Understanding myalgic encephalomyelitis

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe condition characterized by post-exertional neuroimmune exhaustion (PENE) accompanied by neurological, immunological, gastrointestinal (GI), and mitochondrial disturbances (1). The global prevalence of ME/CFS is ∼1%, affecting 17 million to 24 million people (2). ME/CFS is heterogeneous not only in symptom presentation but also illness trajectories, which can be worsening, plateauing, improving, or relapsing-remitting. Approximately 25% of patients with ME/CFS are considered severe and are bound to their homes. Although the etiology of ME/CFS is elusive, a large proportion of patients (∼60%) report post-infectious onset, such as after Epstein-Barr virus infection (3). The recent emergence of a chronic post-infectious condition, called Long Covid, overlaps considerably with ME/CFS in immunological, mitochondrial, and neurological dysfunctions (4). These similarities have resulted in increased interest and acceptance of ME/CFS as a disease and may stimulate research, the development of a diagnostic test, and pharmacotherapeutic interventions in ME/CFS that may be applied to Long Covid.

Neurological disturbances such as cognitive impairment, autonomic dysfunction, altered pain and sensory perception, and sleep disturbances are essential for diagnosis of ME/CFS and are commonly reported in Long Covid (see the figure). The World Health Organization (WHO) categorizes ME/CFS as a disease of the nervous system. Neuroimaging of ME/CFS patients has revealed anatomical, neurochemical, and functional brain changes. For example, brain magnetic resonance imaging (MRI) found global gray and white matter volume changes and also differences in the cortical and subcortical regional volumes in ME/CFS patients (5). Impaired brainstem connectivity identified with functional MRI (fMRI) and regression of white matter was associated with autonomic nervous system (ANS) measures in ME/CFS, including sleep disturbances and respiratory rate, which may lead to other symptoms, including pain, fatigue, impaired concentration and memory, and sensory and motor dysfunction (6). Such neurological symptoms are also commonly reported by Long Covid patients, and brain MRI has shown higher gray matter volumes in hippocampi that correlated with memory loss, a result also reported in ME/CFS (4). Overall, the underlying mechanism resulting in these MRI findings is unclear. Nonetheless, MRI and fMRI are important techniques to help elucidate the pathology of ME/CFS, as well as Long Covid.

GRAPIHC: N. CARY/SCIENCE

Many ME/CFS and Long Covid patients report GI symptoms, including abdominal pain, nausea, constipation, and diarrhea associated with changes to motility (in which the activity of nerves and muscles of the GI tract are impaired) and dysbiosis (imbalanced gut bacteria) (7). Dysregulated gut-brain signaling is proposed to play a role in the neurological dysfunction observed in patients with ME/CFS. For example, production of neurotransmitters such as serotonin, dopamine, and g-aminobutyric acid by enteroendocrine cells can be stimulated by intestinal bacteria through the production of neurotransmitter precursors, which may influence memory, cognition, mood, and sleep (8). However, this does not explain other symptoms, such as neurosensory and autonomic dysfunctions. Instead, the presence of GI dysregulation, through proposed disturbances in GI nerve and consequently smooth muscle activity, emphasizes the involvement of impaired ANS regulation in the symptomatology of ME/CFS. Yet, GI symptoms and irritable bowel are not specific to ME/CFS. An analysis reported that the role of dysbiosis and intestinal barrier permeability in ME/CFS and post-infectious syndromes remain unclear, and results are often unequivocal. Thus, further investigation using larger cohorts and consistent inclusion criteria is required; confounding variables such as irritable bowel disease should also be accounted for (7, 8).

Cross talk between the nervous, GI, and immune systems has been reported in other post-infectious disease states, such as Long Covid. Pathological interactions between GI disturbances and the immune system may result from translocation of immunogenic bacteria into the bloodstream of ME/CFS patients (9). Immune dysfunction is a key feature of ME/CFS, and many symptoms indicate chronic immune activation—for example, persistent sore throat, tender and enlarged lymph nodes, and fever. The consistent findings of immune dysfunction, demonstrated through aberrations in function and number of B- and T-lymphocytes and natural killer (NK) cells, suggest that ME/CFS is better classified as a neuroimmune disorder (4). It has also been suggested that ME/CFS is an autoimmune condition (10). A small number of studies in ME/CFS patients reported autoantibodies to neuroendocrine receptors and elevated CD20⁺ and CD21⁺ B lymphocytes, which are both commonly increased in patients with autoimmune diseases (10). No additional evidence of ME/CFS as an autoimmune disease has been reported. Furthermore, in a large ME/CFS cohort, clinical trials that used B-lymphocyte depletion found no improvement in symptoms (11). Changes in surface receptors, lytic proteins, degranulation, protein kinase phosphorylation, and cytokine production suggest that immune cell exhaustion plays a role in immunological symptoms of ME/CFS, including susceptibility to infection (12). Notably, T lymphocyte exhaustion also plays a role in recovery from COVID-19 and is associated with more severe outcomes for COVID-19 patients, and they persist in Long Covid. The only consistent immunological finding in ME/CFS patients is impaired NK cell cytotoxicity, which should be investigated further to understand the pathology of ME/CFS (12).

