Myalgic encephalomyelitis/chronic fatigue syndrome

• 1. Introduction

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  Myalgic encephalomyelitis/chronic fatigue syndrome, shortened to ME/CFS, is an illness in which an ordinary shower can set off a collapse. The resulting crash can last for months. The people who go through this are not out of shape, and they are not short of rest. They have a chronic, disabling illness. This documentary asks what that illness does to a body, and what researchers have found when they search for its roots. It asks why the condition has carried so many names, and why it has been argued over for decades. It asks how anyone is diagnosed when no laboratory test exists. It also asks what a person can actually do to live with it, and why research on it has received so little money.

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• 2. The Crash

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  Twelve to 48 hours is the usual delay between an activity and the moment its cost arrives for someone with ME/CFS. Doctors call this delayed worsening post-exertional malaise, or PEM, and it is the hallmark of the illness. Sometimes it strikes immediately instead. It can bring flu-like symptoms, pain, trouble thinking, stomach problems, nausea and disrupted sleep on top of deeper fatigue.

  Almost any effort can set it off, whether physical, mental, social or emotional. Attending a school event or shopping for food is enough for some people. For others, simply being in a stimulating environment does it. Patients call the result a crash or a flare-up. It can last hours, days, weeks or months, and a long one can become a prolonged relapse.

  The fatigue underneath is unlike ordinary tiredness. Early in the illness, patients often call it "flu-like," and many describe themselves as "wired but tired." Rest brings only limited relief. When an activity begins, muscle strength can drop quickly, causing clumsiness or sudden weakness. Compared with other conditions that involve fatigue, it lasts longer and is more severe.

  Sleep offers no repair either. People with ME/CFS wake up exhausted and stiff, even after a full night. Some have insomnia, some sleep excessively, and some have vivid nightmares.

  "Brain fog" is the phrase patients use for the thinking problems. They struggle to find words and names, to concentrate, to multitask and to hold on to short-term memories. Tests often show weaknesses in short-term visual memory, reaction time and reading speed. This cognitive dysfunction can be as disabling as the physical symptoms.

  Standing up brings its own trouble, called orthostatic intolerance. Nausea, lightheadedness and clouded thinking often ease after lying down. Some people have postural orthostatic tachycardia syndrome, or POTS, in which the heart rate climbs excessively after standing and can lead to fainting. Others see their blood pressure drop on standing.

  Pain is common too, including pain behind the eyes and in the neck, with no swelling or redness. Headaches and migraines may appear that never occurred before the illness. How much of all this a person endures differs enormously from one patient to the next.

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• 3. Scale and Severity

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  Roughly one in 150 people has ME/CFS, though the figure moves with the definition used. Under the 1994 CDC criteria, the global prevalence is 0.89%. Stricter definitions, such as the 2003 Canadian Consensus Criteria, produce only 0.17%. Before the COVID-19 pandemic, the range was two to nine people in every 1,000.

  In England and Wales, over 250,000 people are estimated to be affected, using data from before the pandemic. A 2021-2022 CDC survey found that 1.3% of American adults, or 3.3 million people, had ME/CFS. Women are diagnosed about 1.5 to four times as often as men. New cases peak twice, at ages 10-19 and again at 30-39, while the total number of people affected is highest in middle age.

  Severity is usually sorted into four categories. People with mild ME/CFS can still work and look after themselves, but they spend their free time recovering rather than socialising. Moderate illness makes daily tasks such as preparing a meal difficult, and most people at this level cannot work.

  Severe illness leaves a person homebound, able to manage only limited tasks such as brushing their teeth. Some use a wheelchair and spend most of the day in bed. At the very severe level, people are mostly bed-bound and cannot care for themselves. Roughly a quarter of patients are mild, half are moderate or moderate-to-severe, and a final quarter are severe or very severe.

  The most severe cases bring the most extreme symptoms. A person may lose the ability to speak, swallow or communicate at all because of cognitive problems. Touch, light, sound and smell can become unbearable. Severity can also shift over time, and someone who feels better may overextend and trigger a crash.

  On the SF-36 questionnaire, quality of life falls sharply in physical and social functioning, general health and vitality. Emotional functioning and mental health, however, are not much lower than in healthy people. Functional impairment can exceed that of multiple sclerosis, heart disease or lung cancer. Fewer than half of people with ME/CFS are employed, and roughly one in five has a full-time job.

