autoantibody-induced self destruction is called autoimmunity.⁴It is possible that SARS-CoV-2 viral infections induce AE through an autoimmune process that generates antibodies targeting brain cells.

What implications might this have for AE research?

AE is notoriously rare and frequently misdiagnosed.¹⁵Evidence for a link between SARS-CoV-2 infections and the development of AE means more of the scientific spotlight is being given to AE. This increased awareness could make physicians more likely to explore AE as a possible diagnosis, decreasing the time patients spend in limbo waiting for answers and treatment. Perhaps more importantly, in scientific research, money and resources flow where attention goes. This could mean more funding for AE research and more AE clinical trials. Hopefully, this will lead to a better understanding not only of the relationship between COVID-19 and AE, but AE and autoimmunity more broadly.

A final note: It’s important to remember that getting infected or re-infected with COVID-19 doesn’t mean you will end up with AE. While there have been a fair number of case reports of post-COVID AE, it is still a rare outcome. Moreover, it is very difficult to establish any sort of causal link between SARS-CoV-2 infection and the later development of a disease. In most cases it is impossible to know whether some of these patients would have developed AE even without exposure to COVID-19. Nonetheless, the best path forward is to be aware of ongoing research and continue preventive measures, like wearing a mask in high-risk situations and making sure you stay up to date on COVID-19 vaccinations.

Work cited:

WHO Coronavirus (COVID-19) Dashboard. (n.d.). Retrieved May 1, 2023, from https://covid19.who.int
Nearly One in Five American Adults Who Have Had COVID-19 Still Have “Long COVID.” (2022, June 22).https://www.cdc.gov/nchs/pressroom/nchs_press_releases/2022/20220622.htm
Lledó, G. M., Sellares, J., Brotons, C., Sans, M., Antón, J. D., Blanco, J., Bassat, Q., Sarukhan, A., Miró, J. M., & de Sanjosé, S. (2022). Post-acute COVID-19 syndrome: A new tsunami requiring a universal case definition. Clinical Microbiology and Infection, 28(3), 315–318. https://doi.org/10.1016/j.cmi.2021.11.015
Stoian, A., Stoian, M., Bajko, Z., Maier, S., Andone, S., Cioflinc, R. A., Motataianu, A., Barcutean, L., & Balasa, R. (2022). Autoimmune Encephalitis in COVID-19 Infection: Our Experience and Systematic Review of the Literature. Biomedicines, 10(4), 774. https://doi.org/10.3390/biomedicines10040774
Nabizadeh, F., Balabandian, M., Sodeifian, F., Rezaei, N., Rostami, M. R., & Naser Moghadasi, A. (2022). Autoimmune encephalitis associated with COVID-19: A systematic review. Multiple Sclerosis and Related Disorders, 62, 103795.https://doi.org/10.1016/j.msard.2022.103795
Payus, A. O., Jeffree, M. S., Ohn, M. H., Tan, H. J., Ibrahim, A., Chia, Y. K., & Raymond, A. A. (2022). Immune-mediated neurological syndrome in SARS-CoV-2 infection: A review of literature on autoimmune encephalitis in COVID-19. Neurological Sciences, 43(3), 1533–1547. https://doi.org/10.1007/s10072-021-05785-z
Armangue, T., Spatola, M., Vlagea, A., Mattozzi, S., Cárceles-Cordon, M., Martinez-Heras, E., Llufriu, S., Muchart, J., Erro, M. E., Abraira, L., Moris, G., Monros-Giménez, L., Corral-Corral, Í., Montejo, C., Toledo, M., Bataller, L., Secondi, G., Ariño, H., Martínez-Hernández, E., … Zabalza, A. (2018). Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: A prospective observational study and retrospective analysis. The Lancet Neurology, 17(9), 760–772. https://doi.org/10.1016/S1474-4422(18)30244-8
Saffari, P., Aliakbar, R., Haritounian, A., Mughnetsyan, R., Do, C., Jacobs, J., Hoffer, J., Arieli, R., Liu, A. K., Saffari, P., Aliakbar, R., Haritounian, A., Mughnetsyan, R., Do, C., Jacobs, J., Hoffer, J., Arieli, R., & Liu, A. K. (2023). A Sharp Rise in Autoimmune Encephalitis in the COVID-19 Era: A Case Series. Cureus, 15(2). https://doi.org/10.7759/cureus.34658
Mekheal, E., Mekheal, M., Roman, S., Mikhael, D., Mekheal, N., Manickam, R., Mekheal, E., Mekheal, M., Roman, S., Mikhael, D., Mekheal, N., & Manickam, R. (2022). A Case Report of Autoimmune Encephalitis: Could Post-COVID-19 Autoimmunity Become a Lethal Health Issue? Cureus, 14(6). https://doi.org/10.7759/cureus.25910
Kim, E. Y., & Moudgil, K. D. (2008). Regulation of autoimmune inflammation by pro-inflammatory cytokines. Immunology Letters, 120(1), 1–5. https://doi.org/10.1016/j.imlet.2008.07.008
Byun, J.-I., Lee, S.-T., Moon, J., Jung, K.-H., Sunwoo, J.-S., Lim, J.-A., Kim, T.-J., Shin, Y.-W., Lee, K.-J., Jun, J.-S., Lee, H. S., Lee, W.-J., Kim, Y.-S., Kim, S., Jeon, D., Park, K.-I., Jung, K.-Y., Kim, M., Chu, K., & Lee, S. K. (2016). Distinct intrathecal interleukin-17/interleukin-6 activation in anti-N-methyl-d-aspartate receptor encephalitis. Journal of Neuroimmunology, 297, 141–147. https://doi.org/10.1016/j.jneuroim.2016.05.023
Liu, J., Li, S., Liu, J., Liang, B., Wang, X., Wang, H., Li, W., Tong, Q., Yi, J., Zhao, L., Xiong, L., Guo, C., Tian, J., Luo, J., Yao, J., Pang, R., Shen, H., Peng, C., Liu, T., … Zheng, X. (2020). Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients. EBioMedicine, 55, 102763.https://doi.org/10.1016/j.ebiom.2020.102763
Liu, J., Liu, L., Kang, W., Peng, G., Yu, D., Ma, Q., Li, Y., Zhao, Y., Li, L., Dai, F., & Wang, J. (2020). Cytokines/Chemokines: Potential Biomarkers for Non-paraneoplastic Anti-N-Methyl-D-Aspartate Receptor Encephalitis. Frontiers in Neurology, 11.https://www.frontiersin.org/articles/10.3389/fneur.2020.582296
Byun, J.-I., Lee, S.-T., Moon, J., Jung, K.-H., Sunwoo, J.-S., Lim, J.-A., Kim, T.-J., Shin, Y.-W., Lee, K.-J., Jun, J.-S., Lee, H. S., Lee, W.-J., Kim, Y.-S., Kim, S., Jeon, D., Park, K.-I., Jung, K.-Y., Kim, M., Chu, K., & Lee, S. K. (2016). Distinct intrathecal interleukin-17/interleukin-6 activation in anti-N-methyl-d-aspartate receptor encephalitis. Journal of Neuroimmunology, 297, 141–147. https://doi.org/10.1016/j.jneuroim.2016.05.023
Lancaster, E. (2016). The Diagnosis and Treatment of Autoimmune Encephalitis. Journal of Clinical Neurology (Seoul, Korea), 12(1), 1–13. https://doi.org/10.3988/jcn.2016.12.1.1

