Chronic Fatigue Syndrome: What Science Tells Us About This Complex Condition

Introduction

“You could say I was the recipient of a miracle” [1]. Fiona Symington has suffered from myalgic encephalomyelitis (ME), or chronic fatigue syndrome (CFS), for 14 years, and in 2018, she did “what many say is impossible” - she recovered completely.

When Fiona was 11 years old, she abruptly began experiencing pain in her knee, which then spread to her lower back, left hip, and eventually, to multiple other joints in her body. By 20, Fiona had received multiple diagnoses from different physicians, none of which completely encapsulated her symptoms.

As Fiona continued with her life, her ability to perform daily activities was affected to the extent that she was not able to walk across her bedroom. After many doctor visits, Fiona’s rheumatologist finally diagnosed her with chronic fatigue syndrome. However, this illness had no cure, and Fiona continued to endure the mental and physical pain she had been experiencing for years.

Fourteen years later, in November 2018, Fiona tried her hand at an exercise program, exercising for short periods of time and resting for long hours in between. After six weeks of consistent exercise, her ME/CFS symptoms significantly improved, and Fiona was able to begin physically exerting herself for longer periods of time [1].

While Fiona’s story may not represent the challenges faced by the larger population of ME/CFS patients, she is one of millions impacted by this disease. The illness continues to be researched across the world, and while there is no cure currently, potential treatments are gradually emerging.

ME/CFS is a neurological condition characterized by severe fatigue, cognitive dysfunction, sleep problems, and other symptoms that impair a patient's daily living [2]. ME/CFS was originally classified as two separate diseases, but since the terms describe similar conditions, the two were deemed identical disorders in 2016 [3]. Causes of the disorder are currently unknown, but possible genetic and biological factors may contribute [3]. The development of treatments for ME/CFS is in progress, and awareness and understanding of the illness are crucial to supporting anyone with the disease.

Prevalence and Diagnosis

There are several underlying problems with measuring the prevalence of ME/CFS, such as relying on patient self-reported symptoms, challenges in conducting unbiased studies, and the absence of a specific biomarker or physical measurable substance indicative of the disease [3]. Estimates from multiple studies suggest that 0.89% of the United States population is affected, or approximately three million individuals [3].

The prevalence of ME/CFS varies with race, with Black patients generally facing more severe symptoms than White patients [4]. This may be due to greater disparities in healthcare accessibility, a lack of awareness, and preferences to manage symptoms without medical intervention [4]. Prevalence also varies by gender, with 60% of ME/CFS patients being women and 40% being men. This is likely due to biological differences, reproductive function, and genetic, hormonal, and neurometabolic factors [3] [5]. ME/CFS has also been found to have distinctly higher incidence rates at 10-19 years and 30-39 years of age [6].

The 1994 Fukuda CFS criteria have been used in research studies for the past 20 years to define and diagnose ME/CFS [7]. To be diagnosed, an individual must experience at least six months of chronic fatigue that reduces daily activity levels and is not alleviated by rest. Additionally, an individual must experience at least four of the following to be diagnosed: substantial impairment of short-term memory or concentration, sore throat, tender cervical and axillary lymph nodes, muscle pain, multi-joint pain without swelling or redness, headaches of a new type, pattern, or severity, unrefreshing sleep, or post-exertional malaise and discomfort [7]. A prominent lacking point in the Fukuda CFS criteria is that critical CFS symptoms, like post-exertional malaise and memory and concentration problems, are not required to diagnose CFS [8].

Due to this inadequacy, in clinical settings, the 2015 Institute of Medicine criteria is used as a diagnostic tool to reduce the risk of under or over-diagnosis [8] [9]. The 2015 criteria require the presence of unrefreshing sleep and post-exertional malaise, where even minor activities lead to an increase in symptoms and illness. Furthermore, diagnosis with ME/CFS requires the presence of one or both of the following: cognitive impairment and orthostatic intolerance [8]. 

One of the complexities of identifying ME/CFS is the fluctuating and unpredictable nature of the symptoms. Generally, if symptoms persist for over six months, the disorder is strongly suspected [4].

