a misconception that diagnosing me/cfs worsens prognosis, and that accurate diagnosis is key to appropriate management.: 222 : 235 pathophysiology me/cfs is associated with changes in several areas, including the nervous, immune, and endocrine systems. reported neurological differences include altered brain structure and metabolism, and autonomic nervous system dysfunction. observed immunological changes include decreased natural killer cell activity, increased cytokines, and slightly increased levels of certain antibodies. endocrine differences, such as modestly low cortisol and hpa axis dysregulation, have been noted as well. impaired energy production and the possibility of autoimmunity are other areas of interest. neurological brain imaging, comparing adolescents with cfs and healthy controls showing abnormal network activity in regions of the brain.a range of neurological structural and functional abnormalities is found in people with cfs, including lowered metabolism at the brain stem and reduced blood flow to cortical areas of the brain; these differences are consistent with neurological illness, but not depression or psychological illness. the world health organization classes chronic fatigue syndrome as a central nervous system disease. some neuroimaging studies have observed prefrontal and brainstem hypometabolism; however, sample size was limited. neuroimaging studies in persons with cfs have identified changes in brain structure and correlations with various symptoms. results were not consistent across the neuroimaging brain structure studies, and more research is needed to resolve the discrepancies found between the disparate studies. tentative evidence suggests a relationship between autonomic nervous system dysfunction and diseases such as cfs, fibromyalgia, irritable bowel syndrome, and interstitial cystitis. however, it is unknown if this relationship is causative. reviews of cfs literature have found autonomic abnormalities such as decreased sleep efficiency, increased sleep latency, decreased slow wave sleep, and abnormal heart rate response to tilt table tests, suggesting a role of the autonomic nervous system in cfs. however, these results were limited by inconsistency. central sensitization, or increased sensitivity to sensory stimuli such as pain have been observed in cfs. sensitivity to pain increases after exertion, which is opposite to the normal pattern. immunological immunological abnormalities are frequently observed in those with cfs. decreased nk cell activity is found more often in people with cfs and this correlates with severity of symptoms. people with cfs have an abnormal response to exercise, including increased production of complement products, increased oxidative stress combined with decreased antioxidant response, and increased interleukin 10, and tlr4, some of which correlates with symptom severity. increased levels of cytokines have been proposed to account for the decreased atp production and increased lactate during exercise; however, the elevations of cytokine levels are inconsistent in specific cytokine, albeit frequently found. similarities have been drawn between cancer and cfs with regard to abnormal intracellular immunological signaling. abnormalities observed include hyperactivity of ribonuclease l, a protein activated by ifn, and hyperactivity of nf-κb. endocrine evidence points to abnormalities in the hypothalamic-pituitary-adrenal axis (hpa axis) in some, but not all, persons with cfs, which may include slightly low cortisol levels, a decrease in the variation of cortisol levels throughout the day, decreased responsiveness of the hpa axis, and a high serotonergic state, which can be considered to be a "hpa axis phenotype" that is also present in some other conditions, including post-traumatic stress disorder and some autoimmune conditions. it is unclear whether or not decreased cortisol levels of the hpa axis plays a primary role as a cause of cfs, or has a secondary role in the continuation or worsening of symptoms later in the illness. in most healthy adults, the cortisol awakening response shows an increase in cortisol levels averaging 50% in the first half-hour after waking. in people with cfs, this increase apparently is significantly less, but methods of measuring cortisol levels vary, so this is not certain. autoimmunity autoimmunity has been proposed to be a factor in cfs, but there are only a few relevant findings so far. there are a subset of patients with increased b cell activity and autoantibodies, possibly as a result of decreased nk cell regulation or viral mimicry. in 2015, a large german study found 29% of me/cfs patients had elevated autoantibodies to m3 and m4 muscarinic acetylcholine receptors as well as to ß2 adrenergic receptors. a 2016 australian study found that me/cfs patients had significantly greater numbers of single nucleotide polymorphisms associated with the gene encoding for m3 muscarinic acetylcholine receptors. energy metabolism studies have observed mitochondrial abnormalities in cellular energy production, but recent focus has concentrated on secondary effects that may result in aberrant mitochondrial function because inherent problems with the mitochondria structure or genetics have not been replicated. diagnosis could you have me/cfs? from us centers for disease control no characteristic laboratory abnormalities are approved to diagnose cfs; while physical abnormalities can be found, no single finding is considered sufficient for diagnosis. blood, urine, and other tests are used to rule out other conditions that could be responsible for the symptoms. the cdc states that a medical history should be taken and a mental and physical examination should be done to aid diagnosis. diagnostic tools the cdc recommends considering the questionnaires and tools described in the 2015 institute of medicine report, which include: the chalder fatigue scale multidimensional fatigue inventory fisk fatigue impact scale the krupp fatigue severity scale depaul symptom questionnaire cdc symptom inventory for cfs work and social adjustment scale (wsas) sf-36 / rand-36: 270 a two-day cardiopulmonary exercise test (cpet) is not necessary for diagnosis, although lower readings on the second day may be helpful in supporting a claim for social security disability. a two-day cpet cannot be used to rule out chronic fatigue syndrome.: 216 definitions main article: clinical descriptions of chronic fatigue syndrome many sets of diagnostic criteria for cfs have been proposed. required symptoms vary, with post-exertional malaise, fatigue, cognitive impairment, and sleep disruption being the most commonly cited. notable definitions include: centers for disease control and prevention (cdc) definition (1994), the most widely used clinical and research description of cfs, is also called the fukuda definition and is a revision of the holmes or cdc 1988 scoring system. the 1994 criteria require the presence of four or more symptoms beyond fatigue, while the 1988 criteria require