5th April 2001

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DEFINITION

(1) Professor Anthony Komaroff (Harvard School of Medicine)

Professor Anthony Komaroff gave an overall summary of the current status of CFS/ME. He started by asking the question “Is CFS/ME real”?

1. Are there objective biological markers that are abnormal in CFS/ME?

2. Do we understand the pathogenesis of CFS/ME?

He answered these questions with Yes and No answers. He asked the question - why isn’t Chronic Fatigue Syndrome just depression? He answered:

1. There are differences in objective neuroendocrine studies

2. The results of treatment studies

3. The results of formal psychiatric assessment.

Most patients with Chronic Fatigue Syndrome have no prior history of significant psychiatric disease prior to the onset of CFS/ME. However, at least 50% of patients develop depression, anxiety or other psychoneurotic disorders in the years after the onset of CFS/ME. He commented that most studies using antidepressants have found no evidence of any benefit.

Immunologic studies have reported a variety of abnormalities, especially impaired function of natural killer cells and increased numbers of activated CD8+ T-cells. Neither of these two abnormalities, though, is adequately sensitive or specific to constitute a diagnostic test. They imply the immune system is chronically activated. Recently, there have been a number of reports of more specific immune system abnormalities - increased activity of the 2-5 enzymatic pathway in lymphocytes. A novel low-molecular weight form of RNaseL has been found (see later for more information on this). This 2-5A binding protein has been found in 72% of Chronic Fatigue Syndrome sufferers, 1% of healthy controls, zero percent in Fibromyalgia patients and zero percent in patients with depression.

The involvement of the central nervous system was discussed. MRI scans have found punctuate areas of high signal density in the white matter. There have also been disturbances found in cognition with deficits in the ability to process complex information, in acquiring new information, in learning and recalling new material, with higher order skills such as planning not involved. Autonomic dysfunction, sleep disorders and neuroendocrine dysfunction also imply central nervous system involvement.

Autonomic nervous system involvement shows sympathetic and parasympathetic neuropathy in patients with CFS/ME. Many patients meet the criteria for neurally-mediated hypotension and postural tachycardia syndrome. A number of neuroendocrine abnormalities have also been found, for example, reduced hypothalamic production of corticotrophin releasing hormone (CRH) leading to diminished pituitary release of ACTH leading to basal hypocortisolism. This axis abnormality is the opposite of what is seen in major depression. A recent study using CT scan found that the adrenal glands of CFS/ME patients were half the size of the adrenal glands from healthy controls.

Looking at infectious agents the direct evidence is that CFS/ME can follow a few well-documented infections and is also reported after less well -known infections. A post-mononucleosis fatigue syndrome has been described with acute fatigue in 47% and lasting a median of 8 weeks. Chronic Fatigue Syndrome can follow in 9% of cases versus zero percent after a typical upper respiratory tract infection. A CFS/ME-like syndrome occurs in 20% of patients following Q-fever and can last 5-10 years. Evidence for reactivation of human herpes virus-6 (HHV-6) is also discussed. This can produce life-long infection and can invade a variety of cells for example central nervous system or gastrointestinal cells. With respect to HHV and the brain it can infect cultured neuroblastoma and glyoma cells and can produce neurological sequelae in infants and young children after primary infection. It has been shown to persist in the central nervous system and can cause encephalopathy in the immunosuppressed. It is also associated with demyelenated plaques thus posing an association between this infection and multiple sclerosis.

Professor Komaroff finished his paper by presenting his current favourite model of the pathogenesis of CFS/ME and stated that there are over 4,000 peer reviewed papers to support this model.