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Who do you become when you are sleepy?

by Alanna | Jul 11, 2023 | PennNeuroKnow

July 12, 2023 | by Lindsay Ejoh, PennNeuroKnow and IAES Collaboration

A message from IAES Blog Staff:

For all of us with AE, sleep can be an ongoing issue whether it be too little, too much, interrupted sleep cycles and everything in-between! Sleep issues often go hand in hand with an AE diagnosis. PNK author Lindsay Ejoh wrote this piece for the PNK weekly series and graciously gave IAES permission to publish it in our monthly series. We hope you find this as informative as we have!

——-

Introduction

Sleep experts recommend that most adults get 7-9 hours of good-quality sleep each day^1,2 to avoid the myriad of issues that can occur when the brain and body are sleep-deprived. We all know what it is like to be tired. We may feel cranky and sluggish, as well as physically and mentally exhausted. We may also face issues with memory and attention³, emotional regulation, and diminished sex drive^4,11. It is hard to feel like yourself when sleep-deprived- so what occurs in the brain during sleep deprivation, and how does it affect our daily lives?

Memory

As a child, I remember learning to trick my mother, a sleep-deprived emergency room nurse that worked the night shift, by asking her for permission to do things while she was coming home from work in the mornings, half-asleep. When I’d approach her in bed to ask for permission to go on a sleepover across town or to eat food we were saving for an occasion, she would always say yes. Eventually, she caught on, and warned me against waiting until she was sleepy to get my way, but the reason it worked at first is because sleep deprivation impacts decision-making⁵.

It also affects short-term memory, so as a result, my mother would never remember giving her approval. Long-term memory is affected as well, as sleep is very important for consolidation, or storage of memories. This is also why you may not remember everything you studied after cramming for an exam all night.

Reaction time

Being awake is not the same thing as being alert. When we are sleepy, we tend to have slow reaction times, or time to respond to a change in our environment. This can have devastating effects for those who operate cars and other heavy machinery while sleepy and can be dangerous for people who work with under these conditions. Sleep deprivation can make you 70% more likely to get into work-place accidents, which happen at higher rates in people with insomnia⁶. Additionally, missing just a couple hours of sleep can substantially increase the risk of having a car accident⁷. It may seem in the moment like you can stay awake while driving, but as explained in a previous NeuroKnow article, going 24 hours without sleep can be just as dangerous as driving drunk.

Changes in the brain

Sleep deprivation impacts many regions of your brain, but two are of notable importance: amygdala and prefrontal cortex.

Amygdala

Scientists can measure brain activity by taking functional magnetic resonance imaging (fMRI) scans. Using this method, researchers found that sleep deprivation leads to a hyperactive amygdala³. The amygdala is critical for emotional regulation, and its dysfunction may be related mood issues that occur from sleep deprivation. A single sleepless night can trigger a 30% increase in anxiety levels⁹, due to the loss of ability to regulate emotions or deal with stress, and people with anxiety disorders also have hyperactive amygdalae when faced with unpleasant changes in their environment¹⁰. In other words, sleep deprivation causes disruption in emotional centers in the brain, which is linked to increased anxiety.

Prefrontal Cortex

Another brain region with altered activity during sleep deprivation is the prefrontal cortex, which is important for rational thinking and decision-making³. This region has decreased activity during sleep deprivation, and these activity patterns are associated with impaired judgment, a common symptom of sleep deprivation.

Chronic sleep deprivation and sleep apnea

Most of us have experienced sleep-deprivation in our lives, but for some, it is the norm. People who suffer from inadequate sleep for a prolonged period of time (weeks to years) are in a state of chronic sleep deprivation⁶. Many people wake up in the mornings feeling symptoms of sleep deprivation despite getting a long night of sleep, which may be indicative of a sleep disorder known as sleep apnea. Patients with sleep apnea wake up over a hundred times throughout the night, due to difficulty breathing¹². A research lab in Australia found that sleep apnea patients have altered brain activity during wakefulness¹³. Certain parts of their brains “go offline” briefly, despite being awake, and brain activity resembles that of a sleeping person^14. Sleep disorder patients aren’t the only ones that experience this- it can occur from other forms of sleep deprivation. When sleep intrudes into the waking brain, this can lead to errors in tasks like driving. Despite being abnormal for humans, this brain activity phenomenon is not uncommon in the animal kingdom. Some animals like seals and dolphins sleep with half of their brains “awake” while the other halves are “asleep.”

