ME/CFS: The fatigue that sleep can’t shake

Sketch of ME/CFS symptoms showing a woman slumped over with exhaustion.

A sketch of a woman suffering from ME/CFS, slumped over with exhaustion. Jem Yoshioka from Wellington, New Zealand, CC BY-SA 2.0, via Wikimedia Commons

Fatigue is a normal response to day-to-day exertions, stresses, and sleep deprivation. Persistent fatigue, however, can act as a sign of underlying mental or physical ailments and is a common symptom of many infections and medical conditions. Typically, when caused by infection, fatigue is short-lasting and most often improves with disease cessation. For some, debilitating and widespread fatigue is the illness itself, rather than merely a symptom of another biological process. This condition was first officially recognized in 1988 and later named Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Despite its recognition as a distinct illness, ME/CFS remains a medical mystery.

ME/CFS affects between 17 and 24 million people worldwide. Despite its vast prevalence, little is known about the condition—there is no single cause or treatment identified. Scientists have a limited understanding of the disease, other than the fact that it can leave patients chronically bedbound with a plethora of physical and psychological symptoms. In addition to persistent fatigue, patients often experience muscle and joint pain, sleep problems, and dizziness. Cognitive dysfunction, often described as “brain fog”, is also common, where patients have headaches, slower thinking, and difficulties with memory. These symptoms are further exacerbated by physical or mental exertion beyond the patient’s limits.

Challenges in diagnosis and treatment

ME/CFS is a complex disease with multi-system repercussions. With such widespread effects, the extensive nature of the disease poses several challenges. For starters, the involvement of several bodily systems results in a vast array of clinical presentations, which makes ME/CFS difficult to distinguish from other chronic illnesses, such as fibromyalgia and Lyme disease. Not only does the disease present differently among patients, but it also has marked variation in its progression. Symptoms range from mild to severe, with some patients able to complete daily activities, while others are unable to leave their beds. Such heterogeneity between individuals may indicate different progression rates of the disease or different causes of the condition entirely. The marked variation in disease presentation may result in discrete patient subgroups, each requiring unique treatment plans.

The diagnosis of ME/CFS is further complicated by its lack of physical indicators. Biomarkers—molecules in the blood or cells which can help identify a disease—are integral in the diagnosis of many diseases. However, ME/CFS has no clear biomarkers that can be assessed. Therefore, the diagnosis and management of the disease can only be evaluated through subjective scales.

Finding treatments for any disease relies upon understanding both the biological cause and how the condition progresses. Understanding these mechanisms allows researchers to find key molecules or pathways to target with treatment. Through a lack of understanding the aetiology and pathogenesis of the condition, challenges arise in finding ME/CFS treatments. Many of the current treatment options rely on easing the disease symptoms rather than targeting the root cause of the condition. For example, selective serotonin reuptake inhibitors and cognitive behavioural therapy (CBT) are often used to treat symptoms of low mood associated with ME/CFS. Meanwhile, typical pain medications such as non-steroidal anti-inflammatories can be used to manage pain associated with the condition. Energy management is also used in moderate or severe cases. In this instance, complete avoidance of certain activities outside of the patient’s energy capacity, and rest after exertion, are used to minimise fatigue.  Whilst some symptoms can be managed in this manner, there is still no treatment for the root cause of the condition.

Graded exercise therapy (GET), an exercise regime with incremental increases in time spent being active, was included in the National Institute for Health and Care Excellence (NICE) treatment guidelines for ME/CFS following the PACE trial in 2011. The aim was to improve exercise tolerance and endurance in ME/CFS patients by slowly diminishing their fatigue levels after activity. The trial found that those with mild or moderate ME/CFS had slight improvements in symptoms with GET and CBT. Since then, further studies and reviews have concluded that GET is not able to aid in symptoms and, in some cases, worsened the illness severity, resulting in removal from NICE guidelines in 2021.

The PACE trial was based upon the hypothesis that ME/CFS was psychological in origin, causing patients to remain more sedentary and therefore grow weaker until bedbound. GET was a means to re-condition these patients back into normal activities. With new research into potential biological causes, this view became outdated and ME/CFS was no longer thought of as an illness due to depression and de-conditioning. This highlights the challenge in finding cures without a more thorough understanding of the condition. However, with new research into causes, the search for treatments can progress more successfully.

The largest obstacles to finding causes, novel diagnostic tools, and treatments, are underfunding and a lack of awareness about the condition. The National Institute of Health has given ME/CFS $14-15 million annually since 2017 to fund new research. Other chronic conditions with a similar economic burden, such as multiple sclerosis and HIV/AIDs, have received $124 million and $3.1 billion respectively. Fundraising efforts prove challenging as many are unaware of the existence of ME/CFS. For those aware of ME/CFS, there is often stigma associated with the disease. Many believe that the disease is no more than simply feeling tired and that there is a component of laziness associated with ME/CFS. Improving the understanding of the condition in the public and the scientific community will not only allow patient voices to be heard but will also improve research interest and fundraising efforts in the field.

