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*O* The symptoms of Chronic Fatigue Syndrome are related to abnormal ion channel function Peter O. Behan*, Abhijit Chaudhuri*, Walter S. Watson**, John Pearn*** *University Department of Neurology, Institute of Neurological Sciences and **Department of Nuclear Medicine, Southern General Hospital, Glasgow (UK), ***Department of Child Health, University of Queensland, Brisbane (Australia). Presented at the American Association for Chronic Fatigue Syndrome Research Conference
October 10-11, 1998 -- Cambridge, Massachusetts
Objective: Many symptoms of chronic fatigue syndrome (CFS), including severity of fatigue, are periodic, fluctuant and are inducible by physical and mental activities. Chest pain is a common symptom of CFS, like patients with syndrome X, an ion channel disorder. Symptoms in CFS such as fatigue, myalgia and headache bear striking resemblance with neurological disorders that affect ion channel function, such as periodic paralysis and familial hemiplegic migraine. Maintenance of normal transmembrane ionic equilibrium is an active, energy-dependent process, and constitutes an important share of the resting energy expenditure (REE). We wanted to compare and contrast the clinical profile of CFS patients with other neurological disorders that are known to affect ion channel function, and estimate REE in CFS. We also studied the myocardial perfusion in CFS by thallium201 SPECT scans to compare the results with Syndrome X. Methods: All patients who fulfilled the modified CDC criteria for CFS were included in our studies. For investigations that required the administration of radiopharmaceuticals (e.g. cardiac-thallium201 SPECT scans), patients between the age of 18 - 65 years were recruited after informed consent. A comparable group of healthy, sedentary volunteers were tested as controls in the REE study. Results: Fatigue was fluctuant in most patients with CFS. This was induced or worsened by physical activities (exercise), mental stress and chemicals that affect ion channel function (e.g. alcohol, quinine and anaesthetics). Significant perfusion defects were observed in the cardiac-thallium201 SPECT scans in 70% of CFS patients, similar to that described in patients with syndrome X. In a separate study, a significant number of CFS patients were found to have elevated REE as compared to the controls using total body potassium (TBK) as the refererence (REE TBK).4 Conclusion: Abnormal thallium201-cardiac SPECT scans in CFS similar to those described in syndrome X suggest a common mechanism for both these conditions. An abnormality of membrane ion channel function is considered the underlying mechanism in syndrome X. Increased REETBK; in a subgroup of CFS patients suggests that some CFS patients spend more energy in maintaining essential body function at the expense of the energy available for other physical activities. Since 30% of REE is expended to maintain physiological ion gradients in normal health, cell membranes that leak ions increase REETBK Elevated REE and abnormal cardiac perfusion scans in CFS provide the first objective and indirect support to our hypothesis that symptoms in CFS could be the result of an acquired abnormality of the voltage or ligand-gated ion channels. It is possible that such alteration of transmembrane ion traffic could affect normal receptor sensitivity to neurochemicals and neurohormones such as acetylcholine, serotonin or other monoamines, accounting for the neuroendocrine abnormalities previously documented in CFS.
*O* Disturbance of hypothalamic function and evidence for persistent enteroviral infection in patients with chronic fatigue syndrome. Richardson J. Journal of Chronic Fatigue Syndrome 1995; 1(2): 59-66.
Abstract: It has been suggested that one of the major effects of persistent virus infections in the production of disorders such as the chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is on the hypothalamus (1). Buspirone, which is one of the anxiolytic drugs of the azapyrone group, causes a release of prolactin by stimulation of serotonin 5-hydroxytryptamine (5-HT) receptors. The buspirone-prolactin response was studied in a subgroup of patients with CFS/ME and evidence of persistent enteroviral infection, as shown by the repeated detection of the group-specific protein of enteroviruses, VP1, in the blood. Family controls who were asymptomatic were studied at the same time. In addition to the response to buspirone, diurnal variations in cortisol and prolactin levels were studied. It was found that the patients with CFS/ME had much greater rises in prolactin levels one hour after buspirone compared to controls. Cortisol levels were elevated in the patients, but the rise was not significantly different between the two groups. There was a significant association between the pattern of sleep disturbance, which we speak of as the OWL syndrome, and the ratio of pre- and post-buspirone prolactin levels. This study shows that there is a hypothalamic disturbance in the patients who also had evidence of enteroviral infection as part of the disorder of CFS/ME. It represents a quantifiable biochemical alteration to be found in this group of patients.