six to eight. the 2003 canadian consensus criteria state: "a patient with me/cfs will meet the criteria for fatigue, post-exertional malaise and/or fatigue, sleep dysfunction, and pain; have two or more neurological/cognitive manifestations and one or more symptoms from two of the categories of autonomic, neuroendocrine, and immune manifestations; and the illness persists for at least 6 months". the myalgic encephalomyelitis international consensus criteria (icc) published in 2011 is based on the canadian working definition and has an accompanying primer for clinicians the icc does not have a six months waiting time for diagnosis. the icc requires post-exertional neuroimmune exhaustion (pene) which has similarities with post-exertional malaise, plus at least three neurological symptoms, at least one immune or gastrointestinal or genitourinary symptom, and at least one energy metabolism or ion transportation symptom. unrefreshing sleep or sleep dysfunction, headaches or other pain, and problems with thinking or memory, and sensory or movement symptoms are all required under the neurological symptoms criterion. according to the icc, patients with post-exertional neuroimmune exhaustion but only partially meeting the criteria should be given the diagnosis of atypical myalgic encephalomyelitis. the 2015 definition by the national academy of medicine (then referred to as the "institute of medicine") is not a definition of exclusion (differential diagnosis is still required). "diagnosis requires that the patient have the following three symptoms: 1) a substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities, that persists for more than 6 months and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest, and 2) post-exertional malaise* 3) unrefreshing sleep*; at least one of the two following manifestations is also required: 1) cognitive impairment* 2) orthostatic intolerance" and notes that "*frequency and severity of symptoms should be assessed. the diagnosis of me/cfs should be questioned if patients do not have these symptoms at least half the time with moderate, substantial, or severe intensity." the 2021 uk nice guidelines employ a definition of me/cfs that requires severe fatigue, post-exertional malaise, unrefreshing sleep or sleep disturbance, and cognitive difficulties. differential diagnosis certain medical conditions can cause chronic fatigue and must be ruled out before a diagnosis of cfs can be given. hypothyroidism, anemia, coeliac disease (that can occur without gastrointestinal symptoms), diabetes and certain psychiatric disorders are a few of the diseases that must be ruled out if the patient presents with appropriate symptoms. other diseases, listed by the centers for disease control and prevention, include infectious diseases (such as epstein–barr virus, influenza, hiv infection, tuberculosis, lyme disease), neuroendocrine diseases (such as thyroiditis, addison's disease, adrenal insufficiency, cushing's disease), hematologic diseases (such as occult malignancy, lymphoma), rheumatologic diseases (such as fibromyalgia, polymyalgia rheumatica, sjögren's syndrome, lupus, giant-cell arteritis, polymyositis, dermatomyositis), psychiatric diseases (such as bipolar disorder, schizophrenia, delusional disorders, dementia, anorexia/bulimia nervosa), neuropsychologic diseases (such as obstructive sleep apnea, narcolepsy, parkinsonism, multiple sclerosis), and others (such as nasal obstruction from allergies, sinusitis, anatomic obstruction, autoimmune diseases, cancer, chronic hepatitis, some chronic illness, alcohol or other substance abuse, pharmacologic side effects, heavy metal exposure and toxicity, marked body weight fluctuation). like cfs, fibromyalgia causes muscle pain, severe fatigue and sleep disturbances. the presence of allodynia (abnormal pain responses to mild stimulation) and extensive tender points in specific locations differentiates fibromyalgia from cfs, although the two diseases often co-occur. ehlers–danlos syndromes (eds) may also have similar symptoms. medications can also cause side effects that mimic symptoms of cfs. depressive symptoms, if seen in cfs, may be differentially diagnosed from primary depression by the absence of anhedonia, decreased motivation, or guilt; and the presence of bodily symptoms such as sore throat, swollen lymph nodes, and post-exertional malaise. management main article: chronic fatigue syndrome treatment there is no approved pharmacological treatment, therapy or cure for me/cfs, although some symptoms can be treated or managed. according to the cdc, pacing, or managing one's activities to stay within their energy limits, can reduce episodes of post-exertional malaise. addressing sleep problems with good sleep hygiene, or medication if required, may be beneficial. chronic pain is common in me/cfs, and the cdc recommends consulting with a pain management specialist if over-the-counter painkillers are insufficient. the debilitating nature of me/cfs can cause depression or other psychological problems, which should be treated accordingly. for cognitive impairment, adaptations like organizers and calendars may be helpful. comorbid conditions are common and should be treated if present. according to the national institute for health and clinical excellence (nice), graded exercise therapy (get) is not an appropriate treatment for me/cfs. cbt might be offered to help a person manage the difficulties of dealing with chronic illness, but not as a cure for me/cfs. the cdc recommends a strategy treating the most disabling symptom first, and the nice guideline specifies the need for shared decision-making between patients and medical teams. nice recognized that symptoms of severe me/cfs may be misunderstood as neglect or abuse and recommends assessment for safeguarding of persons suspected of having me/cfs be evaluated by professionals with experience and understanding of the illness. clinical management varies widely, with many patients receiving combinations of therapies.: 9 prior to publication of the nice 2021 guideline, andrew goddard, president of the royal college of physicians, stated there was concern nice did not adequately consider the experts' support and evidence of the benefits of get and cbt, and urged they be included in the guideline. various me/cfs patient groups disputed the benefits of the therapies and stated that get can make the illness more severe. comorbid conditions that may interact with and worsen me/cfs symptoms care are common, and appropriate medical intervention for these conditions may be beneficial. the most commonly diagnosed include fibromyalgia, irritable bowel syndrome, depression, anxiety, allergies, and chemical sensitivities. pacing pacing, or activity management, is an illness management strategy based on the observation that symptoms tend to increase following mental or physical exertion, and was recommended for cfs in the 1980s. it is now commonly used as a management strategy in chronic illnesses and in chronic pain. its two forms are