ME Research UK — Energising ME Research

ME/CFS: A research and clinical conundrum

Author

Dr Vance Spence, Senior Research Fellow, Vascular Diseases Research Unit, Department of Medicine, University of Dundee, and Chairman of ME Research UK

Presentation

A presentation given on 3rd October 2003 at the workshop ‘New developments in the biology of ME/CFS’ at the West Park Conference Centre, University of Dundee

Part 2

What was this condition ‘Myalgic Encephalomyelitis’ that existed before 1988, before it was subsumed within the CFS construct, and which is still referred to by patients in the lay literature as ME? Myalgic encephalomyelitis was first defined by Acheson (1). It had been found to occur in epidemic and sporadic forms, and was believed to result from a continuing or persisting viral infection. It has been defined as a systemic illness characterised by marked muscle fatigability (not just weakness); muscle pain, tenderness and swelling; variable involvement of the central nervous system (ataxia and cranial nerve involvement); muscle weakness and/or sensory changes due to neuronal damage; impairment of memory; sleep disorders, etc.; vascular involvement (orthostatic tachycardia, pallor); reticulo-endothelial dysfunction; and recurrences of flu-like symptoms with myalgia.

From 1934 to 1990, there were at least sixty-three outbreaks of epidemic proportions, all well documented, and distributed geographically in North America (29 outbreaks), the UK (16), the rest of Europe (11), Australasia (4), Africa (2) and Asia (1). One of the most studied, and possibly the most controversial, of these outbreaks occurred at the Royal Free Hospital, London, in 1955, during which 292 people were affected. Indeed, outbreaks may still be occurring, and some of the patients who currently come under the CDC-1994 CFS definition have clinical features similar to the classical description of post-infectious ME patients defined above.

The fact that we are still aware of these details is in no small measure due to Dr J Gordon Parish, who is attending this workshop today. Dr Parish has, over many years, collected reports of these outbreaks of ME (2, 3), and has a complete archive of the relevant literature.

Given the heterogeneous nature of the term CFS, and the different ways of defining it, it is probably no surprise that many of the biomedical studies conducted into the illness — a relatively small number given the scale of the problem — have had inconclusive results. Despite this, however, a range of abnormalities have been found by a number of different research groups, and these are summarised in Table 2 below.

Today’s workshop will concentrate on the vascular and biochemical aspects of ME/CFS, but ME Research UK intends to facilitate further workshops concentrating on other aspects of ME/CFS pathophysiology, such as muscle metabolism and function, and neuroimaging and brain function.

Table 2. Physiological and biochemical abnormalities found in groups of patients meeting the broad criteria for ‘CFS’
Biochemical
Oxidative stress (4, 5, 6, 7, 8)
Dysregulation of anti-viral pathways, i.e., abnormal activity of the anti-viral immune responses (9, 10, 11)
Vascular (relating to the circulation)
Endothelial dysregulation, i.e., abnormal responses of small blood vessels selectively to acetylcholine (12, 13, 14)
Altered brain perfusion, i.e., areas of reduced blood flow in the brain (15, 16)
Orthostatic hypotension, i.e., physiological changes to blood pressure/cardiovascular mechanisms on standing (17, 18)
Brain
Metabolic abnormalities, e.g., alterations of brain choline (important in brain function) (19, 20, 21)
Muscle
Altered metabolism, e.g., changes in muscle composition or use of fuel (22, 23)
Abnormal response to exercise (24, 25)
Enteroviral sequences in muscle, i.e., evidence of a persisting virus in some CFS patients (26)

