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Gray matter volume reduction in the chronic fatigue syndrome
Floris P. de Langea, Joke S. Kalkmanb, Gijs Bleijenbergb, Peter Hagoorta, Jos W.M. van der Meerc and Ivan Toni, NeuroImage, Volume 26, Issue 3 , 1 July 2005, Pages 777-781 doi:10.1016/j.neuroimage.2005.02.037

We observed significant reductions in global gray matter volume in both cohorts of CFS patients, as compared to matched control participants. Moreover, the decline in gray matter volume was linked to the reduction in physical activity, a core aspect of CFS. These findings suggest that the central nervous system plays a key role in the pathophysiology of CFS and point to a new objective and quantitative tool for clinical diagnosis of this disabling disorder.

Exercise responsive genes measured in peripheral blood of women with Chronic Fatigue Syndrome and matched control subjects.
Toni Whistler, James F. Jones, Elizabeth R. Unger and Suzanne D. Vernon
BMC Physiology 2005, 5:5, doi:10.1186/1472-6793-5-5, Published 24 March 2005

These results highlight the potential use of an exercise challenge combined with microarray gene expression analysis in identifying gene ontologies associated with CFS.

Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise.

Jammes Y, Steinberg JG, Mambrini O, Bregeon F, Delliaux S.

The response of CFS patients to incremental exercise associates a lengthened and accentuated oxidative stress together with marked alterations of the muscle membrane excitability. These two objective signs of muscle dysfunction are sufficient to explain muscle pain and postexertional malaise reported by our patients.

Spinal Fluid Abnormalities in Patients with Chronic Fatigue Syndrome
Natelson BH, Weaver SA, Tseng CL, Ottenweller JE. Clin Diagn Lab Immunol. 2005 Jan;12(1):52-5.

The results support two hypotheses: that some CFS patients have a neurological abnormality that may contribute to the clinical picture of the illness and that immune dysregulation within the central nervous system may be involved in this process

Objective evidence of cognitive complaints in Chronic Fatigue Syndrome: A BOLD fMRI study of verbal working memory.
Neuroimage. 2005 Jun 1;26(2):513-24. Epub 2005 Apr 7.
Lange G, Steffener J, Cook DB, Bly BM, Christodoulou C, Liu WC, Deluca J, Natelson BH.

Findings showed that individuals with CFS are able to process challenging auditory information as accurately as Controls but utilize more extensive regions of the network associated with the verbal WM system. Individuals with CFS appear to have to exert greater effort to process auditory information as effectively as demographically similar healthy adults. Our findings provide objective evidence for the subjective experience of cognitive difficulties in individuals with CFS.

Increased neutrophil apoptosis in chronic fatigue syndrome
G. Kennedy, V. Spence, C. Underwood, J. J. F. Belch, J Clin Pathol.2004; 57: 891-893.

These findings provide new evidence that patients with CFS have an underlying detectable abnormality in their immune cells.

Peripheral cholinergic function in humans with chronic fatigue syndrome, Gulf War syndrome and with illness following organophosphate exposure.
Faisel KHAN, Gwen KENNEDY, Vance A. SPENCE, David J. NEWTON and Jill J. F. BELCH, Clinical Science 2004; 106:183-9.

Although there are many clinical similarities between these three illnesses, our results indicate peripheral cholinergic abnormalities in the vascular endothelium of only patients with CFS, suggesting that this syndrome has a different aetiology, which might involve inhibition of vascular cholinesterase.

Acetylcholine mediated vasodilatation in the microcirculation of patients with chronic fatigue syndrome
Spence VA, Khan F, Kennedy G, Abbot NC & Belch JJF. Prostaglandins, Leukotrienes and Essential Fatty Acids 2004; 70: 403–7. © 2004 Elsevier.

Most diseases are accompanied by a blunted response to acetylcholine but the opposite is true for CFS. Such sensitivity is normally associated with physical training so the finding in CFS is anomalous and may well be relevant to vascular symptoms that characterize many patients.

Prolonged acetylcholine-induced vasodilatation in the peripheral microcirculation of patients with chronic fatigue syndrome
Faisel Khan, Vance Spence, Gwen Kennedy, Jill J. F. Belch, Clin Physiol Funct Imaging 2003; 23(5): 282–285

Prolongation of ACh-induced vasodilatation is suggestive of a disturbance to cholinergic pathways, perhaps within the vascular endothelium of patients with CFS, and might be related to some of the unusual vascular symptoms, such as hypotension and orthostatic intolerance, which are characteristic of the condition.

Gene expression in peripheral blood mononuclear cells from patients with chronic fatigue syndrome,
Journal: Journal of Clinical Pathology 2005;58:826-832, N Kaushik, D Fear , S C M Richards, C R McDermott, E F Nuwaysir, P Kellam, T J Harrison, R J Wilkinson, D A J Tyrrell [8], S T Holgate and J R Kerr. Korrespondance: j.kerr@imperial.ac.uk

Results: Analysis of microarray data revealed differential expression of 35 genes. Real time PCR confirmed differential expression in the same direction as array results for 16 of these genes, 15 of which were up regulated, and one of which was down regulated (IL-10RA). This profile suggests T cell activation and perturbation of neuronal and mitochondrial function. Up regulation of neuropathy target esterase and eukaryotic translation initiation factor 4G1 may suggest links with organophosphate exposure and virus infection, respectively.
Conclusion: These results suggest that patients with CFS have reproducible alterations in gene regulation.