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• 4. Searching for Causes

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  Between 60 and 80 percent of ME/CFS cases begin after an infection, most often a viral one. Infectious mononucleosis, caused by the Epstein-Barr virus, leads to ME/CFS in around 8 to 15 percent of those who catch it, depending on the criteria. Between 15 and 50 percent of people with long COVID also meet the diagnostic criteria. Influenza A subtype H1N1, the chickenpox virus and SARS-CoV-1 are also on the list.

  How a virus could cause lasting illness is unclear. One idea is viral persistence. Another is a "hit and run" mechanism, in which an infection throws the immune system off balance or provokes autoimmunity. Epstein-Barr virus is present in about 90% of people, usually dormant, and antibody levels against it are commonly higher in ME/CFS. That hints that dormant viruses, including human herpesvirus 6, may reactivate.

  Viruses are not the only reported triggers. Stress, traumatic events and exposure to mould appear in the literature, as do bacterial infections such as Q fever. Physical trauma from an accident or surgery can precede onset. Pregnancy was reported as the trigger in around 3% to 10% of cases. Some cases build through several minor events, followed by a final one that marks a clear start.

  Genes seem to play a part, since the illness runs in families. Yet no single gene is known to be responsible. A 2020 review of published gene studies found no strong, reliable links. The likelier picture is many variants, each with a small effect, that add up to a strong one.

  In the United States, white Americans are diagnosed more often than other groups, but ME/CFS is probably at least as common among African Americans and Hispanics. It was once thought to favour higher incomes. Poorer nutrition, weaker healthcare access and work stress may instead raise the risk for lower-income and minority groups.

  The source of the illness has been traced, at least partly, to the body's major systems. Brain imaging often finds changes in the brainstem and extra brain areas recruited for thinking tasks. Neuroinflammation has been proposed as an explanation, but two small positron emission tomography studies of microglia, the brain's immune cells, gave contradictory results.

  In the immune system, the most consistent finding is weakened function in natural killer cells, which target virus-infected cells and tumour cells. T cells show less metabolic activity and may be exhausted. Some patients have raised autoantibodies to muscarinic acetylcholine receptors and β2 adrenergic receptors, which can impair blood flow. Researchers also report an unusual pattern in the hypothalamic-pituitary-adrenal axis hormones, including lower cortisol.

  The 2-day cardiopulmonary exercise test offers an objective sign of PEM. On the first day, people with ME/CFS perform below healthy controls. On the second, healthy people hold steady or improve slightly, while patients show a clinically significant drop in work rate at the anaerobic threshold. Studies of mitochondria, the cell's power plants, show abnormalities. ATP, the cell's main energy carrier, is likely made more often from lipids and amino acids than from carbohydrates, though differences between studies make firm conclusions hard.

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• 5. A Contested Name

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  In 1934, an unfamiliar illness began appearing in outbreaks across the world, and at first it was mistaken for polio. A 1950s outbreak at London's Royal Free Hospital led to the term "benign myalgic encephalomyelitis." Patients had malaise, a sore throat, pain and signs of nervous system inflammation. The illness appeared both in epidemics and in isolated cases. Its infectious nature was suspected, but the cause stayed elusive.

  The World Health Organization has classed the disease as neurological since 1969, under that first name. Then in 1970, two UK psychiatrists proposed that the outbreaks were psychosocial phenomena, suggesting mass hysteria or altered medical perception. The idea was challenged, but it cast doubt on the illness in the medical community for years.

  Melvin Ramsay's later research stressed how disabling the illness was, and "benign" was dropped from the name. Diagnostic criteria followed in 1986, noting muscles that tire after minor effort and take days to recover, great variability and chronicity. A UK report affirmed that the illness was not psychological. Scepticism lingered, however, and research stayed limited.

  Across the Atlantic, Nevada and New York State saw outbreaks in the middle of the 1980s that resembled mononucleosis. Patients reported "chronic or recurrent fatigue" along with many other symptoms. Elevated antibodies to the Epstein-Barr virus first led to the name "chronic Epstein-Barr virus syndrome." When studies could not confirm a viral cause, the CDC renamed it chronic fatigue syndrome. A first case definition appeared in 1988, and the CDC published new criteria in 1994 that became widely referenced.

  Most people with the illness object to "chronic fatigue syndrome," a name formalised in 1988. They find it simplistic, and they feel it trivialises their symptoms and keeps the illness from being taken seriously. The older name is not free of problems either. Myalgia means muscle pain and encephalomyelitis means inflammation of the brain and spinal cord, yet evidence for brain inflammation is limited.

