Category: Pathophysiology

Hypothesis: cytokines may be activated to cause depressive illness and chronic fatigue syndrome

Abstract:

Abnormalities in the regulation of the hypothalamo-pituitary-adrenal (HPA) axis are a well recognised feature of endogenous depression. The mechanism underlying this phenomenon remains obscure although there is strong evidence suggesting excessive CRH activity at the level of the hypothalamus.

We propose a novel hypothesis in which we suggest that the aetiological antecent to CRH hyperactivity is cytokine activation in the brain. It is now well established both that interleukins -1 and -6 are produced in a number of central loci and that cytokines are potent stimulators of the HPA axis.

Hence, we suggest that activation of IL-1 and IL-6 by specific mechanisms (such as neurotropic viral infection) in combination with the consequent CRH-41 stimulation, may (via their known biological effects) underly many of the features found in major depression and other related disorders, particularly where chronic fatigue is a prominent part of the symptom complex.

This theory has considerable heuristic value and suggests a number of experimental stratagems which may employed in order to confirm or reject it.

 

Source: Ur E, White PD, Grossman A. Hypothesis: cytokines may be activated to cause depressive illness and chronic fatigue syndrome. Eur Arch Psychiatry Clin Neurosci. 1992;241(5):317-22. http://www.ncbi.nlm.nih.gov/pubmed/1606197

 

The pathophysiology of chronic fatigue syndrome: confirmations, contradictions, and conjectures

Abstract:

OBJECTIVE: To examine published data regarding patient cohorts with the recently defined chronic fatigue syndrome.

METHOD: Review of thirty-two peer-assessed research publications that included full disclosure of the methodology employed; classification of the findings as confirmed, contradictory, or non-duplicated.

RESULTS: Research studies have confirmed that the majority of patients with the chronic fatigue syndrome: 1) are white middle-aged women, 2) have a high prevalence of current major depression and somatization disorder, 3) have abnormal personality traits, 4) believe that their fatigue has a physical cause, and 5) show mild abnormalities of humoral immunity. Contradictory data have been presented with regard to: 1) the time of onset of depressive disorders, 2) the etiologic role of herpetic and enteroviral infections, 3) the presence of abnormal cellular immunity, and 4) the clinical utility of immunoglobulin therapy. Non-duplicated research has indicated 1) hypothalamic-pituitary-adrenal axis dysfunction, 2) abnormalities on magnetic resonance images of the brain, 3) altered cytokine production, and 4) the possibility of retroviral infection.

CONCLUSIONS: As presently defined, the chronic fatigue syndrome has many of the clinical and biological features associated with depressive and somatoform disorders. A specific etiologic role for infections or immune dysfunction has not been confirmed.

 

Source: Manu P, Lane TJ, Matthews DA. The pathophysiology of chronic fatigue syndrome: confirmations, contradictions, and conjectures. Int J Psychiatry Med. 1992;22(4):397-408. http://www.ncbi.nlm.nih.gov/pubmed/1338059

 

Muscle biochemistry and pathophysiology in postviral fatigue syndrome

Abstract:

Patients with postviral fatigue syndrome (PVFS) usually complain of the skeletal muscle-related symptoms of fatigue and myalgia. It is not surprising therefore that the muscles have recently been the object of intensive studies which have used a variety of biochemical and physiological techniques. The aim of this chapter is to review these findings, and to discuss their significance or otherwise to the presenting symptoms and course of the condition.

 

Source: Edwards RH, Newham DJ, Peters TJ. Muscle biochemistry and pathophysiology in postviral fatigue syndrome. Br Med Bull. 1991 Oct;47(4):826-37. http://www.ncbi.nlm.nih.gov/pubmed/1794087

 

Neurophysiology of postviral fatigue syndrome

Abstract:

The exact pathophysiology of excessive fatigue in patients with postviral fatigue syndrome (PVFS) remains uncertain in spite of increasing investigation. One objective abnormality of neuromuscular function is the increased jitter on single fibre EMG studies. While this is a sensitive technique which indicates a disturbance in the peripheral part of the motor unit, it is non-specific and its role in the pathophysiology remains unclear.