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(2) Professor DeBecker (Department of Human Physiology, Vrije University, Brussels, Belgium)

Professor DeBecker spoke about the need for a new case definition to strengthen the ability to select Chronic Fatigue Syndrome patients. He suggested for example to remove low-grade fever from the criteria and instead substitute hot flushes. He also believes that there is an argument for incorporating a severity index. He compared patients using the Holmes and Fukuda criteria and found that the Holmes definition was more strongly associated with the symptoms that differentiated CFS/ME patients from those patients who do not comply with CFS/ME definitions. He found that patients fulfilling the Fukuda criteria (the ones normally used) were less severely affected and led to an increase in clinical heterogeneity. They suggest that the use of the Holmes criteria defining symptoms of fatigue, swollen/tender lymph nodes, sore throat, muscle weakness, recurrent flu-like symptoms, post-exertional fatigue, myalgia, memory disturbance, and non-restorative sleep with the addition of certain symptoms/hot flushes (instead of low grade fever), attention deficit, paralysis, new sensitivities to food/drugs, difficulties with words, urinary frequency, cold extremities, photophobia, muscle fasciculations, light-headedness, exertional dyspnoea (shortness of breath) and gastrointestinal disturbance and removal of others (arthraliga and low grade fever) would strengthen the ability to select CFS/ME patients.

Dr Butt has coined a new term “bacterial colonosis” (BC). Patients with this condition usually present with multiple disorders including gastrointestinal symptoms characterised by an absence of gastrointestinal inflammation and a marked alteration of intestinal microbial flora. This has been seen in patients with CFS/ME, fibromyalgia, irritable bowel syndrome and autism. He believes that fatigue is much more severe if bacterial colonosis is present. There is also an increase in other symptoms such as nausea, abdominal pain, constipation, diarrhoea and gastric reflux and also an increase in pain generally. He found that the major change in Chronic Fatigue Syndrome patients is a decrease in the amount of E.coli in the bowel and a large increase in an organism called enterococcus faecalis. The importance of this is that E.coli produces many amino acids, for example chorismic acid which happens to be the precursor of a number of important constituents for the body including Vitamin K, tyrosine, folic acid, tryptophan and phenylalaine. Because of this, about 50% of patients in his group have found to be low in folic acid. The production of tryptophan as it is a precursor of serotonin and this is important for proper gut function. He has found an association between high levels of enterococcus faecalis and an increase in cognitive and neurological dysfunction, nervousness, memory loss, confusion, mind going blank and headaches.

Dr Behan discussed the debate about whether the fatigue in CFS/ME is primarily a peripheral problem in the muscles or a central nervous system problem. She raised the question if this was a different type of fatigue altogether or was in fact related to that of other disorders in which fatigue is experienced such as chronic heart disease, chronic obstructive airways disease and multiple sclerosis. Her conclusion was that CFS/ME is a disorder in which all parts of the exercise pathway can be affected.

Importantly she stated that deconditioning was not a factor, often cited in recent studies on graded exercise therapy as a treatment for Chronic Fatigue Syndrome. She stated that the falling off in the aerobic capacity was in the same line as the controls doing isometric contractions i.e. patients with CFS/ME were doing their best. If you repeat the experiment the next day CFS/ME patients start off weaker and 24 hours later there is a severe reduction in the force of their contractions. This obviously correlated to the clinical findings experienced in CFS/ME where there is often a worsening of fatigue 24-48 hours after over-exertion.

(2) Dr Charlie Sargent (Adelaide Chronic Fatigue Syndrome Research Group,

University of Adelaide)

He and his group did physical fitness testing in approximately 50 CFS/ME patients and they found values were not different from those expected in healthy sedentary members of the general community. They concluded that there was no physiological basis for recommending graded exercise training programs.

They also looked at lactic acid as a possible factor in the fatigue of CFS/ME patients. They did find that exercise time to exhaustion and the peak power output at exhaustion were lower in the CFS patients. However, the increases in lactate concentration with exercise intensity were not different from controls indicating that the production and clearance of lactic acid in CFS/ME patients was normal and does not contribute to their earlier fatigue and reduced power output during exercise.