Symptoms

The primary symptom of ME/CFS is post-exertional malaise (PEM), or the worsening of ME/CFS symptoms after physical exertion [10]. These symptoms are aggravated 12 to 48 hours after exertion, and PEM usually lasts over a day, sometimes even weeks [10]. While scientists are unsure about the cause of PEM, a study in 2020 found that PEM may be due to an increased immunity response, leading to the fever and fatigue that ME/CFS patients commonly experience [11]. Additionally, PEM severity is associated with older age at disease onset, susceptibility to viral infections during the course of the disease, and gastrointestinal infections prior to disease onset [11]. 

In addition to PEM, patients experience secondary symptoms, such as joint pain and chronic headaches on a weekly basis [12]. Muscle pain is also observed, along with disturbed sleep, leading to nighttime insomnia. Other physical symptoms include nausea, vomiting, drenching night sweats, dizziness, and intolerance to alcohol or other medications [12].

ME/CFS also entails mental and psychological symptoms [12]. These are primarily related to cognitive decline, such as slower mental processing speed, poor learning abilities, memory decline, decreased attention span, and poor multitasking ability. Patients can also exhibit uncontrolled anxiety, panic attacks, and impaired social functioning [12].

Causes and Risk Factors

While the causes of ME/CFS are still unknown, the illness is likely caused by a multitude of factors [13]. Current research suggests that multiple physiological and psychological factors work together to give rise to ME/CFS [13].

Some evidence proposes that genetic factors are one of them. Studies have shown that nearly 18.3% of ME/CFS patients have at least one other blood-related family member with the disorder [13]. Another study consisting of twins observed that 55% of both twins had ME/CFS if they were monozygotic, or identical twins sharing nearly 100% of their genes [14]. In comparison, only 19% of both twins had ME/CFS if they were dizygotic, or fraternal twins sharing only about 50% of their genes [14]. This suggests that familial and genetic effects may play a role in ME/CFS.

A 2024 study by the National Institute of Health found that participants with ME/CFS had higher levels of naive B cells, or nonspecific immune cells [15]. They also had lower levels of switched memory B cells, or specific immune cells essential for the body to fight off pathogens and maintain acquired immunity. Deeper analysis of the study further revealed differences between men and women in gene expression patterns, immune cell populations, and metabolic markers. This study, led by National Institute of Neurological Disorders and Stroke clinical director Avindra Nath, validated prior research results and may help identify new ways to target the brain and immune system to help develop treatments for ME/CFS [15].

Treatment

Currently, there are no approved treatment drugs for ME/CFS [16]. Developing drugs to treat ME/CFS has proven to be difficult for several reasons, including insufficient cohesive diagnostic tools and a lack of awareness and recognition of the illness. Despite these challenges, considerable clinical effort has been put into identifying interventions that benefit patients and their quality of life.

One of the most studied treatment drugs that shows possibilities for disease improvement is rintatolimod, an immune modulator that can stimulate or suppress the immune system to help fight infection [16]. In one study of ME/CFS patients, rintatolimod significantly improved physical performance and increased exercise duration by 25% in over half the sample [16]. 

Out of many non-pharmacological treatment approaches, cognitive behavioral therapy (CBT) is the most widely used and has shown promising evidence for improvements in non-severe ME/CFS patients [17]. In CBT, triggers of fatigue symptoms are identified and addressed by implementing strategies such as monitoring sleep, setting goals, establishing routines, promoting sleep hygiene, and managing stress. However, CBT only helps patients adapt to and manage their fatigue, and does not restore their full physical activity levels [17].

Conclusion

ME/CFS is a complex, debilitating condition that affects millions of people worldwide, yet is poorly understood. Diagnosing and treating ME/CFS presents challenges due to the ambiguity of symptoms and lack of clear biomarkers. However, advancements in understanding the potential genetic and immune factors contributing to the disease offer hope for better treatment options in the future. While there is currently no cure for ME/CFS, ongoing research in developing medication and improving cognitive therapies provides patients with ways to manage their symptoms and enhance their quality of life. Continued awareness, research, and support are essential to improving outcomes for individuals living with ME/CFS.

