The person who strays away from the source is unroofed and is like dust blown about by the wind.
Molefi Kete Asante (1942–) US educator
Considerable controversy surrounds the cause or causes of CFS/ME. This chapter looks at the following possibilities:
Many people believe that CFS/ME is an immune disorder1–4 that enables viruses, which are normally controlled within the body, to go rampant and start to attack healthy body tissue in a similar way to AIDS, but without fatal consequences.
The immune system utilises helper T-cells, also known as thymus-dependent lymphocytes, which are cells that circulate through the blood and lymph nodes for many years waiting to attack foreign material that has invaded the body. They are produced in the thymus gland that lies in the upper part of the chest. The thymus gland is a vital part of the immune system.
The immune system produces chemicals as markers that enable the killer cells to blitz the bugs. These chemicals, known as cytokines, produce nasty side-effects such as sickness and lethargy. Patients with CFS/ME initially have an overactive immune system producing far too many T-cells. Certain enzymes, which help drive the immune reaction such as RNaseL, have been shown to be overactive.5–7 This leads to an interesting phenomenon experienced by most CFS/ME patients, at least in the early stages of the disease. Their families and friends may suffer from the occasional cold and bout of flu but CFS/ME patients will just feel groggy and weak with a worsening of their usual symptoms but without full-blown cold or flu symptoms. This is because the viruses in their upper respiratory tract are already being blasted by far too many T-cells, and, consequently, the usual viral symptoms, which are due to the normal immune response, do not occur.
After a while this situation may reverse and the immune system may become severely depressed, with the patient suffering from constant recurrent infections.
Many symptoms associated with CFS/ME, such as enlarged lymph glands, fever, gut symptoms, recurrent respiratory infections and pharyngitis, appear to indicate an immunological disorder. Indeed, the onset of the disease often appears to follow a viral infection. The body provides two basic forms of immune response: humoral and cellular (cell-mediated). Both forms are co-ordinated by the cells of the immune system and their mediators.
Humoral immunity is the major defence mechanism against bacterial infections and utilises circulating antibodies that are produced by specialised cells, B-cells, supported by other cells called T-helper/inducer cells. After recognising foreign material B-cells multiply rapidly and produce antibodies comprised of large immunoglobulins. These protein molecules are produced in large numbers and are usually specific to the infective or foreign agent. The antibodies form complexes with the foreign material and these complexes are then destroyed by other cells, such as macrophages.
Cellular immunity involves a variety of T-cells that are responsible for protection against viruses, cancers, and some disease-causing bacteria such as tuberculosis. T-helper (Th) cells assist B-cells in mounting a humoral response and cytotoxic T lymphocytes (Tc) can actively destroy abnormal cells in disease and malignancies. A further group of cells are natural killer (NK) cells, which play an important part in counteracting viral infections and cancer.
The complex interactions between all the B- and T-cells require cytokines (mentioned above), which are large protein signalling molecules. There are many types of cytokines, which are subdivided into smaller groups (e.g. interleukins and interferons). During an infection both T- and B-cells multiply rapidly, with cell numbers returning to normal levels after the antigen has been defeated. However, some memory cells remain so that a second infection is more rapidly combated. Some research findings8,9 have demonstrated a cytokine involvement in the pathophysiological mechanisms found in CFS/ME.
Inflammation is a complex response to localised injury and trauma and, although it is usually an acute response, there are a number of well-known chronic inflammatory diseases such as rheumatoid arthritis and sinusitis. The inflammatory response involves cytokines together with other classes of inflammatory modulators such as certain prostaglandins.
The recent controversy about the part of the MMR (measles, mumps and rubella) vaccine being associated with the development of autism involved the identification of grossly inflamed tissue in the lower part of the small intestine.10 Inflammation of this part of the gut is common among CFS/ME patients and many have been diagnosed with irritable bowel syndrome, inflammatory bowel disease, and Crohn’s disease. Allergic reactions to food containing gluten are common. The best known of these is coeliac disease in which the structure of the small bowel is destroyed, with a flattening of the deeply folded villi of the gut wall, and diminished capacity properly to absorb many key nutrients from food. Generally, CFS/ME patients do not test positive for coeliac disease but many become sensitive to chemicals and foodstuffs, especially gluten.
