People with CFS/ME suffer from pain, extreme tiredness and viral symptoms.
Although it was not named until 1988, 19th-century physicians were already aware of a condition called neurasthenia, or nervous exhaustion, symptoms of which resembled chronic fatigue syndrome (CFS).
From the 1930s-1950s, outbreaks of disease marked by prolonged fatigue were reported in the US and elsewhere.
First thought to be a psychiatric disorder, CFS is now recognized as a severe physical illness, although the uncertainty of its origin has plagued progress in diagnosis and treatment.
However, growing evidence of physiological biomarkers is now emerging.
A broad spectrum
CFS and myalgic encephalomyelitis (ME), together known as CFS/ME, is a complex, acquired, chronic and multi-system disease, involving systemic exertion intolerance and resulting in significant relapse after exertion of any sort.
While symptoms vary, CFS/ME can involve immune, neurological and cognitive impairment, sleep abnormalities and dysfunction of the autonomic system, which controls several basic bodily functions, resulting in significant functional impairment accompanied by profound fatigue.
The onset of symptoms may be sudden - for example, immediately following a viral illness - or gradual, with no apparent link to a specific event or time.
Effects can range from moderate to severely debilitating. At least 25% of patients are bedbound or housebound at some point in the illness, and many never regain their pre-disease level of functioning.
Although CFS/ME is now established as a genuine illness, lack of progress in pinning down its elusive diagnosis and treatment continues to frustrate patients, carers and professionals.
Difficulties with diagnosis
According to the Centers for Disease Control and Prevention (CDC), CFS/ME affects a million plus Americans, and it has been reported in children under 10 and seniors over 70. Ronald Davis, a biochemist and geneticist at Stanford University in Palo Alto, CA, puts the figure between 836,000 and 2.5 million.
Fatigue is only a part of this complex condition.
In addition, the International Association for Chronic Fatigue Syndrome and Myalgic Encephalomyelitis (IACFS/ME) estimate that up to 80% of people with the disease in the US have not yet been diagnosed.
The condition is so broad and variable that most criteria require patients to show symptoms for at least 6 months before it can be diagnosed, and diagnosis depends heavily on exclusion of other conditions.
Medical providers may be uncomfortable diagnosing and treating it, and patients have reported difficulty finding a knowledgeable physician.
Because the pathology of CFS/ME remains unknown, there is currently no blood or other biological test that can be used to diagnose it.
Even the criteria for diagnosis is disputed. According to British psychiatrist Prof. Sir Simon Wessely, of King's College London in the UK, there are up to 20 different sets of criteria, causing frustration for patients and making the results of scientific studies difficult to compare.
Criteria produced by the CDC are widely used, but advocates such as the UK's ME Association note that some people with genuine ME/CFS do not have a sufficient number of different symptoms to fulfill the strict CDC definition.
Scientific progress has also been limited by lack of funding for research: around $6 million a year in the US, less than the funding for agent orange and dioxin, according to figures from the National Institutes of Health (NIH). Others put the figure as low as $5 million.
Variability of symptoms and severity poses a challenge
One challenge with both diagnosis and research is the broad spectrum of the disease, as this impacts both the degree to which individuals are affected and the results of any survey.
The prognosis, for example, ranges from a small percentage who regain normal health over time, to a further small percentage who experience continued deterioration.
Between these extremes, a majority fluctuate between good and bad periods of health and relapses or exacerbations caused by infections, operations, temperature extremes or stressful events. A significant minority stabilize but remain severely affected, requiring constant practical and social support.
CFS and ME diagnosis: are they the same?
Diagnosis is further complicated by the question: are CFS and ME the same? Does the name reflect the disease?
Some advocates argue that ME has more systemic features, whereas CFS is more focused on fatigue, or that the choice of "fatigue" in the terminology has belittled the condition, implying that patients just feel "tired all the time."