References

[1] Symington, F. (2024). Life Restored: My Recovery from Myalgic Encephalomyelitis, or Chronic Fatigue Syndrome. Medium. https://medium.com/@fionasymington/life-restored-my-recovery-from-myalgic-encephalomyelitis-or-chronic-fatigue-syndrome-7f4801ff4b3c  

[2] Kingdon, C.C., Bowman, E.W., Curran, H. et al. (2018). Functional Status and Well-Being in People with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Compared with People with Multiple Sclerosis and Healthy Controls. PharmacoEconomics Open 2, 381–392. https://doi.org/10.1007/s41669-018-0071-6 

[3] Valdez, A. R., Hancock, E. E., Adebayo, S., Kiernicki, D. J., Proskauer, D., Attewell, J. R., Bateman, L., DeMaria, A., Lapp, C. W., Rowe, P. C., & Proskauer, C. (2019). Estimating prevalence, demographics, and costs of ME/CFS using large scale medical claims data and machine learning. Frontiers in Pediatrics, 6. https://doi.org/10.3389/fped.2018.00412 

[4] Jason LA, Torres C. (2022). Differences in Symptoms among Black and White Patients with ME/CFS. J Clin Med, 11(22):6708. https://doi.org/10.3390/jcm11226708.  

[5] Faro, M., Sàez-Francás, N., Castro-Marrero, J., Aliste, L., Fernández de Sevilla, T., & Alegre, J. (2016). Gender differences in chronic fatigue syndrome. Reumatología Clínica (English Edition), 12(2), 72–77. https://doi.org/10.1016/j.reumae.2015.05.009  

[6] Bakken, I.J., Tveito, K., Gunnes, N. et al. (2014). Two age peaks in the incidence of chronic fatigue syndrome/myalgic encephalomyelitis: a population-based registry study from Norway 2008-2012. BMC Med 12, 167. https://doi.org/10.1186/s12916-014-0167-5 

[7] Fukuda, K., Strauss, S. E., Hickie, I., Sharpe, M. C., Dobbins, J. G., & Komaroff, A. (1995). The Chronic Fatigue Syndrome: A Comprehensive Approach to Its Definition and Study. Journal of Chronic Fatigue Syndrome, 1(2), 67–84. https://doi.org/10.1300/j092v01n02_06  

[8] Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Board on the Health of Select Populations; Institute of Medicine. (2015). Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington (DC): National Academies Press (US). https://doi.org/10.17226/19012 

[9] National Guideline Centre (UK). (2021) Identifying and diagnosing ME/CFS: Myalgic encephalomyelitis (or encephalopathy) / chronic fatigue syndrome: diagnosis and management. National Institute for Health and Care Excellence.  https://www.ncbi.nlm.nih.gov/books/NBK579530/ 

[10] Stussman, B., Williams, A., Snow, J., Gavin, A., Scott, R., Nath, A., & Walitt, B. (2020). Characterization of post–exertional malaise in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Frontiers in Neurology, 11. https://doi.org/10.3389/fneur.2020.01025  

[11] Danilenko OV, Gavrilova NY, Churilov LP. (2022). Chronic Fatigue Exhibits Heterogeneous Autoimmunity Characteristics Which Reflect Etiology. Pathophysiology, 29(2), 187-199. https://doi.org/10.3390/pathophysiology29020016 

[12] Weigel, B., Eaton-Fitch, N., Thapaliya, K. et al. (2024). A pilot cross-sectional investigation of symptom clusters and associations with patient-reported outcomes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post COVID-19 Condition. Qual Life Res. https://doi.org/10.1007/s11136-024-03794-x 

[13] Chu, L., Valencia, I. J., Garvert, D. W., & Montoya, J. G. (2019). Onset patterns and course of myalgic encephalomyelitis/chronic fatigue syndrome. Frontiers in Pediatrics, 7. https://doi.org/10.3389/fped.2019.00012   

[14] Schlauch, K., Khaiboullina, S., De Meirleir, K. et al. (2016). Genome-wide association analysis identifies genetic variations in subjects with myalgic encephalomyelitis/chronic fatigue syndrome. Transl Psychiatry 6, e730. https://doi.org/10.1038/tp.2015.208 

[15] Walitt, B., Singh, K., LaMunion, S.R. et al.  (2024). Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome. Nat Commun 15, 907. https://doi.org/10.1038/s41467-024-45107-3 

[16] Strayer DR, Young D, Mitchell WM. (2020). Effect of disease duration in a randomized Phase III trial of rintatolimod, an immune modulator for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. PLoS One, 29,15(10). https://doi.org/10.1371/journal.pone.0240403. 

[17] Adamson J, Ali S, Santhouse A, Wessely S, Chalder T. (2020). Cognitive behavioural therapy for chronic fatigue and chronic fatigue syndrome: outcomes from a specialist clinic in the UK. J R Soc Med, 113(10), 394-402. https://doi.org/10.1177/0141076820951545.