When digestion is impaired, the larger peptide fragments in food are not broken down. Among these are opioid peptides derived from two principal sources, casein in milk (the casomorphins) and gliadin in gluten (the gliadomorphins), which occur in wheat and other cereal crops such as rye and barley. Opioids are peptides that have been found to possess morphine-like activity and are known to be naturally occurring in important transmitter molecules, particularly in the gut, brain and immune system.
When the gut wall has increased permeability, these opioid peptides, which would normally be excluded, are absorbed and act both locally in the gut and in other organs, particularly the brain. The same factors that render the gut permeable appear to increase the permeability of the blood-brain barrier and allow access of these compounds to the brain.
Depending on the concentration of opioids in the gut, as well as permeability of the gut and blood-brain barrier, the overall level of these compounds in the bloodstream and the brain may vary and give rise to variable expressions of symptoms and dysfunction. Opioids play a significant part in the immune response through receptors found on cells of the immune system. Generally, they suppress the immune response and increase susceptibility to infection.
The gut and the brain communicate via messenger molecules generated by the immune response. There are receptors on brain cells for cytokines.
Sometimes the process that leads to CFS/ME may be linked to other more serious illness. A subset of disease-free breast cancer patients complained of a range of symptoms almost identical to CFS/ME sufferers, such as fatigue and loss of concentration.11 A previous link was made between non-Hodgkin’s lymphomas and CFS/ME following a 1988 epidemiological investigation into a cluster of CFS/ME sufferers in North Carolina.12
The symptoms and signs of CFS/ME are very similar to Addison’s disease (primary adrenal insufficiency). However, corticosteroid replacement, where there are no physical signs of adrenal compromise, is clearly unwarranted, as it would further exacerbate signs and symptoms. In fact, the only physical sign of adrenal dysfunction I have observed in CFS/ME is one usually attributed to high levels of cortisol, namely striae gravida (stretch marks), which are seen in Cushing’s syndrome.
Detoxification systems in the liver play a key part in the generalised stress response via their role in dealing with the metabolic products of stress. The gut has a complex immune system network controlled by an elaborate nerve supply that produces a number of neurotransmitters. Lymphocytes in the gut secrete small amounts of hormones that are thought to play a local part in regulating inflammation in the gut. It is possible that the release of hormones in the gut is influenced by stress. It is conceivable that these impairments may be a result of disrupted communications in the neuroimmune network.
The immune system has been shown to exert numerous effects on the hypothalamus and thus the autonomic nervous system. Immune activation is associated with increased firing rates of hypothalamic neurones. Activated immune cells release cytokines that are important mediators of the stress response. It is known that activated immune cells can cross the blood-brain barrier and release cytokines and other immune mediators into the central nervous system. Central and peripheral administration of cytokines affects a range of behaviours, including feeding, sleeping, drinking, levels of activity and mood, presumably by their action on receptor sites in the limbic system. Infections have an effect on the limbic system, which plays a major part in regulating memory and learning, and is directly involved in hypothalamic and autonomic function. Dysfunction of the limbic system in the brain may lead to many of the symptoms associated with CFS/ME and explain why these patients are very sensitive to both physical and psychological stress.13 Functional changes in limbic areas have been demonstrated in CFS/ME using SPECT scans (single-photon emission computerised tomography).14 The limbic system controls emotions and dream states and it is significant that patients with CFS/ME often complain of mood swings and weird or extremely vivid dreams, nightmares or, in some cases, hallucinations.
Some viruses have been implicated as possible causal factors in CFS/ME, as noted in Chapter 3. A class of virus, known as enteroviruses – such as the Coxsackie B group – are believed to be particularly important in triggering CFS/ME.15 Treatment approaches over recent years have focused on antiviral medications. However, most antiviral treatments have very unpleasant side effects and should be used with caution.