Illness and disability in Danish Chronic Fatigue Syndrome patients at diagnosis and 5-year follow-up
M. M. Andersen, H. Permin and F. Albrecht, Journal of Psychosomatic Research, Volume 56, Issue 2 , February 2004, Pages 217-229;

CFS patients exhibit severe, long-term functional impairment. Substantial improvement is uncommon, less than 6%. Allergies and aspects of cognition may worsen, emotional adjustment often improves.

Severely Neglected,
A report examining the experiences of severely ill people in accessing health and social care.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols
Carruthers et al, Journal of Chronic Fatigue Syndrome, Vol. 11(1) 2003, pp. 7-115

We present a systematic clinical working case definition that encourages a diagnosis based on characteristic patterns of symptom clusters, which reflect specific areas of pathogenesis. Diagnostic and treatment protocols, and a short overview of research are given to facilitate a comprehensive and integrated approach to this illness. Throughout this paper, “myalgic encephalomyelitis” and “chronic fatigue syndrome” are used interchangeably and this illness is referred to as “ME/CFS.”

Abnormalities in response to vasopressin infusion in chronic fatigue syndrome.
ALTEMUS, M et alPsychoneuroendocrinology, 2001,26, 175-188.

We measured the ACTH and cortisol response to a one hour infusion of arginine vasopressin in 19 patients with chronic fatigue syndrome and 19 age and sex matched healthy volunteers. Patients with chronic fatigue syndrome had a reduced ACTH response to the vasopressin infusion and a more rapid cortisol response to the infusion. These results provide further evidence of reduced hypothalamic CRH secretion in patients with chronic fatigue syndrome.


Excessive intracellular acidosis of skeletal muscle on exercise in a patient with a post-viral exhaustion/fatigue syndrome.
Arnold, DL et al Lancet, 1984, 1367-1369.

A patient with prolonged post-viral exhaustion and excessive fatigue was examined by 31P nuclear magnetic resonance. During exercise, muscles of the forearm demonstrated abnormally early intracellular acidosis for the exercise performed. This was out of proportion to the associated changes in high-energy phosphates. This may represent excessive lactic acid formation resulting from a disorder of metabolic regulation. The metabolic abnormality in this patient could not have been demonstrated by traditional diagnostic techniques.

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BLOCKMANS, D. Combination therapy with hydrocortisone and fludrocortisone does not improve symptoms in chronic fatigue syndrome: A randomised, placebo-controlled, double-blind, crossover study. American Journal of Medicine, 2003, 114, 736-741.

BOMBARDIER, C H and BUCHWALD, D.
Outcome and prognosis of patients with chronic fatigue vs chronic fatigue syndrome. Archives of Internal Medicine, 1995, 155, 2105-2110.

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CHAUDHURI, A and BEHAN, P 0. Fatigue and basal ganglia. Journal of the Neurological Sciences, 2000, 179, 34-42.

CHAUDHURI, A et al Chronic fatigue syndrome: a disorder of central chotinergic transmission. Journal of Chronic Fatigue Syndrome, 1997, 3, 3-16.

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DEALE, A and WESSELY, S. Diagnosis of psychiatric disorder in clinical evaluation of chronic fatigue syndrome. Journal of the Royal Society of Medicine, 2000, 93, 310-31 2.

DEALE, A et al Cognitive behaviour therapy for the chronic fatigue syndrome: a randomised controlled trial. American Journal of Psychiatry, 1997, 154, 408-414.

DEALE, A et al Illness beliefs and outcome in chronic fatigue syndrome: do patients need to change their beliefs in order to get better? Journal of Psychosomatic Research. 1998. 45, 77-83.

DeLUCA, I et al Cognitive functioning is impaired in patients with chronic fatigue syndrome devoid of psychiatric disease. Journal of Neurology, Neurosurgery and Psychiatry, 1997, 62, 151-155.

DEMITRACK, M A et al Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. Journal of Clinical Endocrinology and Metabolism, 1991, 73, 1224-1234.

DIAZ-MITOMA, F et al. Clinical improvement in chronic fatigue syndrome is assosiated with enhanced natural killer cell-mediated cytotoxicity : the result of a pilot study with isoprinosine. Journal of Chronic Fatigue Syndrome, 2003, 11, 71-95.

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DOWSETT, F G and COLBY, I. Long term sickness absence due to ME/CFS in UK schools:
an epidemiological study with medical and educational implications. Journal of Chronic Fatigue Syndrome, 1997, 3, 29-42.