  The combined term ME/CFS keeps the familiar phrase without trivialising the disease. Even so, some object, believing the older criteria for ME and for CFS describe separate illnesses. In the WHO's ICD-11, both names sit under post-viral fatigue syndrome. A 2015 report from the US Institute of Medicine recommended yet another name, systemic exertion intolerance disease, or SEID. It was rarely used, and patients mostly disliked it, because it too focused on a single symptom. The CDC did adopt the report's diagnostic criteria.

  That same 2015 report described ME/CFS as a "serious, chronic, complex systemic disease." The US National Institutes of Health then published its Pathways to Prevention report, which set research priorities. Together, these two documents drove the wider recognition that began in the 2010s.

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• 6. Diagnosis by Elimination

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  No blood test, scan or other laboratory procedure can confirm ME/CFS. Doctors instead take a medical history and perform a mental and physical examination. Blood and urine tests mainly serve to rule out other explanations. Symptoms typically last three to six months before a diagnosis can be confirmed, and many patients wait far longer. Some are never diagnosed at all.

  The 1994 CDC criteria, often called the Fukuda criteria, require six months of persistent or relapsing fatigue plus four of eight other symptoms. PEM and cognitive problems are not mandatory, so people with very different illnesses can qualify. The Canadian Consensus Criteria of 2003 require PEM, fatigue, sleep problems, pain, and neurological or cognitive issues. They also demand symptoms from at least two of three categories: orthostatic, thermal instability and immunological.

  The International Consensus Criteria of 2011 define the illness by symptom clusters with no minimum duration. Like the Canadian criteria, they pick out more severely ill people. The 2015 Institute of Medicine criteria were built to be easy for clinicians. They require fatigue, PEM, non-restorative sleep, and either cognitive problems or orthostatic intolerance. The fatigue must last at least six months, and symptoms must be present at least half of the time and be of moderate severity or worse. In 2021, NICE revised its own criteria, based on the IOM criteria, with a three-month threshold.

  Because there are no verified biomarkers, nobody can say which criteria are the most accurate. The choice is a trade-off between overdiagnosis and missed cases. The broad Fukuda criteria risk overdiagnosis, the strict International criteria risk missing people, and the IOM and NICE criteria sit in the middle.

  Children get separate criteria with shorter durations. The Canadian definition asks for three months of symptoms in a child, against six months in an adult. NICE asks for four weeks to suspect the illness in children and six weeks in adults.

  Screening can use the DePaul Symptom Questionnaire, and patients may be asked to keep a symptom diary. A physical exam can look entirely normal, especially if the person has rested heavily before the visit. Standard tests include an HIV test and blood work for blood count, sedimentation rate, C-reactive protein, glucose and thyroid-stimulating hormone. Serum ferritin is worth checking because borderline anaemia can worsen symptoms.

  Orthostatic intolerance can be measured with a tilt table test. When that is unavailable, the simpler NASA 10-minute lean test checks the response to prolonged standing. The two-day exercise test can document the illness and may support a disability claim, but it can also cause severe PEM.

  Many other conditions look similar. Infectious diseases such as Lyme disease, diabetes, hypothyroidism, anaemia, lupus, narcolepsy and multiple sclerosis all appear on the list of possibilities. Fibromyalgia overlaps so heavily that the two are often diagnosed together. Hypermobile Ehlers-Danlos syndrome also co-occurs often, but unlike ME/CFS it is present from birth.

  Depression can be told apart by feelings of worthlessness, loss of pleasure and loss of interest, and by the absence of bodily symptoms such as PEM. Someone whose chronic fatigue is unexplained by ME/CFS or any other illness may receive the label idiopathic chronic fatigue.

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• 7. Pacing and Its Limits

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  The technique called pacing was developed for ME/CFS in the 1980s. It means balancing rest with activity so that a person stays inside an individual energy envelope and avoids the PEM payback of overexertion. Tasks are broken into smaller pieces, extra breaks are taken, and chores are redesigned, such as sitting down while doing laundry. A heart rate monitor helps some people. Studies of pacing mostly report benefits, but they have been small and have rarely checked whether participants truly paced well.

  Pacing is hard to apply when the illness is very severe, because triggers such as eating cannot be avoided. People with stable illness who learn to "listen to their body" may carefully raise their activity level. Intense exercise, so useful in many chronic illnesses, is not recommended here. The CDC states: "Vigorous aerobic exercise can benefit people with many chronic illnesses. But people with ME/CFS do not tolerate such exercise routines."

  Graded exercise therapy, built on the assumption that deconditioning and fear of activity maintain the illness, is no longer recommended. Reviews found either weak evidence of a small to moderate effect or none, and it can have serious adverse effects. A form of cognitive behavioural therapy that assumed unhelpful beliefs keep the illness going has also been dropped.

