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There still remains much doubt as to what causes ME/CFS, however research is helping to shed more light on this perplexing condition. One Doctor with ME has likened the history of research attempts into the condition to that of a 'detective novel' in that clues have arisen, but often some of these clues have transpired to be 'red herrings' (Macintyre,1998).

Research Difficulties in ME/CFS

Research into the condition has also been complicated by the ongoing debate in the medical profession as to whether the condition was a genuine organic illness. As a result, there have been many setbacks and obstacles to overcome which have impeded progress into expanding our knowledge of this illness. In addition, this has not been helped by the mixed publicity the illness has received, with terms like 'Yuppie Flu' often being used by some in the media. Fortunately, medical professionals and governments are increasingly beginning to recognise the condition as a genuinely debilitating physical illness and more research is being carried out. Nevertheless, there is still a great deal of work to be done and there is no consensus as to what causes the condition.

This can be well exemplified by the quotations below from various prominent and experienced researchers into the condition:

1) “The condition (ME) appears to be a rare complication, mainly in non-immune adults, of a widespread often asymptomatic childhood infection. The group of viruses most consistently associated with ME are the non-polio enteroviruses - including Coxsackie and echoviruses. When the host immune response is ineffective, viral parasitism leads to mitochondrial damage with resultant energy deficits at cellular level.”[1] (Dowsett, 1990).

2) “It is presumed that CFIDS (CFS) is a cytokine-mediated illness, virally induced, in genetically susceptible individuals.” [2] (Goldstein, 1990).

3) “Post-viral fatigue syndrome is a metabolic disorder, caused by persistent virus infection and associated with defective immunoregulation[3] (Behan, 1985).

However, according to Dr. Charles Shepherd, there is an acknowledgement that ME/CFS is a three-stage illness which encompasses: (a) predisposing factors which result in people being more susceptible; (b) events that subsequently stress the immune system and thus prompt the onset; and (c) factors that contribute to perpetuating the symptoms and consequent disability.[4]

Predisposing Factors in ME/CFS

It seems that a variety of factors may have a part in contributing to whether a person is susceptible to developing ME/CFS when an event (such as a infection, vaccination, toxin or stress) occurs.  According to Shepherd (1999), the most important of these are age, genetics, sex and psychological influences (constant stress, personality and prior mental health problems).[5]  One study has shown that around 75% of people who develop the condition do so between the end of their teenage years and their mid-40's and that women may be more vulnerable to the illness to a ratio of 3:1.[6]  There are also some who believe that inherited genetic defects may be present in those who have ME/CFS which makes them less able to react to infections and other stresses on their system. Some psychiatrists believe that your mental health and personality-type may make individuals more likely to develop ME/CFS.  However, little research has been done in this area and one of the few studies carried out could find no evidence that those suffering from the condition were perfectionists or had exceptionally high personal standards.[7]

A particularly common cited trigger for the development of ME/CFS is that of excessive physical or mental stress. For instance, one study recorded that one-third of patients reported a stressful event prior to onset,[8] whilst in a second the figure rose to 95%.[9]

How then does stress potentially play a part in ME/CFS? The relationship between stress and ME/CFS has to be understood in terms of the body's reaction to such influences through the hypothalamus (a small gland situated in the brain). In response to stress, this gland releases two important hormones called arginine vasopression (AVP) and cortisol releasing factor (CRF).  At times of high stress, the body normally stimulates the production of cortisol through the production of corticotrophin releasing hormone (CRH) which helps it deal with stress. Under normal circumstances, the amount of CRH and cortisol increase quickly before decreasing to their normal levels. However, in cases where people endure chronic levels of physical and mental stress, something different takes place. What occurs in the body is that the hypothalamus, rather than producing CRH and cortisol, generates AVP which means that the body's does not react to stress in the normal way (Wessely, et al, 1999; Shepherd, 1999).

As a result, increasing attention is being focused on this area of research. Studies have shown that people suffering from chronic fatigue tend to have low cortisol levels.[10][11][12]. This is particularly noteworthy as it stands in contrast to people with depression (who have high levels of cortisol). As a result researchers such as Wessley et al. have argued that "...a good theoretical case can be made for linking low central CRH (corticotrophin releasing hormone), low peripheral cortisol and some of the symptoms of CFS.”[13] (Wessely et al., 1999). Stress may also impact upon ME/CFS through making the blood-brain barrier more permeable (Shepherd, 1999).