Research advancements

Novel research to date focuses both on finding potential causes and searching for biomarkers that can help in the diagnosis and management of the disease. A better understanding of both would immensely aid in diagnostics and therapeutics.

Ongoing research into the immune system investigates the potential involvement of chronic inflammation, autoimmunity, and chronic viral infection in causing the condition. Many patients develop ME/CFS symptoms following a viral infection, most commonly glandular fever caused by the Epstein-Barr Virus or other human herpes viruses such as HHV-6. Patients feel as if they never recover from the illness, with persistent fatigue that lasts long after the infection has dissipated. Novel research has identified changes in immune cells and circulating inflammatory markers, as well as the presence of autoimmune antibodies in some patients, hinting to the role of the immune system in the underlying pathogenesis.

After the COVID-19 pandemic, many patients were left with symptoms months after contracting the virus. One study suggests 87% of COVID-19 patients still experience symptoms four months after initial infection, including fatigue, muscle and joint pain, gastrointestinal problems, dizziness, brain fog, insomnia, and shortness of breath. While these lasting symptoms are broadly considered “long COVID”, there are many similarities between long COVID and ME/CFS. Therefore, many believe that the two conditions could be similar in pathogenesis and progression, and therefore could share effective treatments. The increasing public interest in long COVID may also draw more attention to ME/CFS and help further research into the condition.

Various research groups worldwide are investigating other mechanisms of interest, including hormonal imbalances, disruption to neuroendocrine systems, and genetic changes. The gut microbiome has become a particular area of interest. Gut dysbiosis and altered gut-brain axis activity have recently been suggested to play a role in the neurocognitive impairments in ME/CFS patients. Genetics have also been implicated in the condition. Higher rates of ME/CFS in relatives of patients, as well as higher correlations of prolonged fatigue in identical twins over fraternal twins, point to hereditary causes. Others have identified genetic changes associated with key cellular mechanisms thought to be involved in the condition. These include genes involved in risk of infection, mitochondrial dysfunction, and sleep.

Various groups have also turned to finding potential biomarkers for the condition though analysing the blood of patients. One such group in Spain has studied the microRNA (miRNA) content in a specific type of immune cell—the human peripheral blood mononuclear cell (PBMC)—and in small particles released from cells, called extracellular vesicles (EVs). They found 17 miRNAs in PBMCs and 10 miRNAs in EVs that were significantly different in ME/CFS patient blood samples compared to controls. Of these miRNAs, 15 were believed to have some diagnostic value in the future.

Teams in Oxford have been busy developing single-cell Raman microspectroscopy (SCRM) as a diagnostic tool for ME/CFS. SCRM is used to create a chemical fingerprint of each cell in a sample based upon its light scattering properties. PBMCs from ME/CFS patients were found to have increased phenylalanine peaks compared to healthy controls. This allowed patient samples to be distinguished from healthy samples, suggesting the amino acid phenylalanine could be a potential biomarker for ME/CFS. Cells that lack mitochondrial DNA, and therefore have energetic deficiencies, also showed a similar increase in phenylalanine. This is likely a result of the compensatory changes in metabolism that take place upon mitochondrial dysfunction. The similarities between dysfunctional mitochondria and ME/CFS patients supports the hypothesis that ME/CFS may, in some part, be due to deficiencies in cellular energetics, which is another novel area of research.

Metabolites—small molecules produced during cellular metabolism—also circulate through the bloodstream, and often change in disease. Some metabolites are shown to exhibit changes between ME/CFS patients and healthy controls. For example, in urine samples from ME/CFS patients, urea was consistently decreased across several studies. Meanwhile, many substances are up-regulated in patients, including various amino acids, lactate, and glucose. Identifying changes in metabolites between patients and healthy controls may have potential diagnostic implications, and suggest which metabolic pathways are affected in ME/CFS and therefore provide insight into how the condition may initiate or progress. An improved understanding of the physiology of ME/CFS may shed some light on future treatment targets and finally give rise to a cure for the fatigue which underpins the condition.

A hopeful future for ME/CFS?

Despite affecting up to 24 million people worldwide, ME/CFS still proves to be a medical mystery. With profound advances in medical research over recent years, and new insights into similar fatigue conditions such as long COVID, novel causes and potential biomarkers have started to come to light. This gives patients hope of finding a cure, rather than just managing symptoms. Hopefully one day effective treatments and improved public awareness will help society recognize that ME/CFS is more than just “being tired”.