(3) Dr Adele McGrath (Adelaide Chronic Fatigue Syndrome Research Group,

University of Adelaide)

Dr McGrath presented work that showed that there was no evidence of hypotension or impaired cognitive function with acute orthostatic stress in CFS/ME and thus questioned treatment rationales for orthostatic intolerance in CFS/ME patients.

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INFECTION AND IMMUNE FUNCTION

(1) Dr Garth Nicholson (Institute for Molecular Medicine, Huntington Beach, California)

Dr Nicholson discussed the fact that CFS/ME, Fibromyalgia and Gulf War have overlapping signs and symptoms. They have found that a major source of morbidity is caused by various chronic viral and bacterial infections. In his work, Gulf War illness patients in about 40% of cases have mycoplasmal infections inside blood leukocytes but not in plasma or serum. The most common species in about 80% was M.fermentans. In contrast, healthy adults have incidence of mycoplasma of 6%. In CFS/FM patients in about 50% they found a variety species and many patients had evidence of multiple infections. Interestingly, they have also found that in systemic lupus erythematous (SLE) and multiple sclerosis, 40-45% had evidence of mycoplasma. They also commented that if there were multiple infections present that the patient was more likely to have a more severe form of illness.

Dr Nicholson suggested for these patients positive for mycoplasma, 6 months continuous treatment with antibiotics as this is an infection, which is slow growing, intracellular and insensitive in general to drugs. He talked about multiple cycles of treatment as well as cutting down sugar in the diet which he believes stimulates growth of infections.

Dr Stein commented on a recent publication in the Australian Medical Journal, which concluded that six out of ten patients presenting to general practitioners were diagnosed with a “mental illness” (mainly somatisation). She stated that it was a mistake to use screening instruments such as the Beck Depression Inventory , the General Health Questionnaire or the SPHERE (used to diagnose mental illness in this general practice study) in persons with undiagnosed somatic complaints.

Dr Stein specified the clinical differences between CFS/ME and the two most common psychiatric disorders, anxiety and depression. A clinical psychiatric diagnosis rests upon the patient demonstrating the core psychiatric manifestations of depression e.g. anhedonia (loss of interest) or in anxiety, unrealistic fear, whereas a diagnosis of CFS/ME requires the presence of four out of eight physical symptoms in addition to fatigue.

Depressive and anxious reactions to a serious chronic unpredictable disorder that lacks social legitimacy are common amongst CFS patients. A co-morbid psychiatric diagnosis should only be considered if the psychiatric symptoms pre-dated the onset of CFS/ME, if the symptoms are generalised beyond health and quality of life issues affected by CFS/ME or if the symptoms are so severe that they present a patient from participating in treatment. She pointed out significant differences between CFS/ME and depression. For example in CFS/ME the physical and mental fatigue are worsened by physical or mental exertion whereas in depression fatigue and mood improve with exercise. Personality disorder is no more commonly seen in CFS/ME patients compared to controls whereas in depression there is an increased prevalence of personality disorder. She noted the infectious onset in over 70% of cases of CFS whereas depression rarely follows an infectious illness. She commented on the obvious physical symptoms for example swollen lymph nodes, sore throat in CFS/ME compared with depression and noted the marked variability of severity and nature of symptoms in CFS/ME compared to depression.

Dr Casse commented on the neuropsychiatric symptoms often associated with the mental fatigue such as impaired concentration and slowness of thinking. He stated that most previous studies using radionucleotide cerebral perfusion scans gave conflicting results due to using unhomogeneous patient populations and poor analysis.

He and his group performed a pilot study to address these issues with a Tc-99mHMPAO SPECT and a triple head gamma camera. A uniform group of 13 female subjects with moderate CFS/ME based upon established criteria, pain free, not on medication and not depressed were compared with a group of 11 patients scanned for other conditions.

The results were a definitive deficit in regional cerebral blood flow in 7 patients, an equivocal deficit in 3 patients suggesting that patients with moderately severe CFS/ME have focal cortical and brain stem hypoperfusion.

