Myalgic Encephalomyelitis/Chronic Fatigue Syndrome—Metabolic Disease or Disturbed Homeostasis due to Focal Inflammation in the Hypothalamus?

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease characterized by debilitating fatigue, lasting for at least 6 months, with associated malaise, headaches, sleep disturbance, and cognitive impairment, which severely impacts quality of life. A significant percentage of ME/CFS patients remain undiagnosed, mainly due to the complexity of the disease and the lack of reliable objective biomarkers. ME/CFS patients display decreased metabolism and the severity of symptoms appears to be directly correlated to the degree of metabolic reduction that may be unique to each individual patient. However, the precise pathogenesis is still unknown, preventing the development of effective treatments. The ME/CFS phenotype has been associated with abnormalities in energy metabolism, which are apparently due to mitochondrial dysfunction in the absence of mitochondrial diseases, resulting in reduced oxidative metabolism. Such mitochondria may be further contributing to the ME/CFS symptomatology by extracellular secretion of mitochondrial DNA, which could act as an innate pathogen and create an autoinflammatory state in the hypothalamus. We propose that stimulation of hypothalamic mast cells by environmental, neuroimmune, pathogenic and stress triggers activates microglia, leading to focal inflammation in the brain and disturbed homeostasis. This process could be targeted for the development of novel effective treatments.

Leveraging Prior Knowledge of Endocrine Immune Regulation in the Therapeutically Relevant Phenotyping of Women With Chronic Fatigue Syndrome

“…Mitochondrial dysfunction has also been identified in patients with ME/CFS, 66 and the extracellular release of mitochondrial DNA in the hypothalamus has been proposed as an initiator of neuroinflammation via mast cell activation. 67 These activated mast cells may then go on to establish a self-sustaining positive feedback of neuroinflammation and autoimmunity, 68e70 with further complex interactions with other endocrine systems. 71,72 Our approach is independent of any assumptions about the ultimate underlying cause of ME/CFS.…”

Glial Activation and Expression of the Serotonin Transporter in Chronic Fatigue Syndrome

“…Nevertheless, the reader should be aware that we do not know if these metabolic changes are a cause or a consequence of CFS. Recently, the question has been raised whether CFS is a metabolic disease or the result of disturbed homeostasis, and a multiplicity of physiological/pathophysiological factors related to CFS have been listed ( 36 ). On the other hand, a new concept called circadian metabolomics, the relationship between circadian rhythms and energy metabolism, has been proposed to explain circadian rhythm abnormalities in CFS patients ( 8 ).…”

Myalgic encephalomyelitis - enigma at the medicine’s crossroads

“…Extreme fatigue in ME/CFS, might be the result of energy production disturbances leading to exertion intolerance [2]. Some evidence leads to autonomic nervous system dysfunction such as orthostatic hypotension or tachycardia, at least in some ME/CFS patients [18].…”

“…Myalgic encephalomyelitis (ME) with chronic fatigue syndrome (CFS) (myalgic encephalomyelitis/chronic fatigue syndrome / ME/CFS)or systemic exertion intolerance disease (SEID)is a multifaceted condition involving muscular, nervous, hormonal, and immune systems [1,2]. Patients have difficulties with sleep and attention, experience pain and dizziness, and have extreme fatigue not accountable to any other medical condition [3].Myalgic encephalomyelitis can be incapacitating and often affects activities of daily living, sometimes making patients immobile (up to 25%).…”