Category: Neurology

Acetylcholine mediated vasodilatation in the microcirculation of patients with chronic fatigue syndrome

Abstract:

The aetiology of chronic fatigue syndrome (CFS) remains controversial and a number of hypotheses have been put forward to explain it. Research into the condition is hindered by the considerable heterogeneity seen across patients but several reports have highlighted disturbances to cholinergic mechanisms in terms of central nervous system activity, neuromuscular function and autoantibodies to muscarinic cholinergic receptors. This paper examines an altogether separate function for acetylcholine and that is its role as an important and generalized vasodilator.

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 characterise many patients. There are several mechanisms that might lead to ACh endothelial sensitivity in CFS patients and various experiments have been designed to unravel the enigma. These are reported here.

 

Source: Spence VA, Khan F, Kennedy G, Abbot NC, Belch JJ. Acetylcholine mediated vasodilatation in the microcirculation of patients with chronic fatigue syndrome. Prostaglandins Leukot Essent Fatty Acids. 2004 Apr;70(4):403-7. http://www.ncbi.nlm.nih.gov/pubmed/15041034

 

Autonomic function and serum erythropoietin levels in chronic fatigue syndrome

Abstract:

OBJECTIVE: Given previous findings, we wished to investigate whether there was evidence of autonomic dysfunction in patients with chronic fatigue syndrome, and whether this could be related to reduced erythropoietin levels and altered red blood cell indices.

METHODS: We assessed autonomic function and analysed blood parameters (including erythropoietin) in 22 patients with chronic fatigue syndrome who were medication-free and without comorbid depression or anxiety. Results were compared to 23 iron-deficiency anaemia patients and 18 healthy individuals.

RESULTS: Autonomic testing in patients with chronic fatigue syndrome yielded a significantly greater increase in heart rate together with a more pronounced systolic blood pressure fall on standing compared to healthy individuals. Heart rate beat-to-beat variation on deep breathing and responses to the Valsalva manoeuvre were normal. Two of 22 patients with chronic fatigue had mild normochromic normocytic anaemia with normal ferritin, vitamin B12 and folate levels. Serum erythropoietin levels were within reference range.

CONCLUSION: Some autonomic dysfunction is present in chronic fatigue syndrome (CFS) patients; the explanation remains uncertain, but could relate to cardiovascular deconditioning. There were no major haematological, biochemical or immunological abnormalities in these patients.

 

Source: Winkler AS, Blair D, Marsden JT, Peters TJ, Wessely S, Cleare AJ. Autonomic function and serum erythropoietin levels in chronic fatigue syndrome. J Psychosom Res. 2004 Feb;56(2):179-83. http://www.ncbi.nlm.nih.gov/pubmed/15016575

 

Plasma endothelin-1 levels in chronic fatigue syndrome

Comment on: Increased plasma endothelin-1 levels in fibromyalgia syndrome. [Rheumatology (Oxford). 2003]

 

SIR, We read with interest the report by Pache et al. [1] showing increased endothelin-1 (ET-1) levels in patients with a diagnosis of fibromyalgia syndrome (FMS) and their conclusion that elevated ET-1 levels might contribute to some of the apparent vascular disturbances that characterize the syndrome. Pache et al. also point to the overlap between the clinical presentation of FMS and other ‘stress-associated disorders including chronic fatigue syndrome (CFS) and depression’. Whether FMS or CFS is stress-induced is a contentious issue in itself, but of equal concern is the view that FMS should be considered to be part of the spectrum of illness under the generic name ‘chronic fatigue syndrome’. Clearly, the symptoms of FMS and CFS have much in common [2, 3] but it has been said that FMS represents an additional burden of suffering among those with CFS [4], those patients meeting the case definitions for both FMS and CFS having a worse course, worse overall health and greater disease impact [2]. Furthermore, while many FMS patients experience fatigue, it has been estimated that only about one-fifth fulfil the specific criteria required for CFS [5]. Clinical similarities apart, there are biological differences between the two; for example, cerebrospinal fluid levels of substance P are elevated in FMS but not in CFS patients [6], and cardiovascular responses to postural challenge are characteristic of many CFS patients but are not apparent in those with FMS [7].