Conclusion

Neuroscientists are working to understand the neurobiological consequences of sleep deprivation, so that we can inform and treat people who must continue to perform daily tasks despite running on little sleep. Though harmful for the brain, sleep deprivation is a normal part of daily life for 30-40% of US adults¹⁵, including parents of newborns, procrastinating college students, night-shift workers, military and medical personnel, sleep disorder patients, and many others. We live in a sleep-deprived society, where people are often celebrated for trading rest for productivity. I encourage you to take this as your sign to go to bed early tonight- you are not yourself when you’re sleepy!

References

Watson NF, Badr MS, Belenky G, et al. Recommended amount of sleep for a healthy adult: a joint consensus statement of the American Academy of Sleep Medicine and Sleep Research Society. Sleep. 2015;38(6):843–844.
Consensus Conference Panel, Watson, N. F., Badr, M. S., Belenky, G., Bliwise, D. L., Buxton, O. M., Buysse, D., Dinges, D. F., Gangwisch, J., Grandner, M. A., Kushida, C., Malhotra, R. K., Martin, J. L., Patel, S. R., Quan, S. F., Tasali, E., Non-Participating Observers, Twery, M., Croft, J. B., Maher, E., … Heald, J. L. (2015). Recommended Amount of Sleep for a Healthy Adult: A Joint Consensus Statement of the American Academy of Sleep Medicine and Sleep Research Society. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine, 11(6), 591–592. https://doi.org/10.5664/jcsm.4758
Krause, A. J., Simon, E. B., Mander, B. A., Greer, S. M., Saletin, J. M., Goldstein-Piekarski, A. N., & Walker, M. P. (2017). The sleep-deprived human brain. Nature reviews. Neuroscience, 18(7), 404–418. https://doi.org/10.1038/nrn.2017.55
Chen, K. F., Liang, S. J., Lin, C. L., Liao, W. C., & Kao, C. H. (2016). Sleep disorders increase risk of subsequent erectile dysfunction in individuals without sleep apnea: a nationwide population-base cohort study. Sleep medicine, 17, 64–68. https://doi.org/10.1016/j.sleep.2015.05.018
Rasch, B., & Born, J. (2013). About sleep’s role in memory. Physiological reviews, 93(2), 681–766. https://doi.org/10.1152/physrev.00032.2012
Suni, E. (2023, April 5). The relationship between sleep and workplace accidents. Sleep Foundation. Retrieved April 26, 2023, from https://www.sleepfoundation.org/excessive-sleepiness/workplace-accidents#references-197012
AAA. (2016, December 6). Missing 1-2 hours of sleep doubles crash risk: Study reveals the dangers of getting less than 7 hours of sleep. ScienceDaily. Retrieved April 26, 2023 from www.sciencedaily.com/releases/2016/12/161206110235.htm
Wong, M. M., Robertson, G. C., & Dyson, R. B. (2015). Prospective relationship between poor sleep and substance-related problems in a national sample of adolescents. Alcoholism, clinical and experimental research, 39(2), 355–362. https://doi.org/10.1111/acer.12618
Ben Simon, E., Rossi, A., Harvey, A. G., & Walker, M. P. (2020). Overanxious and underslept. Nature human behaviour, 4(1), 100–110. https://doi.org/10.1038/s41562-019-0754-8
Etkin, A., & Wager, T. D. (2007). Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. The American journal of psychiatry, 164(10), 1476–1488. https://doi.org/10.1176/appi.ajp.2007.07030504
Sleep Center of Middle Tennessee. (2022, June 22). Sleep deprivation and its effects on the brain. Sleep Centers of Middle Tennessee. Retrieved April 26, 2023, from https://sleepcenterinfo.com/blog/sleep-deprivation-effects-on-brain/
Slowik, J. M., Sankari, A., & Collen, J. F. (2022). Obstructive Sleep Apnea. In StatPearls. StatPearls Publishing.
Hung, C. S., Sarasso, S., Ferrarelli, F., Riedner, B., Ghilardi, M. F., Cirelli, C., & Tononi, G. (2013). Local experience-dependent changes in the wake EEG after prolonged wakefulness. Sleep, 36(1), 59–72. https://doi.org/10.5665/sleep.2302
Mannix, L. (2019, January 27). Your brain could be sleeping … even while you’re awake. The Sydney Morning Herald. Retrieved April 26, 2023, from https://www.smh.com.au/national/your-brain-could-be-sleeping-even-while-you-re-awake-20190124-p50tgg.html
Centers for Disease Control and Prevention. (2022, November 2). Adults – sleep and sleep disorders. Centers for Disease Control and Prevention. Retrieved April 26, 2023, from https://www.cdc.gov/sleep/data-and-statistics/adults.html