Dr. Michael Zeinah, of Stanford University, CA, who is currently studying abnormalities in the brain relating to the disease, told Medical News Today that "most would consider these [terms] synonymous."
Prof. Sir Simon Wessely, president of the UK's Royal College of Psychiatrists, told MNT:
"I don't think it matters too much what we call it, what matters is what we can do about it. What [...] matters is that I and any other doctor take it seriously, give them time, believe they are ill and have something to propose."
A modified version of the World Health Organization (WHO) ICD-9-CM diagnosis, used for insurance assessment in the US, presents ME and CFS in the same document: separate but overlapping neurological disorders.
In February 2015, MNT reported that the Institute of Medicine (IOM) proposed changing the name to systemic exertion intolerance disease (SEID), to which some advocates were cautiously optimistic.
The NIH initiative and PACE
In October 2015, the NIH announced plans to strengthen efforts to advance CFS/ME research, including increasing funding, creating a new working group and bringing CFS/ME under the umbrella of the National Institute of Neurological Disorders and Stroke (NINDS), which advocates consider "a meaningful prerequisite for progress."
The announcement came as the latest findings from the UK's PACE trial were published, as reported by MNT. The study has drawn criticism from the CFS/ME community on a number of counts.
The PACE study
The PACE trial focused on the degree to which behavioral and psychological approaches might improve patients' physical capacities and perceptions of their condition.
It is hoped that CBT may help some people with CFS/ME to return to work.
It reviewed progress made through a combination of specialist medical care (SMC) alone, SMC plus cognitive behavioral therapy (CBT), SMC plus graded exercise therapy (GET) or SMC plus adaptive pacing therapy (APT).
CBT and GET are current standards of care in the UK. Aims of the treatments include helping patients regain quality of life and return to work.
The study authors say their results indicate long-term success, especially for CBT, but members of the patient community have disputed them on a number of counts, including recruitment, research methodology and interpretation of results.
One criticism was that by focusing on more able patients, the study was not representative, as it disregarded those who are more severely disabled by the condition, or those who are prone to relapse after exercise.
While PACE aimed to get some of the more able patients back on their feet, the NIH study, in contrast, will focus on the other end of the spectrum, in a study of about 40 people who fell ill suddenly after a flu-like illness and never returned to normal - a common feature of the syndrome. This study will aim to investigate the causes of the problem at the molecular level.
Since CFS/ME is a physical disease, some question the use of a psychological approach to treat it.
For some, the very suggestion of CBT implies that proponents still believe the condition is "all in the mind." However, professionals argue that in the ongoing absence of physical therapy, if psychotherapy can help some patients to add value to their lives, it should be made available.
Does CBT have a role?
Prof. Wessely, who pioneered CBT for CFS/ME patients, told MNT that while there is clear evidence for an underlying biological cause for the disease, as seen in neuroendocrine profiles, CBT can help patients to cope with the challenges they face.
The important thing, he says, is for physicians to start from the basic principle that the patient has a real illness, and he explained that while CBT is not a "magic bullet," it is safe and can help patients make the best of their situation.
Depression may occur alongside the condition.
CFS/ME has been linked with depression, which CBT can also help to combat.
While emphasizing that CFS/ME and depression are not the same thing, and that the role of depression is smaller than originally believed, Prof. Wessely explained that an overlap exists, and "rates of depression are too high to be simply explained by a reaction to physical illness."
He added that it has been "established beyond doubt" that previous depression increases the risk of CFS and mentions that antidepressants "don't seem to be particularly effective."
CBT would therefore be expected to help patients whose condition involves depression, whether as a cause or a result of CFS/ME. According to Nature, CBT has "in many cases brought about substantial improvement, and in some was life transforming."
Some members of the CFS/ ME community, however, reject CBT on the basis that it does not address the condition as a biological disorder.