Drug & Therapeutics Bulletin. Drug treatment of neuropathic pain. 2000, 38, 12, 89-93.

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FARMER, A et al Screening for psychiatric morbidity in subjects presenting with chronic fatigue syndrome. British Journal of Psychiatry
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FORSYTH, L M et al Therapeutic effects of oral NADH on the symptoms of chronic fatigue syndrome. Annals of Allergy Asthma, Immunology, 1999, 82, 185-191

FRIEDB ERG, F and KRUPP, L B. A comparison of cognitive behavioural treatment for chronic fatigue syndrome and depression. Clinical Infectious Diseases, 1994, 18 (Suppl 1), 51 05-110.

FUKADA, K et al The chronic fatigue syndrome. A comprehensive approach to its definition and study. Annals of Internal Medicine, 1994, 121, 953-959. Correspondence: 1995, 123, 74-76.

FULCHER, K Y and WHITE, P D. Randomised controlled trial of graded exercise in patients with chronic fatigue syndrome. British Medical Journal, 1997, 314, 1647-1652. Correspondence: 315, 947-948.

GOW, JW et al. Antiviral pathway activation in patients with chronic fatigue syndrome and acute infections. Clinical Infectious Diseases, 2001, 23, 2080-2081.

HEAP, L C et al. Vitamin B stats in patients with chronic fatigue syndrome. Journal of the Royal Society of Medicine. 1999, 92, 183-185.

HECKlE, I et al. A randomised, double-blind, placebo-controlled trial of moclobemide in patients with chronic fatigue syndrome. Journal of Clinical Psychiatry, 2000, 61, 643-648.
HINDS, G M F et al A retrospective study of the chronic fatigue syndrome. Proceedings of the Royal College of Physicians of Edinburgh, 1993, 23, 10-14.

JACOBSON, W et al Serum folate and chronic fatigue syndrome. Neurology, 1993, 43, 2645-2647 and Neurology 1994, 44, 2214-2215 (letter from Schmidley and Hines).

JASON, L A et al A community-based study of chronic fatigue syndrome. Archives of Internal Medicine, 1999, 159, 2129-2137.

KENNEDY, G et al. Increased neutrophil apoptosis in chronic fatigue syndrome. Journal of Clinical Pathology, 2004, 57, 891-893.

KOMAROFF, AL et al Health status in patients with chronic fatigue syndrome and in the general population and disease comparison groups. American Journal of Medicine, 1996, 101, 281 -290.

LANE, R. Chronic fatigue syndrome: is it physical? Journal of Neurology Neurosurgery and Psychiatry, 2000, 69, 280.

LANE, R J M et al. Enterovirus related metabolic myopathy: a post viral fatigue syndrome. Journal of Neurology, Neurosurgery and Psychiatry, 2003, 74, 1382-1386.

LANGE, G et al. Brain MRI abnormalities exist in a subset of patients with chronic fatigue syndrome. Journal of the Neurological Sciences, 1999, 171, 3-7. Commentary on pages 1-2.

LAPP, C W. Exercise limits in the chronic fatigue syndrome. American Journal of Medicine, 1997, 103, 83-84.

Leading Article: A new clinical entity? Lancet, 1956, i, 789-790.

LLOYD, A R et al Immunologic and psychological therapy for patients with chronic fatigue syndrome. American Journal of Medicine, 1995, 98, 419- 422

LLOYD, A R et al A double-blind, placebocontrolled trial of intravenous immunoglobulin therapy in patients with chronic fatigue syndrome. American Journal of Medicine, 1990, 89, 561 -568.


LYALL, M et al. A systematic review and critical evaluation on the immunology of chronic fatigue syndrome. Journal of Psychosomatic Research, 2003, 55, 79-90.

MAJEED, T et al Abnormalities of carnitine metabolism in chronic fatigue syndrome. European Journal of Neurology, 1995, 2, 425-428.

McCULLY, K and NATELSON, B H. Impaired oxygen delivery to muscle in chronic fatigue syndrome. Clinical Science, 1999, 87, 603-608.

McKENZIE, R et al Low-dose hydrocortisone for treatment of chronic fatigue syndrome: a randomised controlled trial. Journal of the American Medical Association, 1998, 280, 1061-1066.

MICHIELS, V and CLUYDTS, R.
Neuropsychological functioning in chronic fatigue syndrome. Acta Psychiatrica Scandinavia, 2001, 103, 84-93.

MILLER, N A et al Antibody to Coxsackie B virus in diagnosing post-viral fatigue syndrome. British Medical Journal, 1991, 302, 140-1 43.

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NASCHITZ, J et al. Midrodine treatment for chronic fatigue syndrome. Postgraduate Medical Journal,2004, 80, 230-232.

NATELSON, B H et al. Spinal fluid abnormalities in patients with chronic fatigue syndrome. Clinical and Diagnostic Laboratoy Investigations, 2005, 1, 52-55.

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PETERSON, P K et al A preliminary placebo-controlled crossover trial of fludrocortisone for chronic fatigue syndrome. Archives of Internal

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