The antiviral drug val acyclovir has undergone vigorous tests16 to analyse its efficacy in treating CFS/ME. Acyclovir has been successful against the Epstein-Barr virus, but double-blind trials have shown it to have no greater effect on CFS/ME than a placebo.17 Most patients on the acyclovir drug trials reported that any improvement was short-lived and their symptoms returned soon after the treatment was completed.
The hypothalamus is the portion of the brain that controls and receives messages from the sympathetic nervous system. As we have seen (page 5) it becomes dysfunctional in CFS/ME. It also controls the release of the body’s hormones, thus hypothalamic dysfunction in CFS/ME may affect the entire endocrine system. Therefore, one might find excesses or deficiencies in many hormonal levels in patients with the disease. Both raised18 and reduced levels19 of a precursor of the major sex hormones – serum dehydroepiandrosterone (DHEA-S) – secreted from the adrenal glands, have been found in CFS/ME sufferers. As with many hormones, both high and low levels of melatonin, produced by the pineal gland, have been reported in a sample of patients with CFS/ME. Melatonin levels are found to be high when daytime drowsiness and excessive sleep are reported.20 However, when insomnia is a major symptom, supplements of melatonin usually prove to be beneficial.21
Insulin-like growth factor (IGF-1), the main mediator of growth hormone effects, is found to be reduced in CFS/ME sufferers. Growth hormone has been used to treat CFS/ME patients, showing a significant improvement in symptoms after six months in the experimental group compared with the control group of patients treated with a placebo.22 However, the improvement proved short lived after medication was discontinued.
The secondary feeling of depression and anxiety in CFS/ME is different to primary depression. However, antidepressant drugs have been used for symptomatic relief in many non-psychiatric illnesses such as Parkinson’s disease, multiple sclerosis and hypothyroidism. In the same way, antidepressants can sometimes reduce the signs and symptoms of CFS/ME; however, symptomatic improvement occurs at much lower doses and more rapidly than in depression. Many patients with CFS/ME who find it difficult to relax when trying to fall asleep are regularly advised to take 10 to 25 mg of amitriptyline one hour before retiring to bed. This is significantly less than the normal dose of this mild tricyclic antidepressant, which when prescribed for anxiety/depression is 150 mg a day. When the patient suffers with high anxiety a low dose of the selective serotonin re-uptake inhibitor (SSRI) type antidepressant, such as sertraline hydrochloride, has been shown to help but should be taken with caution.
Many patients with CFS/ME cannot tolerate the effects of SSRI antidepressants such as fluoxetine because they increase the amount of the neurotransmitter serotonin within the nervous system. Too much serotonin will overload the sympathetic nervous system aggravating most of the symptoms associated with CFS/ME. Thus dropout rates from studies of antidepressant therapy in CFS/ME exceed those of patients with depression.23–24 Signs and symptoms of depression in CFS/ME may occasionally be sufficiently severe to require full dose antidepressant therapy; however, the patients in these cases may have two distinct disorders, 1. CFS/ME and 2. clinical depression. Patients are of course allowed to have more than one thing wrong with them at a time! However, mostly the symptoms of depression are secondary to suffering such a depressing disorder as CFS/ME, which I term TFUS (Thoroughly Fed Up Syndrome).
