Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA

Abstract:

A subgenomic restriction fragment from cDNA prepared from Coxsackie B2 virus (CVB2) RNA was subcloned into a riboprobe vector allowing the production of enteroviral group-specific RNA probes complementary to either the positive (genomic) or negative (template) strand of enteroviral RNA. These riboprobes were used to follow productive infection of cultured cells by CVB2; as expected, positive strand RNA was synthesized in approximately 100-fold excess over negative strand.

RNA was extracted from muscle biopsy samples from patients with chronic fatigue syndrome and probed for the presence of enteroviral RNA. In cases where enteroviral RNA was detected the amounts of positive and negative strands of enteroviral RNA were approximately equal, in contrast to the situation in lytic infection of cultured cells.

This suggests that enterovirus persistence in muscle is due to a defect in control of viral RNA synthesis.

 

Source: Cunningham L, Bowles NE, Lane RJ, Dubowitz V, Archard LC. Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA. J Gen Virol. 1990 Jun;71 ( Pt 6):1399-402. http://www.ncbi.nlm.nih.gov/pubmed/2161907

 

Depression and myalgic encephalomyelitis

This comment, published in the Journal of the Royal Society of Medicine in May 1990, was written in response to a letter by Dr. Lev. You can read the letter here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1292388/

 

We read the letter from Lev (November 1989 JRSM, p 693) with interest, but see a danger in using assumptions as to aetiology in definition of study groups. Operational definitions not making this assumption will produce replicable findings and progress towards better definitions and understanding of aetiology.

Definitions of depressed control groups are difficult, for example the following need to be controlled:

(1) Demographic variables

(2) Severity of depression symptoms: inappropriate control groups for ME patients would be severely depressed inpatients. Outpatient depressives are not too dissimilar in severity.

(3) Psychotropic medication: this is less likely to be given to ME patients where treatment is not agreed and could modify symptoms to be compared.

(4) Psychiatric history: in possible ME patients a previous significant psychiatric illness prior to fatigue symptoms leads to difficulty in studying this symptom and produces too much overlap with depressed controls.

(5) History of febrile illness: to minimize overlap, one must also control for preceding febrile illness in otherwise typical depressive illness.

Comparison of control groups should be serial, not cross-sectional as physical symptoms and markers may fluctuate, as may fatigue and depression.

Assessment of depressive symptoms is difficult, as Lev points out, due to non-specific ‘biological’ symptoms of depression. However, psychic ones such as pessimism should not overlap and could be assessed.

The concept of fatigue is poorly understood, as is its assessment. The paradigm of pain research has much to offer, where ‘dichotomization’ of physical and psychological components is not thought useful, but assessment emphasizes all components of the experience of pain. Thus, psychometric assessment of fatigue, for example, its severity, frequency, and pattern may be a future research area. Using such a paradigm, our initial findings of differences in fatigue in the two groups are because depressed patients are predominantly anergic, but ‘ME’ patients have more variability and unpredictable onset of fatigue relative to the severity of exercise attempted. Lack of motivation overlaps in both groups, explicable in Lev’s own terms as due to a reaction to a chronic illness.

~SEAN LYNCH Lecturer and Honorary Senior Registrar in Psychiatry

~RAM SETH Senior Registrar in Psychiatry St Charles Hospital, London

 

Source: S Lynch and R Seth. Depression and myalgic encephalomyelitis. J R Soc Med. 1990 May; 83(5): 341. PMCID: PMC1292666. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1292666/pdf/jrsocmed00136-0073a.pdf

 

The low yield of physical examinations and laboratory investigations of patients with chronic fatigue

Abstract:

Fatigue is a common symptom but guidelines for its appropriate evaluation are lacking. The authors prospectively studied 100 adults with a chief complaint of fatigue lasting at least 1 month in order to determine the diagnostic contribution of physical examinations and laboratory investigations.

The evaluations were performed in the specialized clinic of a faculty practice. Physical examinations produced diagnostic information in 2% of patients, and laboratory investigations elucidated the cause of fatigue in 5% of patients. Structured follow-up evaluations after an average interval of 10 months failed to reveal any new organic causes for the fatigue symptom. Minor laboratory abnormalities were relatively common but did not contribute to the diagnostic process and did not seem to influence the clinical outcome.

The authors conclude that the traditional medical evaluation of patients complaining of chronic fatigue has a low yield in discovering treatable physical disorders.

 

Source:  Lane TJ, Matthews DA, Manu P. The low yield of physical examinations and laboratory investigations of patients with chronic fatigue. Am J Med Sci. 1990 May;299(5):313-8. http://www.ncbi.nlm.nih.gov/pubmed/2337122

 

The psychiatric status of patients with the chronic fatigue syndrome

Abstract:

The prevalence of psychiatric disorder in 48 patients with chronic fatigue syndrome (CFS) was determined. Twenty-two had had a major depressive (non-endogenous) episode during the course of their illness, while seven had a current major (non-endogenous) depression.