References

  1. Acheson ED. The clinical syndrome variously called benign myalgic encephalomyelitis, Iceland disease, and epidemic neuromyasthenia. Am J Med 1959; 26: 569–96.
  2. Parish JG. Early outbreaks of epidemic neuromyasthenia. Postgrad Med J 1978; 54: 711–17.
  3. Shelokov A, Parish JG. Epidemic Neuromyasthenia. In: Hoeprich OD, Jordon MC (eds). Infectious Diseases — A modern treatise on infectious processes. Lippincott, 1989.
  4. Richards RS, Roberts TK, McGregor NR et al. Blood parameters indicative of oxidative stress are associated with symptom expression in chronic fatigue syndrome. Redox Rep 2000; 5: 35–41.
  5. Manuel Y, Keenoy B, Moorkens G et al. Antioxidant status and lipoprotein peroxidation in chronic fatigue syndrome. Life Sci 2001; 68: 2037–49.
  6. Pall ML, Scatterle JD. Elevated nitric oxide/peroxynitrite mechanism for the common etiology of multiple chemical sensitivity, chronic fatigue syndrome, and post-traumatic stress disorder. Ann NY Acad Sci 2001; 933: 323–9.
  7. Kennedy G, Spence VA, McLaren M, Hill A, Belch JJF. Increased plasma isoprostanes and other markers of oxidative stress in chronic fatigue syndrome. Journal of Thrombosis and Haemostasis 2003; 1(Suppl 1): P0182.
  8. Vecchiet J, Cipollone F, Falasca K et al. Relationship between musculoskeletal symptoms and blood markers of oxidative stress in patients with chronic fatigue syndrome. Neurosci Lett 2003; 335: 151–4.
  9. Suhadolnik RJ, Reichenbach NL, Hitzges P et al. Upregulation of the 2-5A synthetase/RNase L antiviral pathway associated with chronic fatigue syndrome. Clin Infect Dis 1994; 18 Suppl 1: S96–104.
  10. De Meirleir K, Bisbal C, Campine I et al. A 37-kDa 2-5A binding protein as a potential biochemical marker of chronic fatigue syndrome. Am J Med 2000; 108: 99–105.
  11. Tiev KP, Demettre E, Ercolano P et al. RNase L levels in peripheral blood mononuclear cells: 37-kilodalton/83-kilodalton isoform ratio is a potential test for chronic fatigue syndrome. Clin Diag Lab Immunology 2003; 10: 315–16.
  12. Spence VA, Khan F, Belch JJF. Enhanced sensitivity of the peripheral cholinergic vascular response in patients with chronic fatigue syndrome. Am J Med 2000; 108: 736–9.
  13. Khan F, Spence VA, Kennedy G, Belch JJF. Prolonged acetylcholine-induced vasodilatation in the peripheral microcirculation of patients with chronic fatigue syndrome. Clin Physiol Funct Imaging 2003; 23: 282–5.
  14. Khan F, Kennedy G, Spence VA et al. Peripheral cholinergic function in humans with chronic fatigue syndrome, gulf war syndrome, and with illness following organophosphate exposure. Clinical Science 2004; 106: 183et al9.
  15. Schwartz RB, Garada BM, Komaroff AL et al. Detection of intracranial abnormalities in patients with chronic fatigue syndrome: comparison of MR imaging and SPECT. Am J Roentgenol 1994; 162: 935–41.
  16. Costa DC, Tannock C, Brostoff J. Brainstem perfusion is impaired in the chronic fatigue syndrome. Q J Med 1995; 88: 767–73.
  17. Streeten DH, Thomas D, Bell DS. The roles of orthostatic hypotension, orthostatic tachycardia, and subnormal erythrocyte volume in the pathogenesis of the chronic fatigue syndrome. Am J Med Sci 2000; 320: 1–8.
  18. Stewart JM. Microvascular filtration is increased in postural tachycardia syndrome. Circulation 2003; 107: 2816–22.
  19. Tomoda A, Miike T, Yamada E et al. Chronic fatigue syndrome in childhood. Brain Dev 2000; 22: 60–4.
  20. Puri BK, Counsell SJ, Zaman R et al. Relative increase in choline in the occipital cortex in chronic fatigue syndrome. Acta Psychiatr Scand 2002; 106: 224–6.
  21. Chaudhuri A, Cindon BR, Gow JW et al. Proton magnetic resonance of basal ganglia in chronic fatigue syndrome. Neuroreport 2003; 14: 225–8.
  22. Fulle S, Mecocci P, Fano G et al. Specific oxidative alterations in vastus lateralis muscle of patients with the diagnosis of chronic fatigue syndrome. Free Radic Biol Med 2000; 29: 1252–9.
  23. Vecchiet J, Cipollone F, Falasca K et al. Relationship between musculoskeletal symptoms and blood markers of oxidative stress in patients with chronic fatigue syndrome. Neurosci Lett 2003; 335: 151–4.
  24. Paul L, Wood L, Behan WM et al. Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome. Eur J Neurol 1999; 6: 63–9.
  25. McCully KK, Natelson BH. Impaired oxygen delivery to muscle in chronic fatigue syndrome. Clin Sci 1999; 97: 603–8.
  26. Lane RJM, Soteriou BA, Zhang H, Archard LC. Enterovirus related metabolic myopathy: a postviral fatigue syndrome. J Neurol Neurosurg Psychiatry 2003; 74: 1382–6.

Links