  With no approved drug, care focuses on symptoms, and a primary care clinician often coordinates health, social and school support. Sleep problems start with better sleep habits, then cognitive behavioural therapy for insomnia. Drugs used for insomnia in fibromyalgia, such as trazodone or suvorexant, may also help. Pain is first treated with ibuprofen or paracetamol, then a pain specialist, with pregabalin as one option borrowed from fibromyalgia. Heat, hydrotherapy and gentle massage can ease pain, but stretching and exercise must be balanced against the risk of PEM.

  Salt, extra fluid and compression stockings can help with orthostatic intolerance. Cutting caffeine, alcohol, gluten or dairy helps some people with bowel problems. People with ME/CFS may react unusually strongly to medications, especially those affecting the central nervous system.

  Severe illness calls for home adaptations such as shower chairs, stair lifts and wheelchairs. Perfume-free surroundings, eye masks and earplugs reduce sensory overload. Some patients need intravenous or tube feeding, and those who cannot move in bed need repositioning to prevent pressure sores and stiff joints. Severe ME/CFS can be misread as neglect or abuse during well-being checks, so NICE recommends that professionals with experience in the illness join any safeguarding assessment.

  Full recovery is uncommon, and symptoms generally fluctuate over days, weeks or longer. A large retrospective study found no increase in deaths from all causes, though death from suicide was significantly higher. In extreme cases, people can die from the illness itself.

  Children and teenagers fare better than adults. An Australian study of 6- to 18-year-olds found that two-thirds reported recovery after 10 years, with a typical illness duration of five years.

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• 8. Disbelief and Funding

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  A retrovirus called XMRV once looked like an answer. One study reported a causal link, and some patients began taking antiretroviral drugs developed for HIV/AIDS. National blood supplies were suspected of carrying the virus. After several years of study, the XMRV findings were traced to contamination of the testing materials.

  The 2011 PACE trial, the largest on behavioural interventions, concluded that graded exercise therapy and CBT were moderately effective. Critics pointed out that the authors weakened their definition of recovery during the trial, so some participants met a key recovery criterion before it began. A reanalysis under the original protocol found no significant difference in recovery between the treatment groups and those receiving standard care.

  Most people with ME/CFS report negative experiences with healthcare. Many feel their doctor wrongly calls the illness psychological, or feel forced to prove they are truly ill. Medical school often does not fully cover the illness, so patients may go undiagnosed for years or be misdiagnosed with mental health conditions. As patients learn more, some build a partnership with their doctors, while for others the relationship deteriorates as the gap in knowledge closes.

  Social life suffers as well. Disbelief from family and friends, who may doubt a diagnosis that rests on symptoms, deepens the isolation, and thoughts of suicide are high among those without supportive care. Children miss the growing independence of adolescence and depend more on their families. Caring for someone can become a full-time role.

  In the United States, the yearly economic cost is estimated at $36 to $51 billion, counting lost wages and healthcare. A 2017 estimate for the United Kingdom put the annual burden at £3.3 billion.

  In 2015, the US National Academy of Sciences said that "remarkably little research funding" had gone to the illness's causes, mechanisms and treatment. A study of the NIH, the largest biomedical funder in the world, found that ME/CFS received only 3% to 7% of the average disease's funding per healthy life year lost between 2015 and 2019. Multiple sclerosis, which affects fewer people and causes disability no worse, received 20 times as much worldwide between 2007 and 2015. Funding cuts to Columbia University during the second Trump administration closed a large research program on the disease.

  Several explanations have been proposed. Diseases for which society "blames the victim" are frequently underfunded, and the historical belief in psychological causes may have played that role. Gender bias may contribute, since the NIH spends less on diseases that mostly affect women. Drug companies have invested very little.

  Patient organisations have pushed back, much as AIDS activists did in the 1980s, and some publish research themselves. Citizen scientists helped start discussions about weaknesses in trials of psychological treatments. ME/CFS International Awareness Day falls on the 12th of May, the birthday of Florence Nightingale, who had an unidentified illness similar to ME/CFS.

  The emergence of long COVID has revived interest, since the two conditions may share pathology. Rintatolimod gave a small reduction in symptoms in several trials, though the gains faded after treatment stopped, and it has been approved in Argentina. Rituximab, which depletes B cells, proved ineffective. Natural killer cells are a promising area for biomarker research, because their abnormalities are consistent. In the United Kingdom, a larger genetics study called DecodeME is now underway.

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