Continuing our guest series of articles by Dr Neil Abbot, from independent charity ME Research UK.
At present, there are many ways of diagnosing M.E., CFS, CFIDS (chronic fatigue and immune dysfunction syndrome, as it’s known in the US), CFS/M.E. and M.E./CFS – just listing these acronyms illustrates the confusion that besets the field.
Yet each new definition delivers a diagnosis of exclusion (of other conditions), based on clusters of vaguely defined symptoms shared with other illnesses. The validity of a diagnosis of M.E./CFS really depends critically on the rigour of the initial clinical assessment and the efforts expended to exclude other treatable conditions that might be causing the collection of symptoms.
The guideline produced by the UK’s National Institute for Health and Clinical Excellence (NICE) in 2007 came up with its own variant of diagnostic criteria for CFS/M.E. – new, unexplained, persistent/ recurrent fatigue with a post-exercise component plus one or more of a range of common symptoms such as difficulty with sleeping, muscle and/ or joint pain and headaches. It also recommended that patients be referred to specialist M.E./CFS clinical services.
Such broad-brush criteria, combined with a lack of GP education about M.E./CFS, have led to concerns about the application of the NICE guideline in the surgery or clinic.
Fortunately, a recently published study in the Journal of the Royal College of Physicians Edinburgh has opened a window onto the appropriateness of referrals to one M.E./CFS service.
With funding from ME Research UK, the John Richardson Research Group and the Irish M.E. Trust, Prof Julia Newton and colleagues at Newcastle University examined the records of every patient referred to the Newcastle CFS/M.E. Clinical Service between November 2008 and December 2009. Each patient had complete data on the UK national minimum dataset, a standard M.E./CFS assessment tool, from which the diagnosis could be checked.
Looking at the results, Prof Newton found that 260 patients had been referred to the clinical service in 2008-9 (approximately 19 referrals per month). Interestingly, the proportion of patients found to be correctly diagnosed with M.E./CFS by the Newcastle service increased significantly compared with the results of a previous service audit in 2007 (60% versus 36%, respectively), a finding which might suggest that the introduction of the NICE clinical guideline in 2007 had somewhat improved the correct identification of these patients by GPs.
However, the most important finding was that 103 (40%) of patients seen by the Newcastle Service could, in fact, be diagnosed with other conditions.
The most common alternative diagnosis in these patients was fatigue associated with a chronic disease (47% of all alternative diagnoses). These included metabolic syndrome, neurological disorders, connective tissue disorder, autoimmune disease, fibromyalgia, coeliac disease, overtraining syndrome, cancer, low body mass index, haemochromatosis, microprolactinoma and Lyme disease.
The next common alternative diagnosis was primary sleep disorder (20%), including eight patients with obstructive sleep apnoea and 12 with another primary sleep disorder – an important finding since sleep disorders form a significant and potentially treatable diagnostic group.
A further 15% of all alternative diagnoses were psychological/ psychiatric illnesses (most commonly depression, anxiety and post- traumatic stress disorder); 13% were unexplained but not M.E./CFS (5.2% of total referrals); and 4% were cardiovascular disorders (vasovagal syncope in patients with fatigue symptoms who also had a history of episodes of loss of consciousness, with the diagnosis made after a reproduction of symptoms in head-up tilt testing). Just 1% were diagnosed with other illnesses.
Prof Newton’s results concur with those from two smaller, service audits (Dundee 1993; Newcastle 2007) and reiterate that a significant minority of UK patients referred from primary care with a diagnosis of M.E./CFS can receive alternative, exclusionary diagnoses if investigated at a specialist clinic.
They illustrate that in the absence of a full clinical assessment (which most patients in the community have either never undergone or last had many years ago), the diagnosis of M.E./CFS can easily become a stopping-off point for clinically complex patients with a variety of different illnesses.
This problem is not unique to the UK. A fascinating commentary in 2008 in Minnesota Medicine described the difficulties experienced at a clinic in the USA for patients with fatigue, exercise intolerance and weakness (ie. patients very like M.E./CFS patients in the UK).
After reporting on three paediatric cases (all of whom received serious, new diagnoses), the authors commented that “a thoughtful and thorough physical exam can sometimes reveal otherwise hidden diagnoses.” This certainly raises the question of which treatable diagnoses might be uncovered if all patients currently parked in the M.E./CFS diagnostic lay-by were examined intensively at a specialist centre of excellence by thoughtful and thorough physicians.
How marvellous it would be if M.E./CFS or the subtypes within it could be diagnosed objectively with criteria based on clinical or laboratory measurements. Illnesses are most easily accepted when they have a specific clinical or scientific signature, such as a biochemical test and/or a cluster of specific signs, which establishes diagnostic validity and confers legitimacy in the eyes of healthcare professionals.
The discovery of such a signature specific for M.E./CFS would transform the outlook for patients.
Does m.e./Cfs run in families?
While there is anecdotal evidence from M.E./CFS patients and carers that the illness can run in families – particularly mothers and their daughters or sons – is there any scientific evidence to back this up? Well, surprisingly there is.
One survey of 914 students at the Lyndonville Central School in 1991 found symptoms of M.E./CFS among other family members to be one of the strong predictors of M.E./ CFS in the student, with a high relative risk of 35.9 (other predictors included the ingestion of raw milk and a history of allergy/asthma).
