The following is an edited extract of a transcript of a talk given by Professor Peter Behan of the Institute of Neurological Sciences, University of Glasgow, to an audience of health professional at the Coventry and Warwickshire Post-Graduate Centre on the 23rd November 1995.

Thanks must go to Julia Hamilton, who wrote the original transcript and Robert Ennis, Chairman of the Coventry and Warwickshire Support Group, for permission to reprint it.

Although it remains essentially a diagnosis of exclusion, there are now laboratory techniques which will confirm the diagnosis.

At first his team thought M.E. was precipitated by a virus, but there is now no question that some cases of the illness are precipitated by toxins.

The challenge is to explain why minute doses of toxin re-exposure cause the illness, or why, if there is an acute precipitant such as a viral infection, the illness goes on for 20 years. The first exposure may have induced in the patient a lesion at the DNA level.

Professor Behan then compared a condition known as myeloadenamate deaminase deficiency, from which patients they had taken a piece of muscle and had stained for this enzyme and found it to be missing. It is known that the enzyme is missing after a viral attack. Similarly, in M.E., there is a defect in that the enzyme is not present in muscle, which shows that there must be some persistant abnormality.

He then went on to address the nature of the fatigue found in M.E.; he stated that it occurs acutely and is exactly the same fatigue which occurs in other conditions such as multiple sclerosis, even going so far as to state: "Patients with multiple sclerosis have chronic fatigue syndrome and the fatigue is exactly the same."

Some patients with endogenous depression have exactly the same fatigue, as do patients with Gilbert's syndrome (a familial condition due to an inherited deficiency of an enzyme in the liver cells causing a form of jaundice). It is well documented that patients develop M.E.-like fatigue after stress, or after viral infection, or after exposure to toxins. Why, asked Professor Behan, should that lesion in the liver give patients fatigue?

Post-polio syndrome is another condition in which fatigue is a prominent feature. In line with other recent research findings on the post-polio syndrome, Professor Behan stated catergorically that "PPS is identical in every way to chronic fatigue syndrome".

Another condition in which fatigue occurs is idiopathic cyclic oedema, in which the woman is water-logged throughout the menstrual cycle due to hypothalamic disturbances. Also, there is classic fatigue in Parkinson's disease, a condition in which the fatigue is grossly incapacitating.

He and his team at Glagow have been carrying out tests on M.E patients, along with a group of controls, in which participants are exercised until they are tired. The next day the exercise tests are repeated. In well-defined cases of M.E., by using refined techniques for measuring gait disturbance, and using an ergometer for measuring muscle power, there is a phenomenal drop off in maximum oxygen consumption.

Professor Behan then mentioned single fibre EMG studies (1). In patients with M.E. there are gross abnormalities. About 80% suggest that something is wrong with the muscle.

Professor Behan then observed that if the same thing that is demonstrably wrong with muscle may be wrong with other cells, it is necessary to come back to the concept of a primary stimulas. What might this be?

He turned next to NMR imaging (2). He said NMR studies showed that in M.E. there is very early excessive intrcellular lactic acidosis with exercise and that this tends to persist, suggesting that there is something wrong with the glycolytic pathway (3).

During strenuous exercise, pyruvic acid (a compound derived from carbohydrates) is reduced to lactic acid, which then accumulates in the muscles and causes cramp.

In M.E., there are two indicators that there is undoubtably something wrong: one is nuclear magnetic resonance and nuclear imaging: the other is in the field of neuroendocrinology.

Still on tests for muscle pathology, Professor Behan emphasised that when doing muscle biopsies on patients with M.E., it was necessary to look at them expertly. He showed a slide of a normal muscle biopsy in which the mitochondria (the sites of the cell's energy production) appeared as little red dots. Only careful and expert study revealed an increase in the mitochondria in M.E. The Glasgow team have now done about 400 such biopsies and they have found another abnormality in that cristae (the infoldings of the inner membrane of mitochondria) have gone, leaving honeycombed patterns. This honeycombing suggested to Professor Behan a toxic or a stress phenomenon in the mitochondria.

When cells of M.E. patients are looked at in tissue culture, the lactic/pyruvic ratio of patients falls into two groups: patients are either producing too little or too much. Recently, Professor Behan has been interested in Syndrome X where an individual presents with what seems to be a coronary thrombosis. They may have very severe angina, but all the usual test results are normal: treadmill tests are normal. There is however, an abnormality of the lactic/pyruvic ratio, together with conspicuous abnormalities of carbohydrate metabolism. This Syndrome X has been reported from the Hammersmith Hospital in London, and also from Sweden. Professor Behan's team have discovered that these Syndrome X cases have gone on to develop chronic fatigue syndrome. The team at Glasgow has done thalium scans on patients with chronic fatigue syndrome, and in 100% of cases the scans are abnormal, yet again suggesting a cellular abnormality (4). Professor Behan showed a thallium scan of a young girl of 21 with M.E. He said he currently has a paper in press about these cases, all of whom have gross abnormalities of the myocardium. Referring to Syndrome X, Pr fessor Behan said that other data using PET scans (positron emission tomography) which measured the flow showed no ischaemia and no impairment and this is a metabolic abnormality.

Resuming his review of tests which are abnormal in M.E., Professor Behan said that one of his lecturers had a special interest in liver function abnormalities, and had noted that patients with M.E. had raised cholesterol levels, so they did a study of 30 well-defined cases, looking not only at cholesterol levels but also doing a full lipid profile. Of the 30 patients in the study, 27 showed not only gross but grotesque abnormalities. These same abnormalities have also been observed by Professor Anthony Komaroff at Harvard Medical School. Professor Behan said that in M.E. there is not only abnor,al carnitine metabolism, but abnormal lipid metabolism as well and that this has not so far been looked for in these cases.

