Chronic fatigue syndrome: a hypothesis focusing on the autonomic nervous system

Abstract:

Chronic fatigue syndrome is a debilitating illness of unknown aetiology, with estimated levels of prevalence of up to about 8. 7/100 000 in the U.S.A. Like pain fatigue it is a personal, emotionally rich experience, which may originate from peripheral or central sites (or both). The nature of the symptoms is complex and reflects the interaction of the patient with the environment and cultural milieu. Accordingly the common use of the same terminology for different types of fatigue may be misleading.

Autonomic activation is a key component of both real and simulated physical exercise. Alterations in autonomic nervous system activity are a key component of several physiopathological conditions. In chronic fatigue syndrome disturbances in autonomic activity, and in other homoeostatic mechanisms, such as the hormonal and immune systems, have been reported recently.

In this review we followed the hypothesis that in chronic fatigue syndrome the paradoxical condition of disturbing somatic symptoms in the absence of organic evidence of disease might be addressed by focusing on attending functional correlates. In particular we addressed possible alterations in cardiovascular autonomic control, as can be assessed by spectral analysis of R-R interval and systolic arterial pressure variability.

With this approach, in subjects complaining of unexplained fatigue, we obtained data suggesting a condition of prevailing sympathetic modulation of the sino-atrial node at rest, and reduced responsiveness to excitatory stimuli. Far from considering the issue resolved, we propose that in the context of the multiple physiological and psychological interactions involved in the perception and self-reporting of symptoms, attendant changes in physiological equivalents might furnish a convenient assessment independent from subjective components.

Indices of sympathetic modulation could, accordingly, provide quantifiable signs of the interaction between subject’s efforts and environmental demands, independently of self descriptions, which could provide convenient measurable outcomes, both for diagnosis and treatment titration in chronic fatigue syndrome.

Comment in: Long- and short-term blood pressure and RR-interval variability and psychosomatic distress in chronic fatigue syndrome. [Clin Sci (Lond). 1999]

 

Source: Pagani M, Lucini D. Chronic fatigue syndrome: a hypothesis focusing on the autonomic nervous system. Clin Sci (Lond). 1999 Jan;96(1):117-25. http://www.ncbi.nlm.nih.gov/pubmed/9857114

 

Low levels of serum acylcarnitine in chronic fatigue syndrome and chronic hepatitis type C, but not seen in other diseases

Abstract:

Recently, we found a serum acylcarnitine (ACR) deficiency in Japanese patients with chronic fatigue syndrome (CFS). To clarify whether this ACR abnormality is a characteristic of CFS or not, we also studied the levels of serum carnitine in Swedish subjects.

Both serum ACR and free carnitine (FCR) levels in normal healthy subjects were quite different between Japanese (n=131) and Swedish people (n=46) (p<0.001). However, it is confirmed that Swedish patients with CFS (n=57) also had serum ACR deficiency (p<0.001). When we studied the levels of serum ACR and FCR in Japanese patients with various kinds of diseases (CFS, hematological malignancies, chronic pancreatitis, hypertension, diabetes mellitus, chronic hepatitis type C, psychiatric diseases), a significant decrease in the levels of serum ACR was only found in patients with CFS and chronic hepatitis type C (p<0.001).

Therefore, we concluded that ACR deficiency in serum might be a characteristic abnormality in only certain types of diseases.

 

Source: Kuratsune H, Yamaguti K, Lindh G, Evengard B, Takahashi M, Machii T, Matsumura K, Takaishi J, Kawata S, Långström B, Kanakura Y, Kitani T, Watanabe Y. Low levels of serum acylcarnitine in chronic fatigue syndrome and chronic hepatitis type C, but not seen in other diseases. Int J Mol Med. 1998 Jul;2(1):51-6. http://www.ncbi.nlm.nih.gov/pubmed/9854142

 

Dehydroepiandrosterone sulfate deficiency in chronic fatigue syndrome

Abstract:

The chronic fatigue syndrome (CFS) is a condition of unknown etiology, characterized by a persistent debilitating fatigue, the muscle-related symptoms and the neuropsychiatric symptoms.

Recently, it has been reported that the patients with CFS might have impaired activation of the hypothalamic-pituitary-adrenal axis, and suggested that a part of the patho-genesis of CFS might be associated with abnormalities of the endocrine system.

Herein, we show that the majority of Japanese patients with CFS had a serum dehydroepiandrosterone sulfate (DHEA-S) deficiency. Serum DHEA-S is one of the most abundantly produced hormones which is secreted from the adrenal glands, and its physiological function is thought to be a precursor of sex steroids. DHEA-S has recently been shown to have physiological properties, such as neurosteroids, which are associated with such psychophysiological phenomena as memory, stress, anxiety, sleep and depression.

Therefore, the deficiency of DHEA-S might be related to the neuropsychiatric symptoms in patients with CFS.