Cover image by Karollyne Videira Hubert on Unsplash

References

Zeng, J. & James, L. C. Intracellular antibody immunity and its applications. PLOS Pathog. 16, e1008657 (2020).
CDC. COVID-19 and Your Health. Centers for Disease Control and Preventionhttps://www.cdc.gov/coronavirus/2019-ncov/your-health/about-covid-19/antibodies.html (2020).
Elkon, K. & Casali, P. Nature and functions of autoantibodies. Nat. Clin. Pract. Rheumatol. 4, 491–498 (2008).
Hermetter, C., Fazekas, F. & Hochmeister, S. Systematic Review: Syndromes, Early Diagnosis, and Treatment in Autoimmune Encephalitis. Front. Neurol. 9, 706 (2018).
Graus, F. et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 15, 391–404 (2016).
Anti-NMDA receptor encephalitis. Autoimmune Encephalitis Alliance https://aealliance.org/ae-types/anti-nmda-receptor-encephalitis/.
Anti-AMPAR encephalitis. Autoimmune Encephalitis Alliance https://aealliance.org/ae-types/anti-ampar-encephalitis/.
Anti-GABAA receptor encephalitis. Autoimmune Encephalitis Alliance https://aealliance.org/ae-types/anti-gabaa-receptor-encephalitis/.
Anti-GABAB receptor encephalitis. Autoimmune Encephalitis Alliance https://aealliance.org/ae-types/anti-gabab-receptor-encephalitis/.
LGI1-antibody encephalitis. Autoimmune Encephalitis Alliance https://aealliance.org/ae-types/lgi1-antibody-encephalitis/.
CASPR2-antibody encephalitis. Autoimmune Encephalitis Alliance https://aealliance.org/ae-types/caspr2-antibody-encephalitis/.
Malter, M. P., Helmstaedter, C., Urbach, H., Vincent, A. & Bien, C. G. Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis. Ann. Neurol. 67, 470–478 (2010).
Voltz, R. & Eichen, J. A Serologic Marker of Paraneoplastic Limbic and Brain-Stem Encephalitis in Patients with Testicular Cancer. N. Engl. J. Med. (1999).
Graus, F. & Dalmau, J. Paraneoplastic neurological syndromes in the era of immune-checkpoint inhibitors. Nat. Rev. Clin. Oncol. 16, 535–548 (2019).
Lancaster, E. Encephalitis and antibodies to synaptic and neuronal cell surface proteins. (2011).

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What are intracellular and extracellular antibodies and what do the differences mean for patients with autoimmune encephalitis?

by Alanna | Jun 13, 2023 | PennNeuroKnow

June 14, 2023 | by Catrina Hacker, PennNeuroKnow and IAES Collaboration

A message from IAES Blog Staff:

——-

Introduction

There are many subtypes of autoimmune encephalitis (AE) that vary in their causes, the symptoms that patients experience, and what treatments are most effective. One of several factors that distinguish these different subtypes of AE is whether they involve intracellular or extracellular antibodies. In this post we will explore exactly what these terms mean and how they contribute to the differences between types of AE.

N Engl J Med 2018;378:840-51. DOI: 10.1056/NEJMra1708712 Copyright © 2018 Massachusetts Medical Society

What are intracellular and extracellular antibodies?

When a virus or bacteria enters our body, our immune system mounts an attack to destroy the foreign invader and protect us from harm. If our immune system is like an army ready for battle, then antibodies are like the scouts sent ahead of the battalion, patrolling for signs of a threat. Just like security personnel might scan ID badges to determine who is allowed in a building, each antibody is tasked with looking for a particular feature of something that the body has deemed harmful, called an antigen¹. You might have heard antibodies discussed in reference to COVID-19, where infection with COVID-19 or vaccination can cause your body to produce antibodies that recognize features of the COVID-19 virus². When antibodies are already present in the body, they can recognize the newly-arrived COVID-19 virus and mount an attack more quickly, helping to avoid a more serious infection.

This ability to quickly mount a defense against a threat before getting too sick is what makes antibodies an important part of our body’s immune system army. However, antibodies are only helpful if they recognize and defend against foreign substances that are harmful. Unfortunately, this isn’t the case in AE. Patients with AE have antibodies that bind to proteins found in their own cells, called autoantibodies (the prefix “auto” means self, so autoantibodies are antibodies that bind the body’s own proteins)³. Autoantibodies trigger the body’s immune system to attack itself, leading to the many symptoms of AE.

Each antibody can recognize only a small part of a whole cell, and there are many different parts of a cell that an antibody can recognize. What distinguishes extracellular from intracellular antibodies is whether their antigen (the ID badge they’re looking for) is inside or outside of the cell^1,4. Extracellular antibodies recognize antigens that are on the outer surface of the cell (“extra” meaning outside). Conversely, intracellular antibodies recognize antigens that are inside the cell (“intra” meaning inside). The intracellular antibodies inside the cell trigger a different set of immune reactions than the extracellular antibodies outside of the cell.

Which kinds of AE involve intracellular versus extracellular antibodies?

Subtypes of AE are distinguished by what kind of autoantibody a patient has⁴, which is why they are typically named after the antigen that the autoantibody recognizes. For example, patients with anti-NMDAR AE have antibodies that recognize NMDA receptors. Types of AE associated with antigens outside the cell involve extracellular antibodies and types of AE associated with antigens inside the cell involve intracellular antibodies.

Many of the most common subtypes of AE involve extracellular antibodies^4,5. Most are associated with antibodies that recognize a kind of protein that sits on the surface of the cell called a receptor. Receptors recognize and bind specific molecules and send signals that tell the cell how to respond. The receptors on neurons, a type of brain cell, are especially important because one neuron communicates with another by releasing molecules that can be recognized by the other neuron’s receptors. When antibodies bind the receptors, they activate an immune response and disrupt the ability of those receptors to participate in neural signaling. This leads to the many neurological symptoms of AE. Subtypes with these kinds of antibodies include anti-NMDAR AE⁶, anti-AMPAR AE⁷, anti-mGLUR5 antibody encephalitis^4,5, GlyR antibody encephalitis⁴, anti-GABA_aAE⁸, and anti-GABA_b AE⁹. Several other extracellular antibodies associated with AE have antigens that sit on the cell’s surface and help with neuronal signaling but aren’t receptors themselves. Subtypes of AE with these kinds of antibodies include LGI1-antibody encephalitis¹⁰, CASPR2-antibody encephalitis¹¹, and DPPX-antibody encephalitis^4,5.