As already discussed (pages 31–38) CFS/ME directly affects the immune mechanisms. Besides making the patient more susceptible to infections, it usually reduces the body’s capacity to cope with allergens, leading to increased intolerance to pollen, chemicals or foods. Some CFS/ME patients, with high levels of sensitivity bordering on allergy, have been treated by Miller neutralisation. The Miller technique involves provocation of the skin followed by the administration of a neutralisation ‘vaccine’ of individual allergens. It acts by stimulating the body to produce higher levels of detoxification enzymes, thus helping the body cope with the allergen.25
Enzyme-potentiated desensitisation (EPD) is another anti-allergy treatment that has benefited many CFS/ME patients by actively adding enzymes to enhance the desensitising effect and is applied to a scratch on the skin or by intradermal injection.26
Oxidative stress has been acknowledged as a common feature in many disease processes, including CFS/ME. Oxidative stress may induce many of the symptoms of CFS/ME. Excessive production of the free radical nitric oxide may damage the central nervous system. In an atom small negative charged electrons spin around the central nucleus, akin to planets orbiting the sun. Some atoms have electrons on their outer rings that are shared with other atoms. A group of atoms join to form a larger molecule. A free radical is a molecule with an atom that has lost one of these shared electrons from their outer ring. This will make it highly unstable and it will damage healthy tissue by trying to obtain another electron from an adjacent molecule. Oxygen reacts with free radicals to form peroxidised radicals, which further damage healthy molecules. Oxidative stress increases free radical production leading to further cell damage and worsening toxicity. External factors, such as environmental pollutants and radiation, can lead to major free radical production. Overall nitric oxide synthesis is increased in CFS/ME and may be induced by inflammatory cytokines.27 The neurotoxic effect is further aggravated by amplified sensitivity due to increased nitric oxide stimulation of the neurotransmitter glutamate.28
Antioxidants restore free radicals to healthy molecules. Antioxidants such as vitamin C have been shown to be major combatants in fighting disease ever since the 1950s when Harman29 discovered the part played by free radicals. The rationale for vitamin C infusion in CFS/ME rests on the traditional use of megadose vitamin C infusion treatments in autoimmune disease, allergy and a range of other conditions.30
Multiple chemical sensitivity, together with raised nitric oxide, plus an increase in blood–brain barrier permeability and gut wall permeability, leads to a group of patients with an inability to prevent toxic overload within the central nervous system. Furthermore, this leads to an inability to cope with the toxins.
Age: 48 years
Occupation: Community chaplain
Marital status: Married with 6 children.
The Reverend B had initially consulted me six years previously, when he had suffered from a mechanical strain of the neck. He had collapsed two years before that but no abnormality was detected at that time by his GP. His earlier neck problem was linked to his overall poor posture, especially in the middle part of his back, the dorsal spine, which was severely kyphotic (bent forward) and showed marked spondylotic changes. (Spondylitis is the name given to arthritis of the spine.)
In August 1990 he consulted me complaining of dizziness, nausea, frequent headaches and general fatigue, which was aggravated by exertion. He also complained of pain in both his legs, which worsened after an anti-tetanus injection. He was referred by his doctor to a neurologist, who examined him thoroughly but found no abnormalities. By the time he came to my practice, he was unable to walk. A taxi ferried him between my rooms and his house and, sadly, apart from these treatment sessions he was a virtual prisoner in his own home. He was obviously incapable of working and was clearly depressed about his inability to carry out his pastoral and educational duties.
This case may appear similar to Mr C (see Chapter 3), both with an obvious mechanical strain on the dorsal spine leading to symptoms of fatigue. However, there was one major difference that led to more severe problems affecting the minister. His symptoms were caused by an arthritic condition, leading to a permanent and restrictive disorder of the spine, whereas Mr C’s problem was due to bad posture adopted at home and at his shop.
Corrective exercises, together with spinal manipulation and massage, improved the spinal mechanics of the shopkeeper to bring about a total lasting cure. Unfortunately, this was not the case with the chaplain. Since his CFS/ME, in my estimation, was due to a permanent irritation of the dorsal spine, I could see no hope of a cure, until somebody found a panacea for arthritis. The best I could offer was to help relieve the symptoms.
Fifteen treatments over the first year produced encouraging signs of improvement. The dizziness became less frequent, and he found himself able to take short strolls up the street with less difficulty. Having been housebound, he was now able to lead a more normal existence. For many years after there was still some weakness, especially in his legs, but as the years have gone by he has felt less lethargic, with his headaches and dizziness occurring only very occasionally. He still continues the exercises prescribed during the early stages of treatment, which maintain as much mobility as possible in his thoracic spine.
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