 

Source: Kuratsune H, Yamaguti K, Sawada M, Kodate S, Machii T, Kanakura Y, Kitani T. Dehydroepiandrosterone sulfate deficiency in chronic fatigue syndrome. Int J Mol Med. 1998 Jan;1(1):143-6. http://www.ncbi.nlm.nih.gov/pubmed/9852212

 

Autonomic neuropathies

Abstract:

A limited autonomic neuropathy may underlie some unusual clinical syndromes, including the postural tachycardia syndrome, pseudo-obstruction syndrome, heat intolerance, and perhaps chronic fatigue syndrome. Antibodies to autonomic structures are common in diabetes, but their specificity is unknown. The presence of autonomic failure worsens prognosis in the diabetic state. Some autonomic neuropathies are treatable. Familial amyloid polyneuropathy may respond to liver transplantation. There are anecdotal reports of acute panautonomic neuropathy responding to intravenous gamma globulin. Orthostatic hypotension may respond to erythropoietin or midodrine.

 

Source: Low PA. Autonomic neuropathies. Curr Opin Neurol. 1998 Oct;11(5):531-7. http://www.ncbi.nlm.nih.gov/pubmed/9848003

 

Chronic fatigue syndrome in psychiatric patients: lifetime and premorbid personal history of physical health

Abstract:

OBJECTIVE: This preliminary report compares a group of chronic fatigue syndrome (CFS) patients and controls on several variables of potential significance in the etiology of CFS.

METHOD: The lifetime prevalence of reported physical disorders was compared among 46 CFS psychiatric patients, 92 relatively physically healthy psychiatric patients (C-I), and 46 psychiatric patients selected without regard to physical health (C-II). All patients were matched on age, sex, and psychiatric diagnosis and were drawn from the same psychiatric practice. The same groups were compared on a 7-point scale of lifetime physical health by three raters independently evaluating physical health narratives of the CFS patients up to the time of onset of CFS and that of the controls up to the corresponding age.

RESULTS: The CFS patients had a significantly higher reported lifetime prevalence of irritable bowel syndrome (IBS), infectious mononucleosis-like syndromes (IM), infectious mononucleosis-like syndromes two or more times (IM x 2), and herpes (other than genital or perioral herpes) than one or both control groups. The CFS group also had a higher incidence of allergic rhinitis or asthma, IBS, IM, and IM x 2 than the combined controls. On the independent ratings, the CFS patients had significantly more impaired physical health up to the time of onset of the CFS than C-I at a comparable age.

CONCLUSIONS: The findings suggest that a general health factor may be involved in the pathogenesis of some cases of CFS.

 

Source: Endicott NA. Chronic fatigue syndrome in psychiatric patients: lifetime and premorbid personal history of physical health. Psychosom Med. 1998 Nov-Dec;60(6):744-51. http://www.ncbi.nlm.nih.gov/pubmed/9847035

 

Decreased immunoreactive beta-endorphin in mononuclear leucocytes from patients with chronic fatigue syndrome

Abstract:

OBJECTIVE: To investigate beta-endorphin concentrations in the peripheral blood mononuclear cells (PBMC) of patients with chronic fatigue syndrome (CFS).

METHODS: Sixteen patients with CFS were enrolled in this study. Ten healthy subjects were studied as controls. Beta-endorphin concentrations were measured in PBMC by radioimmunoassay performed with antibodies specific for the C-terminal portion of human beta-endorphin.

RESULTS: Beta-endorphin concentrations in the PBMC of chronic fatigue patients were significantly lower (p < 0.001) than in healthy subjects (mean +/- SD: 8.5 +/- 7.0 vs. 42.6 +/- 22.6).

CONCLUSION: Patients with CFS were found to have low levels of PBMC beta-endorphin. This finding may reflect the condition of chronic immune activation in CFS that has been reported in previous investigations. Beta-endorphin concentrations in PBMC seem to mirror the central nervous system homeostasis of the opioid. Therefore, we would postulate that the fatigue and weakness typical of CFS could be related to low beta-endorphin concentrations at the central nervous system level.

 

Source: Conti F, Pittoni V, Sacerdote P, Priori R, Meroni PL, Valesini G. Decreased immunoreactive beta-endorphin in mononuclear leucocytes from patients with chronic fatigue syndrome. Clin Exp Rheumatol. 1998 Nov-Dec;16(6):729-32. http://www.ncbi.nlm.nih.gov/pubmed/9844768

 

Chronic fatigue syndrome differs from fibromyalgia. No evidence for elevated substance P levels in cerebrospinal fluid of patients with chronic fatigue syndrome

Abstract:

Levels of substance P were determined in the cerebrospinal fluid (CSF) in 15 patients with chronic fatigue syndrome (CFS). All values were within normal range. This is in contrast to fibromyalgia (FM). The majority of patients with FM have increased substance P values in the CSF. The results support the notion that FM and CFS are different disorders in spite of overlapping symptomatology.