The pre-morbid prevalence of major depression (12.5%) and of total psychiatric disorder (24.5%) was no higher than general community estimates. The pattern of psychiatric symptoms in the CFS patients was significantly different to that of 48 patients with non-endogenous depression, but was comparable with that observed in other medical disorders. Patients with CFS were not excessively hypochondriacal.

We conclude that psychological disturbance is likely to be a consequence of, rather than an antecedent risk factor to the syndrome.

 

Source: Hickie I, Lloyd A, Wakefield D, Parker G. The psychiatric status of patients with the chronic fatigue syndrome. Br J Psychiatry. 1990 Apr;156:534-40. http://www.ncbi.nlm.nih.gov/pubmed/2386862

 

Myalgic encephalomyelitis

Note: This letter appeared in the British Journal of General  Practice in April 1990.

 

Sir, During the past few months the Myalgic Encephalomyelitis Association has initiated a determined effort to find a cure for this devastating disease. A scientific and medical advisory panel has been formed under the chairmanship of Professor James Mowbray of St Mary’s Hospital Medical School, and in order to fund much needed research the Breakthrough Trust has been established and is already attracting money.

The scientific and medical advisory panel is anxious to stimulate new thought on research into the causes of myalgic encephalomyelitis, its possible treatments and, most important of all, research into finding a cure. Because of the complexities of the disease members of the panel would welcome new ideas and requests for grants from a wide variety of disciplines. Any such applications should be sent to me at the Myalgic Encephalomyelitis Association.

STEPHEN POWELL

Myalgic Encephalomyelitis Association

PO Box 8, Stanford le Hope

Essex SS17 8EX

 

Source:  S Powell. Myalgic encephalomyelitis. Br J Gen Pract. 1990 Apr; 40(333): 170. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1371257/

 

Myalgic encephalomyelitis

Note: This letter appeared in the Journal of the Royal Society of Medicine in March 1990.

 

We accept that Martin Lev (November 1989 JRSM, p 693) is correct to point out that the anxiety and depression noted in patients labelled as suffering from ‘ME’ are the consequence of ‘underlying organic processes’. The demonstration of hyperventilation in the overwhelming majority of these patients (Rosen SD, King JC, Nixon PGF, unpublished results), provides a clear metabolic reason for the anxiety (1-3). ‘Depression’ is a predictable reaction to the inability to make and sustain effort due in part to the ease of acidosis of muscle cells depleted of buffer base reserves(4).

We agree with Sargant(5), that the sufferers from the late stages of effort syndrome, who have nothing to gain from their ill health and much to lose, are among the most gifted and energetic of people, and consequently the most upset about the frustration caused by loss of performance.

~S D ROSEN Cardiac Registrar

~J C KING Honorary Head Occupational Therapist (Research)

~P G F NIXON Consultant Cardiologist Charing Cross Hospital London

 

 References

1 Lewis T, et al. Breathlessness in soldiers suffering from irritable heart. Br Med J 14 October 1916:517-19

2 Lum LC. The syndrome of chronic habitual hyperventilation. In: Hill OW, ed. Modern trends in psychosomatic medicine, vol. 3. London: Butterworths, 1976: 196-230

3 Groen JJ. The measurement of emotion and arousal in the clinical physiological laboratory and in medical practice. In: Levi L, ed. The emotions: their parameters and measurement. New York: Raven Press, 1975:727-46

4 Rosen SD, King JC, Nixon PGF. Magnetic resonance muscle studies. J R Soc Med 1988;81:676-7 5 Sargant W. Battle for the mind Aphysiology ofconversion and brain-washing. London: Heinemann 1957

 

Source:  Rosen, SD, King, JC, Nixon, PGF. Myalgic encephalomyelitis. Journal of the Royal Society of Medicine Volume 83 March 1990.  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1292587/

 

Sensory and cognitive event-related potentials in myalgic encephalomyelitis

Abstract:

Myalgic Encephalomyelitis (ME) is a form of post viral fatigue syndrome resulting in myalgia and fluctuating fatiguability. Symptoms reflecting central nervous system dysfunction are common and include muscle weakness, headache, sensory disturbances, poor short term memory and impairment of concentration.

In view of the fact that sensory and cognitive disturbances are experienced by many patients objective evidence was sought with multi-modality sensory evoked potentials and auditory event-related cognitive potentials in a group of ME patients both with and without the enteroviral antigen, VP1 test positive.

