Primer for doctors and researchers

Chronic Fatigue Syndrome (CFS) is also known as Myalgic Encephalomyelitis (ME) or ME/CFS. Chronic fatigue is a symptom of many diseases, illnesses, depression and drug therapies and the term is not interchangeable with the grossly misnamed disease CFS.

Disease onset and lifelong illness
ME/CFS usually begins with a flu-like illness, EBV, HHV, Q fever, Virus or other infections. Patient health is never the same and they experience numerous symptoms and disease severity which fluctuate day to day, week to week, month to month, year to year and decade to decade as well as varying symptoms and disease severity among patients.

Symptoms
Symptom presentation varies enormously between individuals. Symptom presentation also varies within individuals, as individuals often report that symptoms change over time (increasing or decreasing) and new symptoms may appear while others disappear. There are many symptoms which people with ME/CFS experience, though those listed below are arguably the most common:
 * Post-exertional malaise (PEM) is the hallmark symptom of ME/CFS. After physical or mental exertion (which for some patients can be a shower or making out a to-do list, others grocery shopping, socializing or reading a news article, while some just walking to the mailbox, getting to the doctor or mentally following a T.V. program) there is a payback which can be delayed 24-48 hours and can last 24 hours or more. The patient will experience even greater fatigue as well as exasperating the flu-like symptoms and body pain.  Every patient experiences different symptoms and symptom severity from different activities and exertion output according to how sick he or she is with the disease.


 * Regarding PEM the CFIDS Association of America states: "This is a term which describes a symptom in which exercise or exertion can bring on malaise (illness). In the case of people with ME/CFS, malaise often occurs during a period some 24-72 hours after exertion. For example, in some cases, a short walk can worsen ME/CFS symptoms two days later. This lack of understanding about the delayed onset of symptoms has, in the past, made it harder to test for ME/CFS. Follow up tests, taken less than 24 hours after an initial exercise test, may show that the patient can still perform activities at the same level (before post exertional malaise has a chance to take hold)."


 * Chronic fatigue
 * Chronic pain
 * Cognitive dysfunction
 * Unrefreshing sleep, and sleep disturbance
 * Orthostatic intolerance, such as Postural orthostatic tachycardia syndrome (POTS) or Neurally mediated hypotension (NMH)
 * Neuroinflammation
 * Neurological disturbances such as muscle spasms, numbness/tingling, sensory overload

Biological abnormalities
Because there is currently no biomedical test for ME/CFS, many have incorrectly assumed that there are no medical abnormalities found in people with the condition. As a result, ME/CFS symptoms are often considered to be medically unexplained, and therefore psychological in origin. Whilst it is true that the condition is poorly understood, many biological abnormalities have been found in a range of different body systems, particularly in the Central Nervous System, Autonomic Nervous System, Immune system and energy metabolism. Unfortunately, none have yet proved to be specific enough to ME/CFS as to be useful as a biomarker of the condition, and many were identified in small studies, which need replication. Whilst there have been abnormalities identified to be associated with the condition, it cannot yet be determined whether these are a cause or consequence of the condition.


 * Neuroinflammation Japanese Neuroinflammation study, Younger's Leptin study
 * Reduced brain white matter study by Stanford ME/CFS Initiative New York Times Article with brain images. Three major brain abnormalities.
 * Immune findings: Mady Hornig & Ian Lipkin
 * Metabolic features of chronic fatigue syndrome by the Open Medicine Foundation show blood chemical signature.
 * Autonomic nervous system:
 * Natural killer cell findings
 * Gut dysbiosis
 * Rituximab

Epidemiology
Prevalence estimates for ME/CFS range between 0.2-2.5%, depending on the definition of the condition used. In the US, estimates range between 836,000 and 2.5 million people with the condition, though true numbers are under reported. It is estimated that 84-91% of people with the condition remain undiagnosed.