Subtypes of AE associated with intracellular antibodies are less common^4,5. One example is GAD-antibody encephalitis¹². Patients with this form of AE have antibodies that target Glutamic Acid Decarboxylase (GAD), a protein found inside the cell that is needed to synthesize GABA, a special type of molecule that is necessary for some kinds of neural signaling. Other subtypes of AE that target intracellular proteins are anti-Hu encephalitis⁵, and Ma2-antibody encephalitis¹³.

How are subtypes of AE associated with intracellular antibodies different from subtypes of AE associated with extracellular antibodies?

One big distinction is that most subtypes of AE associated with intracellular antibodies are also associated with tumors⁴. These subtypes of AE are called paraneoplastic. Paraneoplastic AE can occur when tumor cells express proteins on their surface that are normally expressed elsewhere. Sometimes this includes proteins that are normally found inside healthy neurons. To recognize and fight the tumor, the body’s immune system creates antibodies that recognize these proteins. These antibodies don’t distinguish the proteins found in the tumor cells from the healthy proteins found in neurons, so when they reach the brain, they also bind the naturally-occurring proteins in neurons and trigger the immune response responsible for the symptoms of AE¹⁴.

Patients with subtypes of AE associated with intracellular antibodies also tend to have poorer outcomes and respond worse to immunotherapy than patients with subtypes associated with extracellular antibodies^4,15. This is because many of the symptoms of AE associated with extracellular antibodies are thought to result from the antibodies disrupting the normal function of the cell-surface proteins that they target. Conversely, the presence of intracellular autoantibodies typically accompanies an immune response against neurons more broadly that results in neuronal death. This means that successful treatment can often reverse symptoms of AE resulting from extracellular antibodies, as limiting the action of the antibodies allows the neurons to function normally, whereas even after treatment, symptoms do not typically reverse in subtypes of AE associated with intracellular antibodies, as many neurons have already died. For patients with paraneoplastic AE, removing the tumor is also an important step toward relieving symptoms¹⁵.

Despite general differences in outcomes for subtypes of AE associated with extracellular and intracellular antibodies, early detection and treatment are key to successful outcomes for all subtypes of AE⁴. Determining which type of AE a patient has can have an important impact on how doctors choose to treat and manage the disease. This distinction is also important for researchers developing new treatments and possible cures, as approaches that might work for one type of AE may not work for others. Determining which patients will be most receptive to a particular new treatment leads to better outcomes for clinical trials, which means more treatment options for all patients.

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References

Zeng, J. & James, L. C. Intracellular antibody immunity and its applications. PLOS Pathog. 16, e1008657 (2020).
CDC. COVID-19 and Your Health. Centers for Disease Control and Preventionhttps://www.cdc.gov/coronavirus/2019-ncov/your-health/about-covid-19/antibodies.html (2020).
Elkon, K. & Casali, P. Nature and functions of autoantibodies. Nat. Clin. Pract. Rheumatol. 4, 491–498 (2008).
Hermetter, C., Fazekas, F. & Hochmeister, S. Systematic Review: Syndromes, Early Diagnosis, and Treatment in Autoimmune Encephalitis. Front. Neurol. 9, 706 (2018).
Graus, F. et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 15, 391–404 (2016).
Anti-NMDA receptor encephalitis. Autoimmune Encephalitis Alliance https://aealliance.org/ae-types/anti-nmda-receptor-encephalitis/.
Anti-AMPAR encephalitis. Autoimmune Encephalitis Alliance https://aealliance.org/ae-types/anti-ampar-encephalitis/.
Anti-GABAA receptor encephalitis. Autoimmune Encephalitis Alliance https://aealliance.org/ae-types/anti-gabaa-receptor-encephalitis/.
Anti-GABAB receptor encephalitis. Autoimmune Encephalitis Alliance https://aealliance.org/ae-types/anti-gabab-receptor-encephalitis/.
LGI1-antibody encephalitis. Autoimmune Encephalitis Alliance https://aealliance.org/ae-types/lgi1-antibody-encephalitis/.
CASPR2-antibody encephalitis. Autoimmune Encephalitis Alliance https://aealliance.org/ae-types/caspr2-antibody-encephalitis/.
Malter, M. P., Helmstaedter, C., Urbach, H., Vincent, A. & Bien, C. G. Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis. Ann. Neurol. 67, 470–478 (2010).
Voltz, R. & Eichen, J. A Serologic Marker of Paraneoplastic Limbic and Brain-Stem Encephalitis in Patients with Testicular Cancer. N. Engl. J. Med. (1999).
Graus, F. & Dalmau, J. Paraneoplastic neurological syndromes in the era of immune-checkpoint inhibitors. Nat. Rev. Clin. Oncol. 16, 535–548 (2019).
Lancaster, E. Encephalitis and antibodies to synaptic and neuronal cell surface proteins. (2011).

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Treatments for Autoimmune Encephalitis

by Alanna | Apr 26, 2023 | PennNeuroKnow

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

A message from IAES Blog Staff:

——-

Introduction

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

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

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

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

First-Line Treatments

Steroids

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

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

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

glucocorticoid mechanism summary V1 500x358 - Treatments for Autoimmune Encephalitis

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

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

Plasma Exchange (PLEX)

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

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

PLEX summary V2 500x279 - Treatments for Autoimmune Encephalitis

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

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

Intravenous Immune Globulin (IVIG)

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

IVIG summary V1 500x323 - Treatments for Autoimmune Encephalitis

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

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

Second-Line Treatments

Rituximab

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

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

Cyclophosphamide

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

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

Symptomatic Treatment of AE

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

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

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References

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

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What is a headache?

by Alanna | Mar 7, 2023 | PennNeuroKnow

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

A message from IAES Blog Staff:

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

Introduction

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

What kinds of headaches are there?