The auditory brainstem, median nerve somatosensory and pattern reversal checkerboard visual potentials were normal for all 37 patients tested. In contrast to the sensory potentials significant differences in the mean latencies of the cognitive potential N2 and P3 were found. Reaction times were also significantly prolonged but the performance in terms of error was not significantly affected. No significant difference emerged in any of the parameters for the VP1 test. P3 was abnormal in latency or amplitude in 36% of the VP1 positive patients for the frequency discrimination task and 48% for the more difficult duration discrimination task.

The abnormalities indicate attentional deficits in some patients and slower speed of information processing in others. The prolonged latencies observed in these patients have not been observed in patients with depression in many other studies.

 

Source: Prasher D, Smith A, Findley L. Sensory and cognitive event-related potentials in myalgic encephalomyelitis. J Neurol Neurosurg Psychiatry. 1990 Mar;53(3):247-53. http://www.ncbi.nlm.nih.gov/pubmed/2324756

Note: You can read the full article here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1014138/

 

High frequency of fibromyalgia in patients with chronic fatigue seen in a primary care practice

Abstract:

We administered a standardized history questionnaire and performed a tender point examination on 27 patients with debilitating fatigue of at least 6 months duration, seen in a primary care practice, as well as on 20 patients with fibromyalgia.

Sixteen of the 27 patients with chronic fatigue met the full criteria for the working case definition of chronic fatigue syndrome (CFS). Eight patients with chronic fatigue denied having any current persistent, diffuse musculoskeletal pain, and their tender point scores were similar to those in 10 normal control subjects. In contrast, 19 patients with chronic fatigue (70%) had persistent, diffuse musculoskeletal pain.

The results of their tender point examinations were similar to those of the patients with fibromyalgia. Thus, the majority of these patients with debilitating chronic fatigue, including those who met criteria for CFS, met the historical and tender point diagnostic criteria for fibromyalgia. The presence of current musculoskeletal pain will identify those CFS patients who have fibromyalgia.

 

Source: Goldenberg DL, Simms RW, Geiger A, Komaroff AL. High frequency of fibromyalgia in patients with chronic fatigue seen in a primary care practice. Arthritis Rheum. 1990 Mar;33(3):381-7. http://www.ncbi.nlm.nih.gov/pubmed/2317224

 

Old wine in new bottles: neurasthenia and ‘ME’

Abstract:

The history of  is discussed in the light of current interest in chronic fatigue, and in particular the illness called myalgic encephalomyelitis (‘ME’). A comparison is made of the symptoms, presumed aetiologies and treatment of both illnesses, as well as their social setting.

It is shown that neurasthenia remained popular as long as it was viewed as a non-psychiatric, neurological illness caused by environmental factors which affected successful people and for which the cure was rest. The decline in neurasthenia was related to the changes which occurred in each of these views. It is argued that similar factors are associated with the current interest in myalgic encephalomyelitis.

It is further argued that neither neurasthenia nor ‘ME’ can be fully understood within a single medical or psychiatric model. Instead both have arisen in the context of contemporary explanations and attitudes involving mental illness. Future understanding, treatment and prevention of these and related illnesses will depend upon both psychosocial and neurobiological explanations of physical and mental fatigability.

 

Source:  Wessely S. Old wine in new bottles: neurasthenia and ‘ME’. Psychol Med. 1990 Feb;20(1):35-53.  http://www.ncbi.nlm.nih.gov/pubmed/2181519

 

Management of post-viral fatigue syndrome

Note: This letter appeared in the February 1990 issue of the British Journal of General Practice. The letter was written in response to an article, “Patient management of post-viral fatigue syndrome,” written by Dr. Ho-Yen, in which he advised that patients rest. You can read the article here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1371214/

 

Management of the post-viral fatigue syndrome Sir, We read with interest Dr Ho-Yen’s thoughtful paper on the management of the post-viral fatigue syndrome (January Journal, p.37) and welcome the renewed interest in practical management. Dr HoYen’s article is written in response to our previous paper on the subject, (1) and although there are differences between the two approaches, we must first point out the considerable areas of agreement between us, perhaps no more so than the emphasis on the role of the general practitioner, and of the crucial importance of a healthy doctor-patient relationship.

Many of the apparent differences between our approach and that of Dr HoYen are, as he states, due to sample differences. Our experience is based on patients with chronic illness seen in specialist neurological settings with a mean illness duration of five years.(2 )Dr Ho-Yen is familiar with patients with shorter illness durations, referred for a microbiological opinion. Many of the strategies advocated by Dr Ho-Yen are therefore designed for those in whom spontaneous recovery can still be anticipated. However, what about when such recovery has not occurred? In the two largest samples to date others have noted ‘an alarming tendency to chronicity (1,3) and it has been alleged that ‘most of the cases seen do not improve, give up their work and become permanent invalids’.(4) The current therapeutic approach for these patients is obviously unsatisfactory.