Precipitating Events in ME/CFS

It appears that the majority of people suffering from ME/CFS, generally can trace the onset of their illness to a viral-type illness. A recent series of studies has confirmed this, with 72% in the UK[14], 78% in a Japanese series[15], 86% in Holland[16], increasing to 91% in an American report.[17] As a result a great deal of attention has been placed on various infections and viruses. Initially most of this attention focused on enteroviruses (due to their links with some polio symptoms) and the Epstein-Barr virus. In particular, the latter virus family generated a substantial degree of interest in the USA, which resulted in the condition being called 'Chronic Epstein-Barr' for a period. However, it soon transpired that other viruses and infections could trigger ME/CFS and consequently the focus of attention was broadened to include other viruses in addition to Enteroviruses and the Epstein-Barr virus:

  • Human Herpes Virus 6 (HHV6)
  • Human LymphoTrophic Virus 2 (HLTV2)
  • Borna Virus
  • Inoue-Melnick Virus and Stealth Virus
  • Cytomegalovirus

However, it is important to note that although viruses are often thought to be implicated, for some sufferers, the condition may be precipitated by bacterial infections or even vaccinations, toxins and pesticides (Shepherd, 1999; Macintyre, 1998).

Perpetuating Factors in ME/CFS

At present, most of the research into ME/CFS is being focused into the factors that maintain or perpetuate the poor health and disability that sufferers experience. Most of this attention has been concentrated on the role of infection, immune system responses, muscle abnormalities, and the inter-relationship with psychological factors. Unfortunately, much of the work by researchers has been either inconsistent or conflicting. Nevertheless, there does appear to be an increasing belief that disturbances in brain function exist (especially with regard to chemical transmitters, hormones, blood flow patterns and sleep) in ME/CFS (Shepherd, 1999).

Is ME/CFS the result of a Persistent Viral Infection?

One of the most commonly asked questions centres on whether the condition is the result of an ongoing Persistent Viral Fatigue Syndrome. This school of thought centres on incidences where a virus does not elicit a successful immune response and is thus not destroyed or results in cellular damage/interference. Suggestions for why this might occur are for instance (Shepherd, 1999):

  • Under serious viral infections, such as Polio, when a virus multiplies with such force at an intracellular level that it can result in irreversible cellular damage, impairment or death of the cell.
  • Other instances can occur where viruses in cells are able to persist and remain dormant. While latent these viruses can do little or no damage, but can become reactivated such as the virus associated with Glandular Fever (Epstein-Barr virus).
  • One further potential explanation could lie with the body's immune system continually reacting to dormant viruses within cells, thus causing damage to cells.
  • Additionally, another suggestion is that viruses may rest within cells, and rather than causing any microscopic damage, interfere with the proper functioning of the cell.[18]

So is there any evidence of Ongoing Viral Infection in ME/CFS?

From the research carried out to date, it would appear that whilst there is substantial evidence for viruses triggering ME/CFS, there is much less consensus over whether persisting viruses are responsible for the perpetuating the condition. Likewise, it is still uncertain as to whether reactivated Herpes viruses such as Epstein-Barr (EBV) and Human Herpes Virus 6 (HHV6) play a part. Most specialists now do not believe that viruses such as Epstein-Barr play a part in ME/CFS (Shepherd, 1998). However, this view has been challenged recently in a study that showed that a fatigue syndrome existed after glandular fever, and one that was distinct from depression[19] (Wessely et al., 1999).

Could ME/CFS be the result of Immune System Abnormalities?

Another area that researchers are looking into centres on the manner in which our immune system reacts to the particular circumstance that prompts the beginning of the condition. What has stimulated their interest in this area? Many researchers have begun to speculate as to whether the commonly reported 'flu-like malaise' symptoms (temperatures, sore throats, enlarged glands...) that sufferers commonly report could be the result of the immune system failing to 'shut down' after it has initially responded.

Findings from various research groups in the UK, USA and Australia have highlighted a large number of subtle abnormalities within the immune system. For instance, Levy  (1994) has argued that immunological changes could represent a hyperactive immune system secondary to viral infection
[20]; and Komaroff believes that CFS is a disorder of immune regulation of viral activity.[21]  However, as with most research conducted into ME/CFS, the results have often been at variance with one-another perhaps due to differences of illness duration, severity, age, sex, physical fitness and state of mind (Shepherd, 1999). As a result, Wessely (1999) argues that "..investigating possible abnormalities of the immune system" in CFS patients "...is a daunting task."[22]

What about Muscle Abnormalities?