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

Tension-type headaches

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

Migraines

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

Cluster Headaches

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

How do they start?

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

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

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

Where does the pain come from?

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

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

Sensitization of the brain

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

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

Hyperexcitability

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

Neuropeptide release

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

What are some treatment for migraines?

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

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

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

References

Stovner, L. J., Hagen, K., Linde, M., & Steiner, T. J. (2022). The global prevalence of headache: an update, with analysis of the influences of methodological factors on prevalence estimates. The journal of headache and pain, 23(1), 1-17.
Ashina, S., Mitsikostas, D. D., Lee, M. J., Yamani, N., Wang, S. J., Messina, R., … & Lipton, R. B. (2021). Tension-type headache. Nature Reviews Disease Primers, 7(1), 1-21.
Dodick, D. W. (2018). A phase‐by‐phase review of migraine pathophysiology. Headache: the journal of head and face pain, 58, 4-16.
Pescador Ruschel MA, De Jesus O. Migraine Headache. 2022 Jul 6. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 32809622.
Rossi, P., Whelan, J., Craven, A., & De La Torre, E. R. (2016). What is cluster headache? Fact sheet for patients and their families. A publication to mark Cluster Headache Day 2016. Functional Neurology, 31(3), 181.
Puledda, F., Messina, R., & Goadsby, P. J. (2017). An update on migraine: current understanding and future directions. Journal of neurology, 264(9), 2031-2039.
Stankewitz, A., Aderjan, D., Eippert, F., & May, A. (2011). Trigeminal nociceptive transmission in migraineurs predicts migraine attacks. Journal of Neuroscience, 31(6), 1937-1943.
Schulte, L. H., & May, A. (2016). The migraine generator revisited: continuous scanning of the migraine cycle over 30 days and three spontaneous attacks. Brain, 139(7), 1987-1993.
Karsan, N., & Goadsby, P. J. (2018). Biological insights from the premonitory symptoms of migraine. Nature Reviews Neurology, 14(12), 699-710.
Pietrobon, D., & Moskowitz, M. A. (2013). Pathophysiology of migraine. Annual review of physiology, 75, 365-391.
Burstein, R., Noseda, R., & Borsook, D. (2015). Migraine: multiple processes, complex pathophysiology. Journal of Neuroscience, 35(17), 6619-6629.
Russo, A. F. (2015). Calcitonin gene-related peptide (CGRP): a new target for migraine. Annual review of pharmacology and toxicology, 55, 533.
Iyengar, S., Johnson, K. W., Ossipov, M. H., & Aurora, S. K. (2019). CGRP and the trigeminal system in migraine. Headache: The Journal of Head and Face Pain, 59(5), 659-681.
Buture, A., Gooriah, R., Nimeri, R., & Ahmed, F. (2016). Current understanding on pain mechanism in migraine and cluster headache. Anesthesiology and Pain Medicine, 6(3).
Johnston, M. M., & Rapoport, A. M. (2010). Triptans for the management of migraine. Drugs, 70(12), 1505-1518.

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

by Alanna | Feb 21, 2023 | PennNeuroKnow

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

A message from IAES Blog Staff:

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

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

Introduction

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

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

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

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

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

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

Diseases like autoimmune encephalitis can be hard to categorize and diagnose

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

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

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

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

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

Rigorous science can’t be rushed

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

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

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

Concluding Thoughts

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

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

Image Credits

Cover photo: Photo by Ousa Chea on Unsplash.

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

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What are the different types of autoimmune encephalitis?

by Alanna | Dec 27, 2022 | PennNeuroKnow

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

A message from IAES Blog Staff:

——

Introduction

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

What is autoimmune encephalitis?

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

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

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

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

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

What part of the brain is affected by autoimmune encephalitis?

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

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

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

Is autoimmune encephalitis caused by a tumor?

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

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

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

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

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

Antibody	% of Cases with Presence of Tumor	Common symptoms
Anti-NMDAR	40% (varies)	Limbic encephalitis, psychosis, repetitive movements, unstable blood pressure and heart rate, decreased breathing, seizures
Anti-AMPAR	70%	Limbic encephalitis
Anti-GABA_A		Severe, prolonged seizures
Anti-GABA_B	70%	Limbic encephalitis, frequent seizures
Anti-Caspr2	40%	Limbic encephalitis, confusion, abnormal muscle tone
Anti-LGI1	<10%	Limbic encephalitis, seizures
Anti-Hu	>90%	Limbic encephalitis, problems with cognition
Anti-Ma2	>90%	Limbic encephalitis, brainstem encephalitis
Anti-CV2/CRMP5	>90%	Limbic encephalitis
Anti-Amphiphysin	>90%	Limbic encephalitis, widespread paralysis

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

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

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

References:

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

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

by Alanna | Dec 6, 2022 | PennNeuroKnow

December 7, 2022 | by Kara McGaughey, PennNeuroKnow

A message from IAES Blog Staff:

——

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

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

——

Introduction

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

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

How does the brain heal from autoimmune encephalitis?

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

— Alexandrine Lawrie on AE recovery¹

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

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

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

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

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

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

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

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

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

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

Full of uncertainty if it will ever stop spinning;

Full of frustration as I remain on my couch sitting.

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

I will keep the hope and learn to cope;

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

— Anonymous on living with AE⁸

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

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

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

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

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

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

And that has been absolutely true.