Disordered circadian sleep-wake neuroendocrine and immune functions in Chronic Fatigue Syndrome H. Moldofskv, F.A. Lue, J. Dickstein, L. Poplonski, C.G. Jiang, R. Gorczynski; University of Toronto Centre for Sleep and Chronobiology, Toronto, Ontario, Canada.
Chronic fatigue syndrome (CFS) patients have unrefreshing sleep and show disturbed sleep physiology. According to the theory of chronobiological disturbances in CFS¹, we hypothesized that CFS patients would show altered circadian sleep/wake-related neuroendocrine and immune functions. Method: After overnight acclimatization to the sleep lab, thirty-four 10 ml. serial venous blood samples were collected from eleven CFS (8 f & 3 m, mean age 37.3 yrs.) and two normal comparison groups, H_Sym (healthy with symptoms of fatigue, sleep difficulties, headache, and backache; 5 f & 1 m, mean age 30.3 yrs.) and H_ASym (healthy with absence of symptoms: 4 f &1 m, mean age 30.2 yrs.). Starting at 0700 h, hourly samples were taken until 2300 h, then half-hourly during sleep until 0700 h and then at 0800 h. Polysomnographic monitoring of sleep, symptoms and mood were conducted on both days. NK-cell activity was carried out using a Cr51; release bioassay. The proportions of NK-cells and T cells subsets of peripheral blood mononuclear cells (PBM) were analyzed by immuno-fluorescence technique with flow cytometry; PBM were stained with cell surface markers for natural killer (NK) cells (CD3-, CD16+, CD56+) and T-cells (CD3+, CD16-, CD56-). The plasma was assayed for cortisol, human growth hormone (hGH), and prolactin by immunoradiometric assays. Bioassays were z-transformed for removal of between-subjects' effects. Samples were grouped into hourly means and analyzed using analysis of variance. Significant differences were examined by SNK contrast test. Similar analyses were performed for sleep stages. Cosinor analysis was applied to selected circadian variables. Results: All groups showed NK cell decline in both proportion (F[23,420]=19.0, < .000l) and activity (F[23,413]=6.2, p < .0001) during the night. Similarly, T cell proportion increases during the night in all groups (F[23,420]=6.7, p < .000l). However, NK proportion showed a different diurnal pattern for CFS than normals (F[46,420]=l.5,p < .03). Overall the NK proportion was lower in CFS and H_Sym, than H_ASym F[2,l9]=4.6, p < .02: CFS 7.5% & H_Sym 7.7% vs H_Asym=l1.1% ). Although all groups showed the well-recognized diurnal pattern in cortisol (F[23,421]=24.6, p < .000l), CFS showed a different diurnal pattern than H_ASym and H_Sym (F[46,421]=1.4, p < .05), with phase advance on Cosinor analysis. Similarly, CFS showed a different diurnal pattern of prolactin than H_Sym & H_ASym (F[46,421]=l.9, p < .0005), but CFS and H_ASym showed lower overall prolactin than H_Sym (F[2,87]=3.5, p<.05, CFS 18.8, H_ASym 18.2 vs H_Sym 25.2). All groups showed the sleep-related increase in hGH secretion (F[6,87]=5.0, p < .0002). CFS showed higher alpha non-REM ratings (0-4) than normals (CFS 2.5 vs. H_Sym 1.7 and H_ASym 1.5) and reported more pre-sleep fatigue (p < .00l), sleepiness (p < .004), and pain (p < .00l) than H_Sym & H_ASym. Conclusions: In comparison to normal symptomatic and asymptomatic subjects, CFS patients show altered diurnal patterns in cortisol, prolactin, and NK cells that accompany the alpha EEG sleep disorder, and daytime fatigue, sleepiness and pain. These findings are consistent with the theory of chronobiological disturbances in CFS¹.
Neuroendocrine aspects of chronic fatigue syndrome.Papanicolaou DA, Amsterdam JD, Levine S, McCann SM, Moore RC, Newbrand CH, Allen G, Nisenbaum R, Pfaff DW, Tsokos GC, Vgontzas AN, Kales A. Department of Medicine/Endocrinology, Emory University, Atlanta, GA, USA.