 * Level of disability (Norwegian study HRQoL) (suggests quality of life is LOWER than for many cancers, heart diseases, brain stroke, diabetes I & II, rheumatoid arthritis, chronic renal failure, sclerosis, schizophenia, COPD, etc)

Causes & triggers

 * Outbreaks - see List of outbreaks
 * Possible infectious triggers: Enteroviruses, Herpesviruses including Epstein-Barr virus, Q Fever , Ross River Virus , (Ebola?)
 * Non-viral triggers - trauma, chemical

Persistence hypotheses

 * Immune findings

Prognosis
Three Stages and Poor Long Term Prognosis

Dr. David Bell, who serves on the Scientific Advisory Board for the Open Medicine Foundation, discusses three stages of the disease in the article Prognosis of ME/CFS. At the first stage, there is an acute illness where EBV is likely responsible for most adolescents but there is no standard viral illness. The initial virus likely fades away in a week and the patient feels better and is ready for regular activities. He adds "in a person with a gradual onset of symptoms, this stage would be different." Second stage "occurs when the symptoms do not disappear, but persist for months to years in roughly the same severity. There is little variation day-to-day, and this time is very confusing. Many medical providers are contacted, most giving conflicting opinions varying from psychological disorders to possible exotic infections, but the tests come back normal." In the third stage patients will have mild, gradual improvements over years and patients adjust their lives to the symptoms. Patients may look well and recovery is thought to have taken place. Some patients will make a full recovery in 3-4 years but "recovery and improvement are completely different."

Dr. Bell has great concern for patients 35 years old who had become ill as teens and has been studying a group that first became ill in 1985. "Some of the young adults rated their health as “good,” while the amount of activity they could perform was minimal. They had become so used to their performance level, they accepted it as their new normal. Unfortunately, many of them, while they described their health as good, they were unable to work full time or carry on other duties." It is now understood that persons with ME/CFS do not have a good long term prognosis and it is actually poor as "full recovery from untreated CFS is rare."

Few Return to Pre-illness State of Functioning

In about 40% of people with ME/CFS the condition will improve over time, though recovery rates from the condition are generally quite low (less than 10%). The condition may also take a relapsing/remitting course, so individuals who appear to have recovered, may actually be in remission. For 5-20% of people, the condition is degenerative. Some studies suggest that prognosis is better for those with less severe symptoms, and who developed the condition at a younger age (childhood-young adulthood), though these findings are not consistent. It is clear that few people will return to their pre-illness state of health and functioning.

Treatments
There are currently no FDA approved treatments for ME/CFS. Treatments consist mostly of symptom management, rather than treatment of the underlying cause of the condition, which is not yet understood. There are many potential treatments, though their evidence-base is limited, as most research into treatments has gone into psychological approaches to treatment.

Two treatments that have garnered much attention are Ampligen and Rituximab. Many people have reported enormous benefit from Ampligen, some doctors have been prescribing it for ME/CFS for decades. Attempts to obtain FDA approval for Ampligen in the US have failed so, despite its usefulness, it is unavailable to many. Rituximab, a lymphoma drug, has shown promising results in initial trials in Norway, and there are groups crowdsourcing funding for further trials in other countries. Jarred Younger announced in March 2016 that he will be undertaking a trial of Low dose naltrexone (LDN) in ME/CFS.

Exercise as treatment
Two common treatment recommendations for ME/CFS are Graded Exercise Therapy (GET) and Cognitive behavioral therapy (CBT). These treatments are based on the hypothesis that the condition might have begun with a viral infection, but has been perpetuated by deconditioning from lack of activity, and fear and avoidance of activity. GET & CBT are aimed at addressing these hypothesized causes by challenging the unhelpful thoughts that result in avoidance of activity, and reconditioning through a gradual increase in exercise. These treatments are controversial, and are at odds with much of the research literature, which suggests that exercise may actually be harmful for people with ME/CFS. A large patient survey of treatment responses found that 74% of people who had tried GET, reported that their symptoms subsequently worsened, which is consistent with other patient surveys.

