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

Introduction

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

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

Fatigue is a common symptom of autoimmune encephalitis

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

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

Is your brain making you feel fatigued?

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

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

Are there other explanations for fatigue?

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

Treatments for chronic fatigue

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

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

References:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

15-Encephalitis Society. Managing fatigue after encephalitis.

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

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

Photo by Zohre Nemati on Unsplash

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

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

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

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

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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

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

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

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

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

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

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