HOW TO TREAT 35
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HOW TO TREAT 35
Commonly reported preceding exposures or events are linked with the development of ME / CFS, including stress, injury, infection, exposure to toxic mould and vaccination. Genetic mutations and a familial risk have also been reported.
Adapted using BioRender. com
Figure 2. Model depicting how the combined effect of environmental insults and stress in genetically susceptible individuals can trigger neurological, immune and metabolic dysfunction, which together could contribute to the symptomology observed in ME / CFS.
PVN: paraventricular nucleus; POTS: postural orthostatic tachycardia syndrome; NK cell: natural killer cells; IFNγ: interferon‐gamma; IL2: interleukin-2; NKG2A: natural killer cell receptor G2A; PD1: programmed cell death protein 1; TIM3: T-cell immunoglobulin and mucin domain 3 fatigue, including, but not limited to, psychiatric disorders, hypo- and hyperthyroidism, diabetes mellitus, sleep apnoea, rheumatoid arthritis, SLE, MS, Parkinsonism, myasthenia gravis, chronic hepatitis, cardiovascular disease, metabolic conditions, long COVID, Gulf War illness( with symptoms of muscle aches, joint pain, dizziness, memory lapses, headaches, gastrointestinal problems, respiratory complaints, fatigue and insomnia) and previously treated or current malignancies. 28, 29, 31 However, numerous comorbidities coexist with ME / CFS. These include fibromyalgia, myofascial pain syndrome, postural orthostatic tachycardia syndrome( POTS), temporomandibular joint syndrome, irritable bowel syndrome, interstitial cystitis, irritable bladder syndrome, situational depression, multiple chemical sensitivities, sicca
28, 29 syndrome and thyroiditis.
The DePaul Symptom Questionnaire for ME / CFS can be used as a screening tool to capture key symptoms required for diagnosis and to provide a scale regarding the severity of these symptoms. 32 Defining characteristics of symptoms include those in figure 1 and box 1). 5
Many of the symptoms listed in box 1 are not specific to ME / CFS, and there is no validated diagnostic test. Standard laboratory testing will typically return normal results. 5 According to the NICE guidelines, recommended laboratory testing includes an FBC with white blood cell differential; ESR; CRP; blood glucose; a basic metabolic panel to measure electrolytes, creatinine and blood urea nitrogen; TSH; total protein and LFTs. Subsequent laboratory testing may be used to exclude differential diagnoses, including antinuclear antibodies for SLE; antibody testing for coeliac disease; and serology for infectious diseases, including EBV, hepatitis B and C, and HIV.
PATHOMECHANISM
NEUROLOGICAL disturbances
Box 1. Defining characteristics of symptoms
• Chronic fatigue:— Persistent for more than six months, is of new or definite onset and is not alleviated by rest.
• PEM( also used interchangeably with post-exertional neuroimmune exhaustion):— A marked, rapid physical / cognitive fatigue in response to exertion.— Post-exertional exacerbation of other symptoms.— Immediate or delayed post-exertional exhaustion.— Prolonged recovery period of more than 24 hours.— A lack of stamina that results in a substantial reduction in pre-illness activity level.
• Sleep dysfunction:— Inability to fall asleep, early awakening, prolonged sleep, day / night reversal or frequent naps.
• Pain:— Widespread or migratory pain, myofascial pain, arthralgia and stiffness, abdominal pain, headaches that are more frequent or more severe and migraines.
• Neurological impairments:— Difficulty processing information, short-term memory loss, difficulty finding the right word, slowed thoughts, difficulty recalling information.
• Neurosensory and motor disturbances:— Inability to focus vision; sensitivities to lights, odours or taste; muscle weakness; poor co-ordination.
• Endocrinological disturbances:— Abnormal weight gain / loss, hormone disturbances.
• Autonomic manifestations:— Orthostatic intolerance, disturbance in balance, dyspnoea.
• Genitourinary impairment:— Frequent urination, urgency, changes in urine volume.
• Gastrointestinal complaints:— Irritable bowel syndrome, altered bowel habits, bloating, frequent nausea.
• Thermostatic instability:— Intolerance to extreme temperatures, cold extremities, recurrent fever and / or chills, sweating episodes, subnormal body temperature.
• Immunological disturbances:— Flu-like symptoms, susceptibility to viral infections with prolonged recovery, sensitivities to food, medications or chemicals.
— such as cognitive impairment, autonomic dysfunction, altered pain and sensory perception, and sleep disturbances— are hallmark symptoms of ME / CFS. 29 There is a large body of evidence detailing neurological disturbances through neuroimaging techniques, but it is important to highlight that data are sometimes equivocal.
Current literature has documented changes in grey and white matter volumes, brain structures
( see figure 3), cerebral blood flow, EEG activity, and functional connectivity. 33 Primary regions of interest include reduced bilateral prefrontal cortex, occipital lobes, right angular gyrus and parahippocampal gyrus volume. 34, 35 Neuroimaging techniques are not used as a diagnostic tool for ME / CFS; instead, they are requested to exclude overlapping neurological conditions.
The presentation of symptoms, including fatigue, is associated with changes in functional connectivity— as reported in functional MRI investigations. 33
The role of neuroinflammation is also postulated, following activation of glial cells reported in PET and magnetic resonance spectroscopy investigations. 36
The role of inflammation in ME / CFS is highlighted by the occurrence of immunological symptoms— for example, flu-like symptoms— and research reporting on changes in cytokine profiles and lymphocyte function. Low-grade inflammation is supported by altered cytokine profiles through changes in pro-and anti-inflammatory cytokines. However, cytokine profiles in the role of the pathomechanism of ME / CFS are equivocal. 39 Research has reported significantly reduced T-cell function, autoreactive cells and impaired natural killer cell cytotoxic function( see figure 4). 3, 40
Further, inflammatory processes are associated with systemic disturbances. For example, gut permeability— also referred to as leaky gut— is the translocation of bacteria into the bloodstream, resulting in systemic immune responses. Increased gut permeability provides a method for pro-inflammatory lipopolysaccharide translocation to circulation, which results in inflammasome activation.
Further theories propose an alteration in intestinal microbiota, causing dysbiosis and altered gut – brain communication( see figure 5). However, extensive review of the literature identifies inconsistencies between ME / CFS patients and healthy cohorts. 3 Collectively, these data are inconsistent and inconclusive. 41
The role of mitochondrial dysfunction is an area of interest in ME / CFS as according to more recent diagnostic criteria, impaired energy metabolism is a key symptom category. Biological antioxidant potential measurements and reactive oxygen species are elevated in ME / CFS compared with healthy individuals. 42 Impeded antioxidant capacity has also been reported in ME / CFS patients. 43 However, a systematic review found inconsistent evidence, and further research may elucidate the possible role of mitochondrial dysfunction. 3
An overview of potential pathomechanisms reported in ME / CFS research appears in table 2.