The PACE trial, published in 2011, is the largest GET trial ever conducted. It has received much publicity as a result of its recovery rate claims, though it has come under strong criticism from within both the scientific and patient community for significant flaws in its design, and for overstating (and in some cases misrepresenting) outcomes in both the initial trial, and follow up studies. The study was the subject of a series of investigative pieces by journalist David Tuller in late 2015, that were highly critical of the trial. A petition signed by almost 12,000 ME/CFS patients and allies, and an open letter signed by 42 ME/CFS experts from around the world, were sent to The Lancet, both calling for the data to be reanalyzed. Twenty four ME/CFS organisations from 14 different countries have written to Queen Mary University London requesting that the trial data be released for reanalysis. To date, the authors of the trial and editor of The Lancet have refused such requests. Despite such criticism, the PACE trial continues to influence both government and the medical profession's approach to treatment of ME/CFS in many countries.

One of the reasons that exercise may be harmful to people with ME/CFS, is the presence of Post-Exertional Malaise (PEM), which is an exacerbation of symptoms following physical, mental or even emotional exertion. Studies have revealed immunological, muscular, neurological, autonomic and cardiovascular abnormalities in response to exercise in people with ME/CFS. As these results are not also found in healthy sedentary controls, the adverse effects of exercise cannot be said to be due to deconditioning.

People with ME/CFS should approach exercise with caution, as there is much potential for harm.

Anaerobic threshold, use of HR monitors for activity and pacing. Analeptic, not aerobic. Energy envelope/pacing - people do better if stay within their envelope, than to push to increase activity

Severely ill patients
Considerable variation exists in the severity of the condition. The International Consensus Criteria lists the following severity levels (it should be noted that even "mild" ME/CFS consists of significant debility):


 * Mild = 50% reduction in pre-illness activity levels
 * Moderate = mostly housebound
 * Severe = mostly bedridden
 * Very Severe = totally bedridden, and needing help with basic functions.

At least 25% of people with ME/CFS are bedbound or housebound, often for years or even decades, so are largely an invisible population. So invisible in fact, that they have rarely been included as part of research, because their level of debility precludes them from travelling to laboratories for required testing. The Open Medicine Foundation's Severely Ill Big Data Study will be the first in depth study into people with a severe form of ME/CFS.

Notable patients with severe ME/CFS include Whitney Dafoe, Karina Hansen, Lynn Gilderdale, Laura Hillenbrand, Tom Kindlon, Vanessa Li, Doctor Speedy, Naomi Whittingham.

Though uncommon, there have been instances of deaths which have been attributed to the condition (see Sophia Mirza).

Notable studies

 * Pathways to prevention report (P2P)
 * Institute of Medicine report
 * PACE trial is a highly criticized UK trial designed by psychiatrists to promote GET and CBT as therapy which is deemed harmful and useless for ME/CFS patients by many clinicians, researchers, patients and advocates.

History

 * Osler's Web is a book on the early history of CFS.
 * Thirty Years of Disdain picks up on the ME/CFS history where Osler's Web leaves off.
 * List of news articles on ME and CFS
 * Sophia Mirza's life ended due to CFS.
 * UK agencies involved in implementation of the PACE trial. Disabled in Tory Britain - PACE trial

Learn more

 * IACFS/ME Primer for Clinical Practitioners - 2014 Edition
 * Myalgic Encephalomyelitis - Adult & Pediatric - International Consensus Criteria Primer for Medical Practitioners
 * ME Association clinical guidance
 * ME/CFS Treatment Resource Guide for Practitioners by A Martin Lerner, MD
 * The biological challenge of myalgic encephalomyelitis/chronic fatigue syndrome: a solvable problem, 2016.
 * Beyond the Data – Chronic Fatigue Syndrome: Advancing Research and Clinical Education (CDC Video, 2016)
 * Notable studies