Chronic fatigue syndrome (CFS) is a serious health concern affecting over 800000 Americans of all ages, races, socioeconomic groups and genders. The etiology and pathophysiology of CFS are unknown, yet studies have suggested an involvement of the neuroendocrine system. A symposium was organized in March 2001 to explore the possibility of an association between neuroendocrine dysfunction and CFS, with special emphasis on the interactions between neuroendocrine dysfunction and other abnormalities noted in the immune and autonomic nervous systems of individuals with CFS. This paper represents the consensus of the panel of experts who participated in this meeting. Copyright 2004 S. Karger AG, Basel
Small adrenal glands in chronic fatigue syndrome: a preliminary computer tomography study.Scott LV, Teh J, Reznek R, Martin A, Sohaib A, Dinan TG Department of Psychiatry, Trinity College Dublin Medical School, St. James's, Hospital, Ireland. Journal: Psychoneuroendocrinology 1999 Oct;24(7):759-68
NLM citations: PMID: 10451910, UI: 99381217
The authors studied a group of CFS patients in whom there was evidence of inadequate functioning of the hypothalamic-pituitary-adrenal axis (HPA). In particular, they aimed to establish whether these patients had altered adrenal gland size. CFS patients (as defined by the CDC) underwent a 1 microgram adrenocorticotropin (ACTH) stimulation test (a test of adrenal gland functioning), and 8 of those with subnormal response to the test had a computer tomography assessment of their adrenal glands. The right and left adrenal gland bodies were reduced by over 50% in the CFS subjects, a result with implications for CFS pathophysiology and possibly for therapies.
*O* Possible upregulation of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome. Bakheit AM, Behan PO, Dinan TG, Gray CE, O'Keane V. British Medical Journal 1992; 304(6833): 1010-2.
Abstract: OBJECTIVE-To study the dynamic function of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome. DESIGN-Prospective comparison of patients with postviral fatigue syndrome with two control groups. SETTING-Department of neurology, University of Glasgow, Southern General Hospital; department of psychiatry, St James's Hospital, Dublin. SUBJECTS-15 patients with postviral fatigue syndrome, 13 age and sex matched healthy subjects, and 13 patients with primary depression. MAIN OUTCOME MEASURES-Serum prolactin concentrations before and one, two, and three hours after administration of buspirone. RESULTS-Because of the effects of sex hormones on prolactin secretion data for men and women were analysed separately. There was no significant difference in baseline prolactin concentrations between patients with postviral fatigue syndrome and healthy subjects or those with primary depression. However, the percentage difference between peak and baseline values was significantly higher in patients with postviral fatigue syndrome than the control groups (one way analysis of variance: women, p = 0.003; men, p = 0.004). CONCLUSIONS-The results suggest upregulation of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome but not in those with primary depression. The buspirone challenge test may therefore be useful in distinguishing these two conditions. Larger studies are required to explore the potential value of drugs acting on central 5-hydroxytryptamine receptors in the treatment of patients with the postviral fatigue syndrome.
Abnormal arginine-vasopressin secretion and water metabolism in patients with postviral fatigue syndrome. Bakheit AM, Behan PO, Watson WS, Morton JJ. Acta Neurologica Scandinavica 1993; 87(3): 234-8.
Abstract: Water metabolism and the responses of the neurohypophysis to changes in plasma osmolality during the water loading and water deprivation tests were studied in nine patients with postviral fatigue syndrome (PVFS) and eight age and six-matched healthy control subjects. Secretion of arginine-vasopressin (AVP) was erratic in these patients as shown by lack of correlation between serum and urine osmolality and the corresponding plasma AVP levels. Patients with PVFS had significantly low baseline arginine-vasopressin levels when compared with healthy subjects. Patients with PVFS as a group also showed evidence of increased total body water content. These results may be indicative of hypothalamic dysfunction in patients with PVFS.
*O*Chronic fatigue syndrome: a disorder of central cholinergic transmission. Chaudhuri A, Majeed T, Dinan T, Behan PO. Journal of Chronic Fatigue Syndrome 1997; 3(1): 3-16.
Neurological manifestations of malabsorption. Cooke WT. Postgraduate Medical Journal 1978; 54: 760-62.
Summary: The clinical and pathological findings in patients with neurological disorders in association with disordered function of the small intestine, in particular coeliac disease, are outlined. The possible significance of the abnormalities of pyridoxine, tyrosine and tryptophan metabolism are considered in relation to biopterin derivatives and their relevance to neurological dysfunction.
The neuroendocrinology of chronic fatigue syndrome. Scott LV, Dinan TG. Journal of Chronic Fatigue Syndrome 1996; 2(4): 49-59.