The fact that muscle symptoms (such as post-exercise fatigue, pain and occasionally twitching) are evident in ME/CFS, has prompted some researchers into analysing both the structure and function of muscle. The uncertainty for researchers in this area centres on whether muscle symptoms are the result of a defect in the muscle, the brain ('central fatigue') or a mixture of both. However, a great number of medical professionals linked to ME/CFS are doubtful about studies which have possibly indicated muscle abnormalities (Shepherd, 1999). Research in this area has tended to focus on whether there is evidence of persistent viral infection in muscles as well as areas such as carnitine deficiency (studies in the UK[23] and Japan[24] have reported that CFS sufferers may benefit from the amino acid carnitine).

Are Brain and Nervous System Abnormalities Present in ME/CFS?

In recent years the advent of more modern and advanced technology has permitted researchers to explore in much more depth the brain and nervous system of ME/CFS sufferers. As a consequence, researchers are beginning to report some important findings, especially with regard to hormones, chemical transmitters and blood supply to certain areas of the brain (Shepherd, 1999).

For instance, research at Johns Hopkins University School of Medicine in Boston on the autonomic nervous system specifically looked into whether there was a link between neurally mediated hypotension (NMH) and ME/CFS.[25] The purpose of this research was to see if there were any abnormalities in the co-ordination of nervous messages in connection with the heart and brain. The study measured 23 patients by way of a tilt-table test and showed that 22 of the 23 had an abnormal response.

Brain scans (using Magnetic Resonance Imaging (MRI)) have also showed that some abnormalities may exist in some ME/CFS patients. In addition, studies using SPECT scanning, which highlights the uptake of a radio-labelled substance that is put into the bloodstream, have shown that there is a substantial decrease of blood perfusion in the brainstem of CFS patients (compared to a control group).[26] Findings from both the UK [27] and Italy[28] appear to confirm that an abnormality of perfusion and metabolism exists in the brain stem of ME/CFS sufferers. Some medical professionals have suggested that the location of these abnormalities could help explain why sufferers may experience cognitive dysfunction and depression. However, it is important to note that these findings are not always easy to interpret as similar abnormalities are evident in both healthy and depressed people (Macintyre, 1998).

Perhaps the most exciting and uniform findings to come from research into brain abnormalities in recent years have arisen from studies into the neuro-endocrinology of ME/CFS. Neuro-endocrinology looks at the chemical substances that are generated by nerve cells that have an effect on other neurotransmitters or hormones (which have an effect on glands like the thyroid, adrenal or sex organs). Of the studies to date, the most interesting and key findings have focused on the role of the hypothalamus. This small but critically important part of the brain plays a part in the regulation of (Shepherd, 1999):

  • Autonomic nerves via the limbic system
  • Food intake and appetite
  • Body temperature
  • Sleep patterns
  • Various hormones within the body[29]

The principal abnormalities reported in relation to the hypothalamus have been to do with the hormones: Arginine vasopressin; Prolactin; and Cortisol. Of these three hormones, particular attention and interest has focused on Cortisol. A study by Demitrack and Straus (1991) showed that ME/CFS patients had lowered levels of cortisol.[30] According to Dr. Shepherd (1999) in addition to helping explain fatigue, decreased levels of circulating cortisol could also influence immune function through amplifying allergic responses and reactivating dormant infections such as the Epstein-Barr virus.[31] Other interesting research has been carried out on serotonin and acetylcholine.[32]


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[1] Dowsett, E.G., Ramsay, A.M., McCartney, R.A. and Bell, E.J. (1990) ‘Myalgic encephalomyelitis – a persistent viral infection?’, Postgraduate Medical Journal, 66, 526-30.

[2] Goldstein, J.A., (1990) ‘Presumed pathogenesis and treatment of the chronic fatigue syndrome/finromyalgia complex,’ Conference on chronic fatigue syndrome and fibromyalgia, Los Angeles, February, Abstract p.8.

[3] Behan, P.O., Behan, W.M.H., Bell, E.J. (1985) ‘The postviral fatigue syndrome – an anlaysis of the findings in 50 cases,’ Journal of Infection, 10, 211-22.

[4] Shepherd, C. (1999) ‘Living with M.E.’ p.25-32, p.123-156.

[5] Shepherd, C. ‘Living with M.E.’ p.27.

[6]Dowsett, E.G., Ramsay, A.M., McCartney, R.A. and Bell, E.J. (1990) ‘Myalgic encephalomyelitis – a persistent viral infection?’ Postgraduate Medical Journal, 66, 526-30.