Dr Cosford stated that CFS/ME is characterised by fatigue, gastrointestinal symptoms with irritable bowel, food intolerance, muscle pain, weakness, recurrent illness and neurocognitive symptoms. Neurocognitive symptoms include cognitive dysfunction, sensitivities to stimuli such as bright lights, noise and odours and disordered and fragmented sleep. CFS in adolescents typically has an onset after age 12. Autism is similarly characterised by neurocognitive symptoms with sleep disorder and marked sensory sensitivity. Gastrointestinal symptoms are also common with reactions to certain foods, particularly gluten and casein-containing foods, recurrent infections and easy fatigue. Autism is generally diagnosed between 2-3 years of age. In both conditions there is the probability of an underlying genetic susceptibility but prominent environmental triggers.

Various metabolic abnormalities have been identified in CFS/ME, increased gastric emptying times and increased gastrointestinal permeability with faecal studies demonstrating gastrointestinal dysbiosos with overgrowth of streptococcal/ enterococcal species in approximately 60% of CFS/ME patients. Urinary organic acid analyses demonstrate increased markers of fibrillar and non-fibrillar catabolism in CFS/ME patients and various organic abnormalities in subsets of CFS/ME sufferers. CFS/ME patients with prominent visual and sensory disturbances also show a characteristic pattern of urinary organic acid disturbance.

Similarly, recent research using urinary organic acids, plasma lipids, faecal analyses and intestinal permeability studies in children with autism has identified particular patterns in these children. Urinary organic acids indicate a strongly catabolic picture with fibrillar and non-fibrillar catabolism, generally low urinary glycoamines and abnormalities in the markers for the tricarboccylic acid cycle (TCA cycle) similar to those seen in CFS/ME. In addition raised urinary hydroxy protein - a marker of increased connective tissue breakdown, and raised ornothine - a marker for abnormalities in the urea cycle and ammonium metabolism are typically seen. Raised levels of nervonic acid are found. Nervonic acid is a major component of sphingomyelin and may indicate a disruption of myelination. Faecal studies show a loss of beneficial E.coli, lactobacilli and bifido-bacteria and overgrowth of potentially pathogenic enterococci and streptococci and increased intestinal permeability has been documented to occur in some 50% of children with autism. Endocscopic studies have revealed gastric mucosal inflammation, duodenal inflammation and colonic inflammation in a significant percentage of autistic children. Immune abnormalities are well documented in autism also.

The results indicate that autism children represent a metabolically more homogeneous group than CFS patients. The metabolic disruption in autism is more widespread and severe as are the neurocognitive symptoms but the similarities with the subgroup of CFS/ME patients with gastrointestinal symptoms and neurocognitive symptoms suggest a possible commonality in aetiology. It is hypothesised that the abnormal gastrointestinal flora is producing the measurable increase in intestinal permeability, intestinal inflammation and disturbance in gastrointestinal motility, disruption in digestion and food intolerance. Streptococcal toxins and immune cross reactions have a known association with neurological phenomena and recent literature has noted the connection with streptococcus and Tourette’s Syndrome and obsessive compulsive disorder and attention deficit hyperactivity disorder. It has already been hypothesised that CFS/ME is a toxin-mediated channelopathy disorder. It is therefore hypothesised that in a subgroup of CFS/ME patients and in most children with autism the illness is largely toxin-mediated with a significant contribution from the toxins generated by streptococcal overgrowth in the gastrointestinal tract. The increased severity of the metabolic disruption and neurocognitive effects in autism could be attributed to the different age at which the organism was exposed to the environmental stimuli with the insult occurring in autism whilst the neurological system is still in the process of myelination and maturation and the immune system still maturing.

Dr Cosford has coined a new term the “neuroimmune gastrointestinal dysfunction syndrome” to adequately describe the above phenomena.

(4) Dr Greg Tooley (School of Psychology, Deakin University, Victoria)