Abstract: Since the introduction of operationalized criteria, there has been considerable interest in the pathophysiology of chronic fatigue syndrome (CFS). There is an increasing volume of evidence to support the view that patients with this syndrome have unique neuroendocrinology patterns. Central to this endocrine dysfunction is altered hypothalamic-pituitary-adrenal axis (HPA) activity. The cardinal findings include attenuated adrenocorticotrophic hormone (ACTH) responses to corticotropin-releasing hormone (CRH) and low 24-hour urinary cortisol. These are compatible with a mild central adrenal insufficiency. Adrenal steroids have wide-spread impact in the brain, and of particular importance is their dense concentration on serotonergic and noradrenergic neurotransmitter pathways. Using a variety of different challenge drugs, a supersensitivity of the serotonergic 5 HT 1A receptor has been demonstrated although the results have not been entirely consistent. A blunting of dexamethasone-induced growth hormone release has been described and may reflect a relatively subsensitivity of the steroid receptor. It is proposed that the disruption of the HPA, which may be triggered bya number of stressors including infections, may represent a primary phenomenon, and that the neurotransmitter abnormalities described are in fact secondarily heralded by prolonged HPA dysregulation.
Abnormality of adrenal function in the patients with CFS: the decline of 17-ketosteroid sulfate (17KS-S). Yamaguti K, Kuratsune H, Machi T, Kodate S, Kinani T. Journal of Chronic Fatigue Syndrome 1996; 2(2/3): 124-125.
Abstract: The etiology of CFS has not yet been clarified although many investigators have made efforts to resolve this problem using a number of approaches. In 1991, Demitrack et al. Reported that patients with CFS might have impaired activation of the hypothalamic-pituitary-adrenal axis. It is also well known that during psychological stress serum cortisol concentration and urinary 17-hydroxycoritco-steroid (17-OHCS) excretion increase, while urinary 17-ketosteroid sulfate (17-KS-S) excretion decreases. To investigate the endocrine relationship between psychological and physical stress and CFS, we compared the values of urinary 17-OHCS (mg/g creatinine) and 17-KS-S (mg/gcreatinine) excretion in 49 patients with CFS (26 ± 3.6 years old) and in 35 normal age-matched controls (27 ± 3.9 years old) while they were sleeping at night. We found that the level of 17-KS-S was significantly lower in CFS patients than in normal controls. (1.54 ± 1.04 in CFS vs 3.01 ± 1.04 in control, p<0.001), while the level of 17-OHCS was about the same as the controls (4.31 ± 1.26 in CFS vs 4.22 ± 0.77 in controls). To clarify the abnormality of 17-KS-S in the patients with CFS, we measured the serum level of ACTH, cortisol, 17-OH pregnenolone, dehydroepiandrosterone (DHEA), DHEA-sulphate (DHEA-S) and androstenedione after overnight fasting in 14 patients. The level of ACTH, cortisol, 17-OH pregnenolone and androstenedione in most patients with CFS was within the range of mean ± 2SD of normal controls, while the level of DHEA decreased in some patients and the level of DHEA-S decreased in most patients with CFS. These results suggest that the decline of urinary 17-KS-S excretion while sleeping at night in the patients with CFS was mainly due to the decline of serum DHEA-S. These abnormalities found in CFS are quite different from those found in patients with mental and physical diseases reported previously.
Elevation of bioactive transforming growth factor-beta in serum from patients with chronic fatigue syndrome. Bennett AL, Chao CC, Hu S, Buchwald D, Fagioli LR, Schur PH, Peterson PK, Komaroff AL. Journal of Clinical Immunology 1997; 17(2): 160-66.
Abstract: The level of bioactive transforming growth factor-beta (TGF-beta) was measured in serum from patients with chronic fatigue syndrome (CFS), healthy control subjects, and patients with major depression, systemic lupus erythematosis (SLE), and multiple sclerosis (MS) of both the relapsing/remitting (R/R) and the chronic progressive (CP) types. Patients with CFS had significantly higher levels of bioactive TGF-beta levels compared to the healthy control major depression, SLE, R/R MS, and CP MS groups (P < 0.01). Additionally, no significant differences were found between the healthy control subjects and any of the disease comparison groups. The current finding that TGF-beta is significantly elevated among patients with CFS supports the findings of two previous studies examining smaller numbers of CFS patients. In conclusion, TGF-beta levels were significantly higher in CFS patients compared to patients with various diseases known to be associated with immunologic abnormalities and/or pathologic fatigue. These findings raise interesting questions about the possible role of TGF-beta in the pathogenesis of CFS.