You can read the rest of this comment here: http://rheumatology.oxfordjournals.org/content/43/2/252.long

 

Source: Kennedy G, Spence V, Khan F, Belch JJ. Plasma endothelin-1 levels in chronic fatigue syndrome. Rheumatology (Oxford). 2004 Feb;43(2):252-3; author reply 253-4. http://rheumatology.oxfordjournals.org/content/43/2/252.long (Full article)

 

Association between serotonin transporter gene polymorphism and chronic fatigue syndrome

Abstract:

Interaction between the hypothalamo-pituitary-adrenal axis and the serotonergic system is thought to be disrupted in chronic fatigue syndrome(CFS) patients. We examined a serotonin transporter (5-HTT) gene promoter polymorphism, which affects the transcriptional efficiency of 5-HTT, in 78 CFS patients using PCR amplification of the blood genomic DNA.

A significant increase of longer (L and XL) alleic variants was found in the CFS patients compared to the controls both by the genotype-wise and the allele-wise analyses (both p<0.05, by chi(2) test and Fisher’s exact test). Attenuated concentration of extracellular serotonin due to longer variants may cause higher susceptibility to CFS.

 

Source: Narita M, Nishigami N, Narita N, Yamaguti K, Okado N, Watanabe Y, Kuratsune H. Association between serotonin transporter gene polymorphism and chronic fatigue syndrome. Biochekm Biophys Res Commun. 2003 Nov 14;311(2):264-6. http://www.ncbi.nlm.nih.gov/pubmed/14592408

 

Efficacy of a half dose of oral pyridostigmine in the treatment of chronic fatigue syndrome: three case reports

Abstract:

Chronic fatigue syndrome (CFS) is characterized by persistent mental and physical fatigue for at least 6 months. Its pathophysiology is unknown and there is no proven effective treatment. We describe three cases who fulfill the criteria of CFS, in whom a defect of neuromuscular transmission and dysautonomia are present and who respond to acetylcholine-esterase inhibition.

Case 1: 18-year-old female with a 3-year history of CFS. Response of compound-muscle-action potential, recorded using surface recording electrode, over left abductor pollicis brevis muscle, to repetitive nerve stimulation (RNS) at a rate of 10 Hz showed a 42% incremental response. Composite autonomic scoring system (CASS) showed mild cholinergic impairment (cardiovagal score: 1; sudomotor score: 2). Serological tests for Epstein-Barr virus (EBV) revealed positive antiviral capsid antigens (anti-VCA) immunoglobulins G (IgG). Oral pyridostigmine therapy (30 mg) resulted in marked improvement in symptoms.

Case 2: 28-year-old female with 10-year history of CFS. RNS, using identical protocol, showed a 60% incremental response over the same muscle. CASS showed mild cholinergic impairment (cardiovagal score: 1; sudomotor score: 2) and this patient was also positive for EBV. This patient responded dramatically to 10-mg pyridostigmine.

Case 3: 29-year-old female with a history of CFS for longer than 15 years. Repetitive stimulation, using identical paradigm to left abductor pollicis brevis muscle, showed a 42% incremental response. CASS showed mildly cholinergic impairment (cardiovagal score: 2; sudomotor score: 1). EBV antibody titers were positive. Patient responded to 30-mg pyridostigmine with an improvement in her fatigue.

These three cases generate the hypothesis that the fatigue in some patients with clinical CFS might be due to a combination of mild neuromuscular transmission defect combined with cholinergic dysautonomia. Support for this thesis derives from the improvement with cholinesterase inhibition.

 

Source: Kawamura Y, Kihara M, Nishimoto K, Taki M. Efficacy of a half dose of oral pyridostigmine in the treatment of chronic fatigue syndrome: three case reports. Pathophysiology. 2003 May;9(3):189-194. http://www.ncbi.nlm.nih.gov/pubmed/14567934

 

Baroreceptor reflex and integrative stress responses in chronic fatigue syndrome

Abstract:

OBJECTIVE: Altered cardiovascular responses to mental and postural stressors have been reported in chronic fatigue syndrome (CFS). This study examined whether those findings may involve changes in baroreceptor reflex functioning.

METHODS: Chronotropic baroreceptor reflex (by sequential analysis) and cardiovascular stress responses were recorded during postural (5-minute of active standing) and cognitive (speech task) stress testing in patients with CFS grouped into cases with severe (N = 21) or less severe (N = 22) illness, and in 29 matched control subjects.