Impaired muscular activation with added force in response to superimposed electrical stimulation suggests an extra-muscular and/or central component of fatigue. Conventional neurophysiological studies and those of strength and endurance have shown no objective abnormality in patients compared with controls. The previous reports of disturbed muscle metabolism on NMR spectroscopy have not been confirmed in more recent studies and no consistent abnormality of excitation-contraction coupling has so far emerged.

Finally, unlike patients with depression, cognitive evoked potential studies suggest impaired attention, memory and stimulus evaluation in postviral fatigue syndrome. In future studies, the importance of utilising approved clinical criteria for patient inclusion cannot be overemphasized. Control groups should include sedentary or deconditioned as well as depressed subjects to help standardise these important variables.

 

Source: Jamal GA, Miller RG. Neurophysiology of postviral fatigue syndrome. Br Med Bull. 1991 Oct;47(4):815-25. http://www.ncbi.nlm.nih.gov/pubmed/1794086

 

Postinfectious chronic fatigue syndrome: case history of thirty-five patients in Germany

Abstract:

Thirty-five patients with chronic fatigue syndrome according to the criteria of Holmes were followed for periods of up to eight years. The most frequent symptoms were severe fatigue, arthralgias and myalgias, recurrent oropharyngitis and various psychiatric disorders.

More than half of the patients suffered from neuropathy, lymphadenopathy, gastrointestinal complaints and recurrent low-grade fever. Recurrent or persistent activity of human herpesvirus -6 infection was seen in 73% of the patients and of Epstein-Barr virus in 34.4%. In addition, various other infections were diagnosed at lower frequency.

Initial routine immunologic screening revealed various types of deficiencies, these were yet inconsistent and variable when different patients were compared with each other. Tentative treatments included in immunoglobulins, nonspecific immunostimulation and virostatic drugs. No consistently positive results were obtained with any treatment schedule although immunoglobulins appeared the most efficient measure. In addition, psychologic care of the patients is indicated, since disturbances in the psycho-neuroimmunologic regulation may play a significant role in the pathogenesis of the disease.

 

Source: Hilgers A, Krueger GR, Lembke U, Ramon A. Postinfectious chronic fatigue syndrome: case history of thirty-five patients in Germany. In Vivo. 1991 May-Jun;5(3):201-5. http://www.ncbi.nlm.nih.gov/pubmed/1893076

 

Physiologic measurement of exercise and fatigue with special reference to chronic fatigue syndrome

Abstract:

Oxidative metabolism is the major source of energy for muscle activity, and maximal oxygen uptake (VO2max), the product of maximal cardiac output and maximal arteriovenous oxygen difference, indicates individual capacity for oxidative metabolism and performance of exercise by the large muscles.

Strength, a function of muscle cross-sectional area, motor-unit recruitment, and neuromuscular coordination, is the ability to develop force in a single, brief, maximal-effort voluntary contraction of rested muscle. Weakness is a diminished ability of rested muscle to exert maximal force. Fatigue is a loss of maximal force-generating capacity that develops during muscular activity, likely originates within muscle itself, and persists until muscle is fully recovered. Individual perception of motor effort can be determined with standardized rating scales.

These concepts are discussed in detail, their relevance to the pathophysiology of exercise in chronic fatigue syndrome is analyzed, and a general strategy of exercise evaluation pertinent to chronic fatigue syndrome is presented.

 

Source: Lewis SF, Haller RG. Physiologic measurement of exercise and fatigue with special reference to chronic fatigue syndrome. Rev Infect Dis. 1991 Jan-Feb;13 Suppl 1:S98-108. http://www.ncbi.nlm.nih.gov/pubmed/2020810