Another small family history study in 2001 found significantly higher rates of M.E./CFS in the first-degree relatives of M.E./CFS cases compared with the relatives of control subjects.
Finally, studies on twins have shown a higher concordance rate for M.E./CFS between monozygotic (identical) twins than between dizygotic (non-identical) twins – suggesting that genetic factors might have an important role.
Building upon these reports, researchers at the University of Utah (Albright et al, BMC Neurology, May 2011) focused on M.E./CFS using specialist methods previously used to investigate heritable components of diseases such as prostate cancer, influenza mortality, aneurysm, cancer, and diabetes.
From genealogical records of Utah pioneers and their descendants, representing 15 generations of genealogy data, cross-referenced against medical diagnosis data from 1993, a sample group of 811 was chosen. The Genealogical Index of Familiality (GIF) statistic was used to test the hypothesis of excess relatedness among M.E./CFS cases.
The results showed that the average relatedness of M.E./CFS cases was significantly greater than expected when all relationships were considered (p<0.001), strong evidence for excess clustering of the illness in families. This could be due to a shared environmental factor (location, diet, infection), shared genes or a combination of the two.
However, there was also a significant relative risk of M.E./CFS amongst first, second and third- degree relatives of existing M.E./CFS patients compared with control individuals. First-degree relatives (parent/offspring) had 2.7 times the risk of also having M.E./CFS, while second-degree relatives (siblings or grandparent/grandchild) had 2.3 times the risk.
The authors point out that this strongly supports a genetic contribution to a predisposition to M.E./CFS as it has been defined and diagnosed by clinicians in Utah since 1993. Their study is the first population-based analysis to present such evidence.
Exploding the depression myth
The hypothesis that depression is at the root of the symptoms of M.E./ CFS – a myth particularly prevalent in the 1990s – is slowly crumbling. In fact, a review in 2008 described the range of symptoms that the two illnesses do not share and listed biological abnormalities separating M.E./CFS from depression, such as sleep problems (reduced REM sleep latency in depression versus reduced slow-wave deep sleep in M.E./CFS) and hypothalamus and pituitary function (high circulating cortisol levels in depression versus low in M.E./CFS, compared with controls).
Further evidence of differences has come in a recent report from Harvard Medical School (Duffy et al, BMC Neurology, July 2011) which compared electroencephalogram (EEG) data from the brains of different groups of patients. The researchers employed spectral coherence, a complex computational derivative of EEG spectral data, which estimates connectivity between brain regions.
Their study involved 390 healthy volunteers, 70 people with M.E./CFS, 24 people meeting DSM-IV criteria for major depression and 148 people with unspecified fatigue. Using principal components analysis on the EEG results, the team were able to identify and correctly classify approximately 90% of the 47 unmedicated M.E./CFS patients and 82-92% of the healthy controls. Importantly, no person with depression was classified as having M.E./CFS. The researchers say that this fundamental finding indicates that M.E./CFS patients “manifest patterns of functional brain coupling that differ from those of normal controls,” something that “may help explain known differences in cognition, memory, sleep” that afflict patients.
Also, their finding of bilateral temporal lobe involvement in nine of 10 most discriminating coherence factors could be highly clinically significant since greater temporal lobe involvement is consistent with the impairment of global memory frequently observed in people with M.E./CFS.
Low mitochondrial content
Mitochondria are found in most cells and their main job is to generate chemical energy. Disorders of mitochondrial function are implicated in a number of diseases, including mental disorders and heart problems, as well as being involved in the ageing process. Since M.E./ CFS is characterised by a profound, generalised post-exertional loss of muscle power, it seems reasonable to suggest that mitochondrial dysfunction may be involved.
The most recent mitochondrial study (Smits et al, Mitochondrion, July 2011) comes from the Neuromuscular Centre in Nijmegen. It compared skeletal muscle biopsies from 16 people with M.E./CFS plus symptoms of muscle pain and/or exercise intolerance to those of 11 healthy controls. Also, the group measured mitochondrial respiratory chain complex (RCC) activity – an indication of mitochondrial function – by comparing biopsy data from the M.E./CFS patients with two groups of patients with genetically confirmed mitochondrial disorders (22 people with chronic progressive external ophthalmoplegia and 27 with an A3243G mutation in skeletal muscle).
The researchers found that citrate synthase activity (a marker of mitochondrial content) was decreased in M.E./CFS compared to healthy people. However, the activity of the RCC enzymes (and hence energy production) of M.E./CFS patients was not at the low levels found in patients with mitochondrial disorders who generally have deficiencies in the RCCs as part of their illness. Furthermore, energy production rate was within the normal range in all M.E./CFS patients, whereas it was decreased greatly in three quarters of the patients with mitochondrial disorders.
The fact the mitochondrial function was unaffected in skeletal muscle of M.E./CFS patients but that mitochondrial content was notably decreased does not support the concept of “primary mitochondrial dysfunction” in M.E./CFS, as the authors point out. However, they speculate that “low mitochondrial content might be a perpetuating factor for complaints such as fatigue, myalgia and exercise intolerance” in the illness.
Articles have been extracted from the autumn 2011 issue of Breakthrough magazine. Read it online or contact ME Research UK, The Gateway, North Methven Street, Perth PH1 5PP. Tel: 01738 451234. Email
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