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

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

–Amy on her AE journey¹²

Work Cited:

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

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Fatigue and Autoimmune Encephalitis: You’re Not Alone

by Alanna | Nov 29, 2022 | PennNeuroKnow

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

Introduction

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

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

Fatigue is a common symptom of autoimmune encephalitis

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

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

Is your brain making you feel fatigued?

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

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

Are there other explanations for fatigue?

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

Treatments for chronic fatigue

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

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

References:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

15-Encephalitis Society. Managing fatigue after encephalitis.

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

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

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Movement disorders as a window into the diversity of autoimmune encephalitis

by Alanna | Sep 13, 2022 | PennNeuroKnow

September 14, 2022 | by Catrina Hacker, PennNeuroKnow

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

Learning the language of movement disorders

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

Ataxia. Ataxia describes difficulty balancing and coordinating movements. In the most classic presentation of ataxia patients struggle with walking and running, particularly in situations that require more coordination such as walking up and down stairs¹. Patients with ataxia can have a high risk of falling and in some cases they might have difficulty coordinating the movements necessary for speaking or writing². One type of ataxia is thought to be caused by degeneration of neurons in a brain region known to be important for movement called the cerebellum^1,2.

Chorea. Patients with chorea make involuntary, random movements. These brief and random movements are not repetitive or rhythmic but do appear to flow from one muscle to the next³. Chorea can occur in any muscle group, ranging from fingers and toes to facial movements. Interestingly, chorea subsides when patients are asleep⁴. Chorea is associated with too much activity of a neurotransmitter called dopamine that plays an important role in coordinating and initiating movement^3,4.

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

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

Movement disorders across different types of autoimmune encephalitis

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

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

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

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

Many other types of AE are associated with movement disorders including (but not limited to) GlyR-, DDPX-, LGI1-, and mGluR1-antibody associated encephalitis^7,8. It is important to note that although movement disruptions are common in many types of AE, they are rarely the only symptom and are not diagnostic on their own^7,8,10. Instead, they can serve as one of many clues leading doctors toward a correct diagnosis. The neural explanation for how each type of AE leads to these movement disorders is not well understood. Determining the biological basis of the relationship between AE and movement disorders is an important area for future research that might help us to better understand these distinct subtypes of AE.

Movement disorders in children and adults with autoimmune encephalitis

In addition to distinguishing different types of AE, movement disorders are proving to be an especially important diagnostic tool for children with AE. Movement disorders can be observed in both children and adults, but they are more common in children, particularly those with anti-NMDAR AE. The presentation of anti-NMDAR AE in adults is now well understood and typically involves psychiatric symptoms and cognitive impairment as well as the movement disorders described above. The presentation of anti-NMDAR AE in children isn’t as well documented, but diverges from adults in that it more often includes seizures and movement disturbances^7,10,11.

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

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

References

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

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Genetic Predisposition for Autoimmune Encephalitis

by tabitha orth | Jan 7, 2022 | PennNeuroKnow

January 12, 2022 | by Greer Prettyman, PennNeuroKnow

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

Not many disorders have such a clear genetic cause. However, the set of genes inherited from the parents can increase someone’s risk, or predisposition, for developing certain diseases, even if it doesn’t directly cause the disease. For example, people can have genetic predispositions for some types of cancer, psychiatric illnesses, and health risks like high cholesterol^2,3,4. Recent research suggests that certain types of autoimmune encephalitis (AE) may also be linked to genetic factors that put some people at higher risk of developing this disease than others⁵.

Genes and Heritability

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

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

Genetic Risk for AE

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

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

The most common form of limbic encephalitis that is not caused by cancer involves anti-leucine-rich glioma-inactivated 1 (anti-LGI1) antibodies⁷. Anti-LGI1 limbic encephalitis is associated with a mutation in part of the class II HLA gene complex. Anti-LGI1 antibodies are in the IgG4 isotype, which has been associated with HLA genes in a variety of autoimmune conditions^7,8. A genetic mutation called DRB1*07:01 was found to be carried in up to 90% of people with anti-LGI1 encephalitis⁹. This suggests that this specific HLA mutation is associated with the development of limbic encephalitis, although the exact biological mechanisms are still unknown⁷.

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

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

References:

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

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Why getting better at baseball might require just a little sleep

by Alanna | Dec 22, 2021 | PennNeuroKnow

December 22, 2021 | by Claudia Lopez Lloreda, PennNeuroKnow

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

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

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

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

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

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

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

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

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

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Cover image. From Pixabay.

References

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

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Ataxia and Autoimmune Encephalitis

