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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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