Blunted serotonin-mediated activation of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome. Dinan TG, Majeed T, Lavelle E, Scott LV, Berti C, Behan P. Psychoneuroendocrinology 1997; 22(4): 261-7.
Abstract: We examined 5HT1a-mediated ACTH release in patients with chronic fatigue syndrome (CFS) using a between-subjects design. Patients attending a specialist outpatient clinic for CFS, who fulfilled CDC criteria, together with age- and sex-matched healthy comparison subjects, were recruited. Subjects had a cannula inserted in a forearm vein at 0830 h and were allowed to relax until 0900 h, when baseline bloods for ACTH and cortisol were drawn. They were then given ipsapirone 20 mg PO and further blood for hormone estimation was taken at +30, +60, +90, +120 and +180 min. Baseline ACTH and cortisol levels did not differ between the two groups. Release of ACTH (but not cortisol) in response to ipsapirone challenge was significantly blunted in patients with CFS. We conclude that serotonergic activation of the hypothalamic-pituitary-adrenal axis is defective in CFS. This defect may be of pathophysiological significance.
Mild adrenocortical deficiency, chronic allergies, autoimmune disorders and the chronic fatigue syndrome: a continuation of the cortisone story. Jeffries WMcK. Medical Hypotheses 1994; 42, 3: 183-189.
Abstract: The possibility that patients with disorders that improve with administration of large, pharmacologic dosages of glucocorticoids, such as chronic allergies and autoimmune disorders, might have mild deficiency of cortisol production or utilization has received little attention. Yet evidence that patients with rheumatoid arthritis improved with small, physiologic dosages of cortisol or cortisone acetate was reported over 25 years ago, and that patients with chronic allergic disorders or unexplained chronic fatigue also improved with administration of such small dosages was reported over 15 years ago, suggesting that these disorders might be associated with mild adrenocortical deficiency. The apparent reasons for the failure of these reports to be confirmed or mentioned in medical textbooks and the facts needed to restore perspective are reviewed, and the need for further studies of the possible relationship of a mild deficiency of the production or utilization of cortisol and possibly other normal adrenocortical hormones to the development of these disorders is discussed.
Serum angiotensin-converting enzyme as a marker for the chronic fatigue-immune dysfunction syndrome: a comparison to serum angiotensin-converting enzyme in sarcoidosis. Lieberman J, Bell DS. American Journal of Medicine 1993; 95(4): 407-12.
Abstract: PURPOSE: To study the reliability of a serum angiotensin-converting enzyme (ACE) assay as a marker for the chronic fatigue-immune dysfunction syndrome (CFIDS), and to compare some enzyme characteristics of ACE in CFIDS with that in sarcoidosis. PATIENTS AND METHODS: Forty-nine patients with CFIDS and 56 endemic control subjects from Lyndonville, New York, and Charlotte, North Carolina; plus 23 untreated patients with active sarcoidosis, 24 with sarcoidosis receiving corticosteroid therapy, and 32 patient controls without sarcoidosis from California. Serum ACE levels were determined with a spectrophotometric method. The effect of freezing and thawing and the effect of storage at 4 degrees C were compared between CFIDS and sarcoidosis samples. RESULTS: Serum ACE levels were elevated in 80% of patients with CFIDS and 30% of endemic control subjects as compared with 9.4% of nonendemic California control subjects. The ACE activity in CFIDS differed from that in sarcoidosis because of its lability with storage at 4 degrees C in CFIDS and its partial activation with freezing and thawing. Thus, ACE activity was elevated in the majority of CFIDS patients either upon initial assay or upon a subsequent assay after refreezing. ACE activity was elevated in 87% of patients with active sarcoidosis and was not affected by storage or freezing and thawing. CONCLUSIONS: Serum ACE elevations may be a useful marker for CFIDS, especially if a method can be developed to distinguish ACE in CFIDS from that in sarcoidosis. The sensitivity for CFIDS was 80%, with 68% specificity in an endemic area. The increased prevalence of serum ACE elevations in endemic controls as compared with nonendemic controls suggests that an ACE increase may be an early manifestation of CFIDS and supports the concept that CFIDS is a definite disease state.
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