Other treatments aimed at reducing symptoms include a range of "mainstream" and "complementary" methods, including drugs such as painkillers, antidepressants and antiemetics, homeopathy, acupuncture and dietary changes.
Exercise regimes have helped some people, but since the symptoms can include relapse after exertion, exercise does not suit everyone.
In 2014, a team at the University of Toronto, Canada, claimed an "indisputable biological basis" for ME/CFS in a discovery that they believe could lead to identification of diagnostic biomarkers and potential treatment and interventions for the condition.
Led by Dr. Patrick McGowan, researchers found signs of epigenetic modifications throughout the genome in ME/CFS patients.
Epigenetic modifications affect the way genes are turned on or off, without changing the inherited gene sequences. Such modifications were found in and around immune genes, of the type that would be expected to affect immune cell function in ME/CFS patients.
The results could help to decipher the molecular mechanisms of the immune dysfunction that may be at the root of ME/CFS.
Dr. McGowan told MNT:
"Our work is still in the early stages, but it fits into a larger body of work on identifying biological changes in complex disease using genomics. With the revolution in genomic technology, large databases of patient data are being constructed for a variety of illnesses.
We plan to compare biological changes we identify in ME/CFS to other diseases with some of the same symptoms to begin to identify specific markers of CFS. Some physicians still believe that CFS is not a 'real disease' because no specific biological markers or specific causes (such as an infectious agent) have been discovered, so we expect that any markers we identify will be helpful to patients seeking treatment."
Dr. McGowan added that there are probably different subtypes of CFS/ME, and that his team hopes to develop biological markers that can be linked to specific physiological pathways and subsequently used to subtype ME/CFS and potentially tailor treatments.
In a study at Stanford University, published in 2014, radiology researchers led by Dr. Michael Zeinah found diminished white matter and white matter abnormalities in the right hemisphere of the brains of patients with CFS/ME.
Levels of abnormality were also found that seemed to correlate with the severity of the patient's condition. In addition, thickening of gray matter had occurred in an area where it joined with white matter, corresponding with abnormality in the adjoining white matter.
Gray matter tends to process information, while white matter conveys information from one part of the brain to another.
Inflammation is known to affect white matter; it is thought that these abnormalities could be due to CFS/ME-related chronic inflammation, possibly as a protracted immunological response to some kind of viral infection.
Dr. Zeinah told MNT:
"Since this has been published, we have been designing a well-controlled, multi-year study that should address this. Our effort will take some time, but we are hopeful it will be productive."
He added that they hope to discern in this next study which symptoms might be directly affected or caused by specific parts of the brain.
Immune signatures indicate distinct disease stages
In February 2015, a team from Columbia University in New York, NY, provided further evidence that the condition is a biological illness when they identified distinct immune changes in patients with CFS/ME. The findings also showed that the disease has distinct stages.
- CSF/ME affects more Americans than multiple sclerosis, lupus and many forms of cancer.
- The illness occurs most often in people in their 40s and 50s, but can affect any age
- All ethnic, racial and socioeconomic groups are affected equally.
Researchers tested the levels of 51 immune biomarkers from 298 patients and found specific patterns in patients who had the disease 3 years or less that were absent in those who had the disease for more than 3 years.
These included increased amounts of immune molecules called cytokines, including one in particular that has been linked to the fatigue that follows a virus. One such virus is Epstein-Barr, a common virus sometimes linked with the onset of CFS/ME.
The findings suggest that these infections "throw a wrench in the immune system's ability to quiet itself after the acute infection, to return to a homeostatic balance; the immune response becomes like a car stuck in high gear." The researchers describe this as a kind of "infectious hit-and-run event."
These studies have been welcomed as evidence that ME/CFS is not psychological. It is hoped that these findings could lead to viable treatment options in the future.
In fact, there is an antibody already on the market that can dampen levels of a cytokine called interleukin-17A, which is shown to be elevated in early-stage patients.
Perhaps an effective treatment could finally be on the horizon?