 

Source: Evengard B, Nilsson CG, Lindh G, Lindquist L, Eneroth P, Fredrikson S, Terenius L, Henriksson KG. Chronic fatigue syndrome differs from fibromyalgia. No evidence for elevated substance P levels in cerebrospinal fluid of patients with chronic fatigue syndrome. Pain. 1998 Nov;78(2):153-5. http://www.ncbi.nlm.nih.gov/pubmed/9839828

 

Assessing illness representations of chronic illness: explorations of their disease-specific nature

Abstract:

Elaborating on the five-dimensional structure of illness representation, as described in the self-regulation model of Leventhal (1980), the present study is aimed at identifying the relevance of this generic structure for two chronic illnesses: chronic fatigue syndrome (CFS) and Addison’s disease (AD).

Factor analyses showed the importance of the five dimensions identity, time-line, control/cure, cause, and consequences to differ according to the type of disease. That is, the items representing the five dimensions merged together for CFS patients and AD patients in a different manner and thereby produced different factor solutions for the two patient groups.

In CFS patients, a four-factor solution was identified with manageability, seriousness, personal responsibility, and external cause as the factors. In AD patients a four-factor solution was also identified but with seriousness, cause, chronicity, and controllability as the factors. The value of these findings for our understanding of the disease-specific nature of illness representation is discussed.

 

Source: Heijmans M, de Ridder D. Assessing illness representations of chronic illness: explorations of their disease-specific nature. J Behav Med. 1998 Oct;21(5):485-503. http://www.ncbi.nlm.nih.gov/pubmed/9836133

 

Exploring the validity of the Chalder Fatigue scale in chronic fatigue syndrome

Abstract:

The Chalder fatigue scale is widely used to measure physical and mental fatigue in chronic fatigue syndrome patients, but the constructs of the scale have not been examined in this patient sample. We examined the constructs of the 14-item fatigue scale in a sample of 136 chronic fatigue syndrome patients through principal components analysis, followed by correlations with measures of subjective and objective cognitive performance, physiological measures of strength and functional work capacity, depression, anxiety, and subjective sleep difficulties.

There were four factors of fatigue explaining 67% of the total variance. Factor 1 was correlated with subjective everyday cognitive difficulties, concentration difficulties, and a deficit in paired associate learning. Factor 2 was correlated with difficulties in maintaining sleep. Factor 3 was inversely correlated with grip strength, peak VO2, peak heart rate, and peak functional work capacity. Factor 4 was correlated with interview and self-rated measures of depression.

The results support the validity of mental and physical fatigue subscales and the dropping of the “loss of interest” item in the 11-item version of the fatigue scale.

 

Source: Morriss RK, Wearden AJ, Mullis R. Exploring the validity of the Chalder Fatigue scale in chronic fatigue syndrome. J Psychosom Res. 1998 Nov;45(5):411-7. http://www.ncbi.nlm.nih.gov/pubmed/9835234

 

The in vitro immunomodulatory effects of glyconutrients on peripheral blood mononuclear cells of patients with chronic fatigue syndrome

Abstract:

In humans, eight monosaccharides are required for the synthesis of glycoproteins. Dietary supplements that supply these crucial sugars are known as glyconutrients. A glyconutrient compound was added to Peripheral Blood Mononuclear Cells (PBMC) isolated from normal controls and patients with the Chronic Fatigue Syndrome (CFS), a disease associated with immune dysregulation. The in vitro immunomodulatory effects were investigated.

Cell surface expression of the glycoproteins CD5, CD8, and CD11a were significantly lower in patients with CFS compared to normal controls. Addition of glyconutrient homogenate to PBMC from patients with CFS stimulated with phytohemagglutinin significantly increased the expression of each glycoprotein.

Furthermore, natural killer (NK) cell function was reduced in CFS patients. The glyconutrient preparation significantly enhanced NK cell activity versus human herpes virus 6 (HHV-6)-infected H9 cells in an 8 h 51Cr release assay compared to placebo for PBMC from patients with CFS (p< .01).

Finally, apoptosis was significantly higher in patients with CFS. The percentage of apoptotic cells was significantly decreased in PBMC from patients with CFS that had been incubated for 48 h with glyconutrients. Thus, glyconutrients improved abnormal immune parameters in vitro in patients with CFS.

 

Source: See DM, Cimoch P, Chou S, Chang J, Tilles J. The in vitro immunomodulatory effects of glyconutrients on peripheral blood mononuclear cells of patients with chronic fatigue syndrome. Integr Physiol Behav Sci. 1998 Jul-Sep;33(3):280-7. http://www.ncbi.nlm.nih.gov/pubmed/9829439