Immune dysfunction, cognitive and GI disturbances, and PENE in ME/CFS and Long Covid have been suggested to be associated, at least in part, with mitochondrial dysfunction. These include changes in mitochondrial structure, DNA, membrane potential, respiratory function, reactive oxygen species (ROS), antioxidant defense, metabolites, and coenzymes in plasma, urine, peripheral blood mononuclear cells (PBMCs), and isolated immune cells (9, 13). Changes in metabolite concentrations suggest disturbances in cellular energy production (9, 13). Conversely, mitochondrial adenosine triphosphate (ATP) concentrations and absolute ATP synthesis rates remained unchanged in PBMCs from ME/CFS patients compared with healthy controls (9). These findings are limited by the inclusion of patients who were diagnosed using criteria with low sensitivity for ME/CFS. Mitochondrial disturbances in both Long Covid and ME/CFS are believed to contribute to loss of cell activity. For example, lymphocytes exhibit impaired oxidative phosphorylation and increased ROS, contributing to immune exhaustion. However, further research is required to validate mitochondrial dysfunction as a biomarker of illness in patients with ME/CFS because current evidence is insufficient to determine causation.

An overlapping feature of these disruptions to the nervous, GI, and immune systems is calcium (Ca²⁺) signaling. Ca²⁺ is a universal second messenger that affects numerous biological processes in all cell types (9). Transient receptor potential (TRP) channels are a superfamily of nonselective ion channels with high permeability to Ca²⁺. Notably, TRP channels are widely expressed by cells composing multiple organ systems, including the nervous, musculoskeletal, cardiovascular, and GI systems, all of which are associated with symptoms reported by ME/CFS and Long Covid patients. The occurrence of ME/CFS as a result of abnormal ion channel function (a channelopathy) gained interest in the 1990s, and recently, TRP ion channels have been implicated in not only ME/CFS but also the pathology of Long Covid (4). Single-nucleotide polymorphisms have been identified to impair TRPM3 (also called melastatin) ion channel function and Ca²⁺ mobilization in NK cells of ME/CFS patients (9, 12). Impaired TRP channel function and Ca²⁺ signaling is likely to impede cell and mitochondrial function, resulting in cognitive, immune, and GI manifestations. There is no animal model of ME/CFS; thus, NK cells provide an accessible cell model with which to investigate TRP pathology in vitro. However, alterations in TRP ion channels are yet to be validated as an underlying cause of ME/CFS.

The difficulty in identifying the mechanism of ME/CFS means that there are limited internationally accepted treatments for patients. Rintatolimod is an immunomodulatory drug that is used off-label to restore NK cell cytotoxicity in ME/CFS to improve symptoms associated with immune exhaustion, such as persistent sore throat and tender lymph nodes. However, because only mild improvements have been reported in ∼40% of 412 patients across several clinical trials, rintatolimod has received orphan drug designation in the United States and is approved for severe cases of ME/CFS in limited countries (11). Other treatment interventions include antivirals, immunomodulators, analgesics, nutritional supplements, cognitive behavioral therapy, and graded exercise therapy to target specific symptoms. But a review reported insufficient evidence of the effectiveness of these interventions in improving symptoms (11), and many patients report susceptibility to side effects, thus posing further challenges to their care and studies of effective drugs (14). The lack of consistent findings is attributed to a low number of study samples, the use of nonspecific criteria for participation, and absent reporting of confounding variables, such as polypharmacy. More recently, promising results for the off-label use of low-dose naltrexone (LDN), an opioid receptor inhibitor used to treat drug and alcohol addiction, have been reported. Treatment of ME/CFS patients with LDN restored TRPM3 ion channel dysfunction in NK cells (11). Furthermore, 73.9% of 218 ME/CFS patients routinely taking LDN reported improved sleep and reduced pain and neurological disturbances (15). Although there is potential benefit in applying repurposed therapeutics in the treatment of ME/CFS, clinical trials are required to substantiate these claims.

An important research challenge is the lack of a validated biomarker, laboratory-based test, and animal model, likely attributed to inconsistency in protocols, such as cell isolation, sample type, and technique. These challenges provide important lessons for research of Long Covid. By developing interdisciplinary and consistent research protocols, the pathomechanism of ME/CFS and Long Covid can be elucidated. The recent interest in the overlap that exists between ME/CFS and Long Covid poses several questions, such as whether Long Covid predisposes a person to ME/CFS, and whether an individual has Long Covid or ME/CFS. Research into the etiology of ME/CFS and Long Covid should simultaneously identify the mechanism and diagnostic approach to both. ME/CFS poses a substantial health concern and has recently been taken more seriously since the emergence of Long Covid, and renewed focus on diagnostic, research, and treatment practices is needed.