He then mentioned briefly that there is abnormal immune function in M.E. and that there is non-specific impairment of NK cells especially (natural killer cells are able to kill certain types of cancer cells), and this is another abnormality in which there are gross differences between these patients and normal controls.

Professor Behan then moved on the SPECT scans, which his team have been doing for some years. They use serial SPECT scans to see if the abnormality which was present on one scan would have disappeared the next time. Patients with M.E. demonstrate that there are metabolic deficits in the temporal, occipital and fronto-parietal areas, all amounting to gross lesions within these patients.

Another test used by the Glasgow team in M.E. patients is the water-loading test, which is given in the morning; the urinary output is measured over the next three hours, and in M.E. patients the results were grossly abnormal.

This study done by the Glasgow team was to measure the serum osmolarity and the urine osmolarity and also to measure the pruduct of the posterior pituitary, argenine vasopressin (AGP) (5). The stimulus for AGP comes from the paraventricular nucleus of the hypothalamus, and when patients were given the water deprivation and water loading tests, there was an erratic, crazy production in these cases.

At this point, Prfessor Behan stated that in his opinion, these test results bring home the fallacy of simply examining someone in a clinic with a tendon hammer and a stethoscope and pronouncing the patient to be normal.

He then showed a slide of the paraventricular nuclei of a perfectly healthy ratt which was stained to look for activated receptors on neuroendoctrine cells, and also to measure a hormone, the presence of which is an index of the activity of that part of the gland. He told us that Professor Christiansen of Sweden had injected these normal rats with trypanosomes (mycroscopic parasites) and that the trypanosome does not get into the hypothalamus, but does get into other parts of the brain stem where the blood-brain-barrier is broken down (6). Having got into parts of the brain stem, an immune reaction is elicited. The activated T-cells produce cytokines (chemical messengers) and once these cytokines are produced, an enormous turn-on of the hypothalamus occurs; this is a selective turn-on of the paraventricular nuclei.

Professor Behan then showed a slide of the brain stem demonstrating the reticular formation and various nuclei in the hypothalamus to which he had been referring, stating that these nuclei are the ones involved in viral infections, particularly polio infections. He said it is known that in the post-polio syndrome (PPS), if patients with severe fatigue have their growth hormone measured, it is low. Growth hormone has rapid daily fluctuations, but it is carried by a protein which does not fluctuate. The Glasgow team decided to measure growth hormone levels in patients with M.E., in patients with depression and in controls. They found that in M.E, at base line, the growth hormone levels are very low. Moreover, if patients are then stimulated by being given steroids (which should result in a massive up-swing), ther is no question that compared with controls, M.E. patients have no response. This work has been repeated in five different laboratories and the growth hormone abnormality in M.E has been absolutely confirmed. (Among other things, growth hormone increases protein synthesis.)

To tie the whole thing up, Professor Behan explained that 5 H-T is particularly interesting. It is produced in the median eminance of the midbrain and sends fibres directly to the paraventricular nucleus and from there to the median eminance controlling the release of steroids. Thus if you give a 5 H-T agonist, there would be a rise in cortisol, so with this in mind, the team did an experiment with a pure 5 H-T agonist and found that in patients with M.E. there is a very blunted response. This demonstrates that there is something wrong between the 5 H-T axis and the production of cortisol (the hormone required for normal response to any stress). This test has also been done with prolactin; again, there is a conspicuous difference between patients with M.E., with depressives and with controls. The depressives react entirely differently from patients with this syndrome. Professor Behan noted that with any adrenal damage, there is supersensitivity to 5 H-T receptors.

So what causes this illness? Is it a defect of carbohydrate metabolism? Is it a muscle abnormality? The illness cannot be due to all of these but if you have a central cellular deficit which was giving rise to a number of other abnormalities, that might explain the whole picture.

The thinking at the moment is that in patients who are perhaps susceptiple, and depending on the stimulus and upon the time the stimulus is given, whether this is a virus or a toxin, damage occurs. This damage has to be fundamental because of the number of tissues involved, and is almost certainly at an enzyme level. this affects the subtle metabolism of the cell, probably in relation to potassium channels.

At present, professional departments in Sweden, London, Harvard, and of course Glasgow are looking carefully to see if they can dissect out of this abnormality in very subtle ways, to see what the lesion is. This lesion will have enormous importance, not only for M.E., but particularly in multiple sclerosis and all those other diseases where fatigue is a feature. Until this particular lesion is understood, a rational mode of therapy cannot be brought about.

Professor Behan concluded that in his own time of looking at M.E., he has seen far too many people who have been told that it's all in their head and that they are crazy. The end result has been that several committed suicide and others have been caused the most terrible distress.

1. Electromyogram, is a continuous recording of the electrical activity of a muscle by means of electrodes inserted into muscle fibres.

2. Nuclear magnetic resonance is a technique of chemical analysis used in the diagnosis of brain abnormalities based on the absorption of specific radio frequencies by atomic nuclei, enabling imaging of soft tissues anywhere in the body in any plane.

3. Glycolysis is the conversion of glucose to lactic acid, which process involves the production of energy.

4. Thallium scans are a method of studying blood flow theough the heart muscle using an injection of the radioosotope thallium-201.

5. Argenine is an amino acid which plays an important role in the formation of urea (the main breakdown product of protein metabolism by the liver, and vasopressin is the anti-diuretic hormone, or ADH.

6. Blood-brain-barrier (BBB) is the mechanism whereby circulating blood is kept separate from the tissue fluids surrounding the brain cells and which excludes solid particles and large molecules; this can break down after injuries such as whiplash.