How does such chronicity develop? Dr Ho-Yen criticizes the first stage of the model we proposed to explain such chronicity, and points out that far from initially adopting forced inactivity after a viral infection, many chronic sufferers did the opposite, and tried to exercise away the fatigue. We accept his observation. Dr HoYen’s comments do indeed coincide with our own clinical impressions: many patients report initially adopting such strategies, and find that these are unsatisfactory, leading to a rapid recurrence of symptoms. However, we suggest this is an even more convincing explanation of the remainder of the model we propose Simple operant conditioning suggests that such a powerful experience of failure will lead to persistent avoidance, perhaps when the original need for it is no longer present. We also suggest that early and repeated exposure to uncontrollable, aversive and mysterious symptoms, such as the profound muscle pain that characterizes the syndrome, is another potent cause of the demoralization and helplessness so frequently found (Powell R, Wessely S, manuscript submitted for publication) and may in turn explain the high rates of mood disorder that have been observed in several studies.

We do, however, disagree that the management we advocate is to ‘get out and exercise’. This is a common misconception. Cognitive behavioural therapy is not exercise therapy, and we are not physiotherapists. It is true that in the later stages of treatment patients are encouraged to increase their activity (which must ultimately be the aim of any treatment) but therapy does not involve the simple prescription of set amounts of exercise. Instead, treatment is based on mutually agreed targets, which are themselves jointly chosen as being some activity that the patient wishes to undertake, but has avoided. In practice this may simply be brushing one’s teeth, or sitting out of bed to eat a meal. The behaviour is chosen solely on the basis of avoidance; the physiological and ergonomic consequences of such activity are irrelevant. The aim is to introduce predictability, and the return of self-control and self efficacy, not to restore muscle power. Furthermore, the other important component of our approach to management is an awareness of emotional disorders, and a recognition that these may need treatment in their own right.

We agree that the management we advocate is neither new nor unique. Almost identical management is now the treatment of choice for chronic pain (5) and fibromyalgia. (6) The latter is particularly relevant, since it is increasingly accepted that fibromyalgia may indeed be the same condition as post-viral fatigue.(7) Furthermore, it is difficult to think of a pathological mechanism by which gradual increased activity could be harmful, (8’9) even in the minority of patients with clear cut neuromuscular pathology.

The final decision must be based on evidence. We have already announced preliminary details of a pilot evaluation of cognitive behavioural therapy (Wessely S, et al, abstract presented at the scientific meeting of the Royal College of Psychiatrists, London, 25 September 1989). Our conclusion was that the advice currently offered to these patients may not be accurate, and that the current therapeutic nihilism in this condition may be unduly pessimistic.

In summary, the differences between our approach and that of Dr Ho-Yen may be less marked than at first sight. Given the difference in our samples and clinical experience, one might summarize by saying that whereas Dr Ho-Yen correctly emphasizes the dangers of doing too much, too early in the natural history of the condition, we emphasize the equally damaging consequences of doing too little, too late. The most appropriate strategy depends upon the stage of the illness reached by the patient.

~SIMON WESSELY , ANTHONY DAVID Institute of Psychiatry De Crespigny Park London SE5 8AF

~SUE BUTLER, TRUDIE CHALDER National Hospital for Nervous Diseases Queen Square London WC1N 3BG

References

  1. Wessely S, David A, Butler S, Chalder T. The management of chronic post-viral fatigue syndrome. J R Coll Gen Pract 1989; 39: 26-29.
  2. Wessely S, Powell R. Fatigue syndromes: a comparison of chronic ‘postviral’ fatigue with neuromuscular and affective disorders. J Neurol Neurosurg Psychiatry 1989; 52: 940-948.
  3. Smith D. Myalgic encephalomyelitis. In: 1989 Members’ reference book. London: Sabrecrown Publishing, 1989: 247-250.
  4. Behan P, Behan W. The postviral fatigue syndrome. CRC Crit Rev Neurobiol 1988; 42: 157-158.
  5. Pither C. Treatment of persistent pain. Br Med J 1989; 299: 1239.
  6. Yunus M. Diagnosis, etiology and management of fibromyalgia syndrome: an update. Comp Ther 1988; 14: 8-20.
  7. Goldenberg D. Fibromyalgia and other chronic fatigue syndromes: is there evidence for chronic viral disease? Semin Arthritis Rheum 1988; 18: 111-120.
  8. Vignos P. Physical models of rehabilitation in neuromuscular disease. Muscle Nerve 1981; 6: 323-338.
  9. Milner-Brown S, Miller R. Muscle strengthening through high-resistance weight training in patients with neuromuscular disorders. Arch Phys Med Rehabil 1988; 69; 14-19

 

Source: Wessely S, David A, Butler S, Chalder T. Management of post-viral fatigue syndrome. Br J Gen Pract. 1990 Feb;40(331):82-3. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1371151/pdf/brjgenprac00083-0040.pdf