by Alanna | Oct 26, 2021 | PennNeuroKnow

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

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

Damage to the cerebellum results in a condition known as Ataxia. Ataxia symptoms vary between each individual, but hallmark symptoms include trouble with coordination, walking, swallowing, speech, and on rare occasions, eye or heart problems^2,3,6. Anyone is susceptible to developing ataxia. It can be acquired through alcohol abuse, head trauma, stroke, vitamin deficiency, and/or autoimmunity². In some cases, ataxia is hereditary; someone can inherit either a dominant gene from one parent (autosomal dominant disorder), or a recessive gene from both parents (autosomal recessive disorder)^2,3. A common cause of ataxia and/or problems with balance and gait is due to the progressive loss and degeneration of cerebellar neurons, specifically Purkinje cells. Purkinje cells are one of the largest neurons in the brain and are the cerebellum’s main communicators with the rest of the brain⁸.Once a patient is diagnosed with ataxia, physicians will try to identify the root cause by performing neurological examinations and laboratory tests⁵. While the neurological examination is used to determine the extent and severity of symptoms, the laboratory tests can help to ascertain if the ataxia is genetic, infectious, or immune related³. For instance, if a patient develops ataxia through a nutritional or immune-mediated cause, their abnormal vitamin or antibody levels would be detected during the laboratory tests⁵. A patient’s cerebrospinal fluid (CSF), the bodily fluid that surrounds the brain and spinal cord, can be examined to measure specific antibody levels and provide information about specific types of immune-mediated ataxia^3,4.
The cerebellum is particularly susceptible to damage and autoimmune attacks⁵. Autoimmune-related ataxias can encompass a spectrum of disorders including autoimmune encephalitis (AE), gluten ataxia, and Hashimoto’s encephalopathy⁴. This type of ataxia can also be episodic – presenting as sudden and intense episodes of ataxia accompanied by vertigo and dizziness. These episodes are especially prevalent in a type of AE called anti–CASPR2 antibody-associated autoimmune encephalitis^5-7.
Is cerebellar degeneration observed in autoimmune-related ataxias? Not really³. For example, scientists who study anti-NMDA receptor (anti-NMDAR) encephalitis use magnetic resonance imaging (MRI) to produce detailed images of the cerebellum and found that 2 out of 15 patients exhibited cerebellar atrophy, which was a surprise because it has never been reported in this disease⁹. While it is not exactly clear why cerebellar atrophy is occurring in these anti-NMDAR encephalitis patients, one hypothesis posits that NMDAR antibodies act like NDMAR antagonists (blocking and inhibiting an NMDA receptor from turning on)⁹. NMDA receptors are critical for relaying signals between neurons and for a signal to be passed, the receptor must open. So, if an antibody is acting like an antagonist, the receptor can’t open and the signal won’t be relayed. In other words, if a cerebellar neuron (Purkinje cell) cannot receive or relay a signal to another neuron, then there is improper communication throughout the whole brain, resulting in impaired balance or coordination.
Above all, ataxia is an extremely rare condition and sometimes manifests with AE. Motor deficits are an early indicator that something is wrong and are typically the first thing doctors use to properly diagnose an autoimmune-related ataxia. Because there is no direct treatment, current methods focus on improving a patient’s balance and gait, in addition to immunotherapy and/or medications that may ease a patient’s symptoms like fatigue or muscle cramps². The cerebellum remains an enigma and everyday new research is coming to light. With new work, scientists are constantly able to develop new treatment options. For example, Dr. Beverly Davidson, a renowned scientist at the Children’s Hospital of Philadelphia has dedicated over 20 years of her work towards developing genetic therapies for cerebellar ataxias, giving hope to the next generation of ataxia research!
References:
1. Reeber, S. L., Otis, T. S., & Sillitoe, R. V. (2013). New roles for the cerebellum in health and disease. Frontiers in systems neuroscience, 7, 83.
2. What is ataxia? National Ataxia Foundation. (2021, April 26). https://www.ataxia.org/what-is-ataxia/.
3. Kuo, S. H. (2019). Ataxia. Continuum (Minneapolis, Minn.), 25(4), 1036.
4. Nanri, K., Yoshikura, N., Kimura, A., Nakayama, S., Otomo, T., Shimohata, T., … & Yamada, J. (2018). Cerebellar Ataxia and Autoantibodies. Brain and nerve= Shinkei kenkyu no shinpo, 70(4), 371-382.
5. Lim, J. A., Lee, S. T., Moon, J., Jun, J. S., Kim, T. J., Shin, Y. W., … & Lee, S. K. (2019). Development of the clinical assessment scale in autoimmune encephalitis. Annals of neurology, 85(3), 352-358.
6. Orsucci, D., Raglione, L. M., Mazzoni, M., & Vista, M. (2019). Therapy of episodic ataxias: Case report and review of the literature. Drugs in context, 8.
7. Joubert, B., Gobert, F., Thomas, L., Saint-Martin, M., Desestret, V., Convers, P., … & Honnorat, J. (2017). Autoimmune episodic ataxia in patients with anti-CASPR2 antibody-associated encephalitis. Neurology-Neuroimmunology Neuroinflammation, 4(4).
8. Voogd, J. & Glickstein, M. The anatomy of the cerebellum. Trends Neurosci. 21, 370–375 (1998).
9. Iizuka, T., Kaneko, J., Tominaga, N., Someko, H., Nakamura, M., Ishima, D., … & Nishiyama, K. (2016). Association of progressive cerebellar atrophy with long-term outcome in patients with anti-N-methyl-D-aspartate receptor encephalitis. JAMA neurology, 73(6), 706-713.
To learn more about ataxia, read this fact-sheet provided by the National Ataxia Foundation.

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Introduction

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Introduction

What is the connection between COVID-19 and AE?

How can SARS-CoV-2 infection lead to AE?

What implications might this have for AE research?

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Introduction

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Introduction

What are intracellular and extracellular antibodies?

Which kinds of AE involve intracellular versus extracellular antibodies?

How are subtypes of AE associated with intracellular antibodies different from subtypes of AE associated with extracellular antibodies?

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Introduction

First-Line Treatments

Steroids

Plasma Exchange (PLEX)

Intravenous Immune Globulin (IVIG)

Second-Line Treatments

Rituximab

Cyclophosphamide

Symptomatic Treatment of AE

References

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Introduction

What kinds of headaches are there?

How do they start?

Where does the pain come from?

What are some treatment for migraines?

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Introduction

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

Diseases like autoimmune encephalitis can be hard to categorize and diagnose

Rigorous science can’t be rushed

Concluding Thoughts

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Introduction

What is autoimmune encephalitis?

What part of the brain is affected by autoimmune encephalitis?

Is autoimmune encephalitis caused by a tumor?

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

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Introduction

How does the brain heal from autoimmune encephalitis?

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

Work Cited:

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Introduction

Fatigue is a common symptom of autoimmune encephalitis

Is your brain making you feel fatigued?

Are there other explanations for fatigue?

Treatments for chronic fatigue

References:

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