[7] Wood, B. and Wessely, S. (1998), ‘Personality and social attitudes in chronic fatigue syndrome,’ Psychosomatic Medicine.  

[8] Wood, G., Bentall, R., Gopfert, M., Edwards, R. (1991) ‘A comparative psychiatric assessment of patients with chronic fatigue syndrome and muscle disease,’ Psychol. Medicine, 21: 619-628.

[9] Dobbins et al., (1995) ‘Physical, behavioural and psychological risk factors for chronic fatigue syndrome: a central role for stress?’ Journal of Chronic Fatigue Syndrome, 1: 43-58.

[10] Isaacs, R. (1948) ‘Chronic infectious mononucleosis,’ Blood, 3:858-861.

[11] Kleinman, A., Straus, S. (ed.) (1993) ‘Chronic Fatigue Syndrome.’

[12] Poletiakhoff, A. (1981) ‘Adrenocortical activity and some clinical findings in chronic fatigue,’ Journal of Psychosom. Research, 25: 91-95.

[13] Wessely et al., (1999) ‘Chronic Fatigue and its Syndromes’ p.259.

[14] Wessely, S., Powell, R. ‘Fatigue syndromes: a comparison of chronic ‘postviral’ fatigue with neuromuscular and affective disorder,’ Journal Neurol. Neurosurg. Psychiatry, 52: 940-948.

[15] Hashimoto, N. Kuraishi, Y., Yokose, T., et al. (1992) ‘Chronic fatigue syndrome – 51 cases in the Jikei University School of Medicine,’ Nippon Rinsho,  50:2653-64.

[16] Vercoulen, J., Swanink, C., Fennis, J., Galama, J., van de Meer, J., Bleijenberg, G. (1994) ‘Dimensional assessment of chronic fatigue syndrome,’ Journal Psychosom. Research, 38:383:392.

[17] Petersen, P., Schenck, C., Sherman, R. (1991) ‘Chronic fatigue syndrome in Minnesota,’ Minnesota Med. , 74:21-26.

[18] Shepherd, C. (1999) ‘Living with M.E.’ p. 125-127.

[19] White, P., Thomas, J. et al. (1995) ‘ The existence of a fatigue syndrome after glandular fever’, Psychol. Medicine, 25: 917-924.

[20] Levy, J et al. (1993) ‘Chronic Fatigue Syndrome: is it a state of chronic immune activation against an infectious virus?’ Contemp. Issues Infectious Diseases, 10: 127-145.

[21] Wessely et al., (1999) ‘Chronic Fatigue and its Syndromes’ p.208.

[22] Wessely et al., (1999) ‘Chronic Fatigue and its Syndromes’ p.205.

[23] Majeed, T. et al. (1995) ‘Abnormalities of carnitine metabolism in chronic fatigue syndrome,’ European  Journal of Neurology, 2, p. 425-8

[24] Kuratsune, H. et al. (1994) ‘Acylcarnitine deficiency in chronic fatigue syndrome,’ Clinical Infectious Diseases, 18 Suppl.1) p.62-7. 

[25] Rowe, C. et al. (1995) ‘Is neurally mediated hypotension an unrecognised cause of chronic fatigue?’ Lancet, p.345, 623-4.  Correspondence: 1995, 345, p.1112-1113.

[26] Costa, D.C., Tannock, C and Brostoff, J. (1995) ‘Brainstem perfusion is impaired in patients with chronic fatigue syndrome,’ Quarterly Journal of Medicine 88, p.767-73. 

[27] Costa, D.C., Tannock, C and Brostoff, J. (1995) ‘Brainstem perfusion is impaired in patients with chronic fatigue syndrome,’ Quarterly Journal of Medicine 88, p.767-73. 

[28] Tavio, M. et al. (1996) ‘Brain positron emission tomography (PET) in chronic fatigue syndrome: A useful tool for differential diagnosis,’ American Association for Chronic Fatigue Syndrome: Research Conference, San Francisco, 1996.

[29] Shepherd, C. (1999) ‘Living with M.E.’ p.147.

[30] Demitrack, M., Dale, J., Straus, S. et al. (1991) ‘Evidence for impaired activation of the hypothalamic –pituitary-adrenal axis in patients with chronic fatigue syndrome,’ J. Clin. Endocrinol. Metabol., 73: 1224-1234.

[31] Shepherd, C. (1999) ‘Living with M.E.’ p.149.

[32] Shepherd, C. (1999) ‘Living with M.E.’ p.154.