RESULTS: Patients with CFS had a greater decline in baroreceptor reflex sensitivity (BRS) during standing, although only those with severe CFS were significantly different from the controls. Systolic blood pressure declined during standing in the control group but was maintained in the CFS patients. In contrast, the patients with less severe CFS had blunted increases in blood pressure during the speech task, which could not, however, be explained by inadequate inhibition of the baroreceptor reflex, with all groups showing an appropriate reduction in BRS during the task.

CONCLUSIONS: These results indicate that in CFS, deficiencies in orthostatic regulation, but not in centrally mediated stress responses, may involve the baroreceptor reflex. This study also suggests that classifying patients with CFS on illness severity may discriminate between patients with abnormalities in peripheral vs. central mechanisms of cardiovascular stress responses.

 

Source: Peckerman A, LaManca JJ, Qureishi B, Dahl KA, Golfetti R, Yamamoto Y, Natelson BH. Baroreceptor reflex and integrative stress responses in chronic fatigue syndrome. Psychosom Med. 2003 Sep-Oct;65(5):889-95. http://www.ncbi.nlm.nih.gov/pubmed/14508037

 

Prolonged acetylcholine-induced vasodilatation in the peripheral microcirculation of patients with chronic fatigue syndrome

Abstract:

Although the aetiology of chronic fatigue syndrome (CFS) is unknown, there have been a number of reports of blood flow abnormalities within the cerebral circulation and systemic blood pressure defects manifesting as orthostatic intolerance. Neither of these phenomena has been explained adequately, but recent reports have linked cerebral hypoperfusion to abnormalities in cholinergic metabolism.

Our group has previously reported enhanced skin vasodilatation in response to cumulative doses of transdermally applied acetylcholine (ACh), implying an alteration of peripheral cholinergic function. To investigate this further, we studied the time course of ACh-induced vasodilatation following a single dose of ACh in 30 patients with CFS and 30 age- and gender-matched healthy control subjects.

No differences in peak blood flow was seen between patients and controls, but the time taken for the ACh response to recover to baseline was significantly longer in the CFS patients than in control subjects. The time taken to decay to 75% of the peak response in patients and controls was 13.7 +/- 11.3 versus 8.9 +/- 3.7 min (P = 0.03), respectively, and time taken to decay to 50% of the peak response was 24.5 +/- 18.8 versus 15.1 +/- 8.9 min (P = 0.03), respectively.

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.

 

Source: Khan F, Spence V, Kennedy G, Belch JJ. Prolonged acetylcholine-induced vasodilatation in the peripheral microcirculation of patients with chronic fatigue syndrome. Clin Physiol Funct Imaging. 2003 Sep;23(5):282-5. http://www.ncbi.nlm.nih.gov/pubmed/12950326

Observer independent analysis of cerebral glucose metabolism in patients with chronic fatigue syndrome

Abstract:

OBJECTIVES: To evaluate cerebral glucose metabolism, assessed by 18-fluorodeoxyglucose positron emission tomography (FDG-PET), in patients with chronic fatigue syndrome (CFS), using an observer independent analytical approach; and to characterise any observed alterations by correlating them with neuropsychological deficits.

METHODS: 26 patients (13 female, 13 male) were examined. They all fulfilled the CDC diagnostic criteria for CFS. Their ages ranged from 26 to 61 years (mean (SD) age, 43 (9.3) years). They underwent extensive psychometric testing including the hospital anxiety and depression scale (HADS) and the short form 36 item health questionnaire (SF-36). Brain FDG-PET was done in all the subjects. After stereotactic normalisation, single subject comparisons with an age and sex matched normal database (n = 18) and a group comparison between the patients and normal controls were undertaken, along with additional correlation analyses between brain metabolism and psychometric test scores.

RESULTS: 12 of the 26 patients showed no significant decrease in FDG uptake compared with the controls. Of the remaining 14, 12 showed hypometabolism bilaterally in the cingulate gyrus and the adjacent mesial cortical areas. Five of these 12 patients also had decreased metabolism in the orbitofrontal cortex. The two remaining patients had hypometabolism in the cuneus/praecuneus. Correlation analyses showed significant correlations between some test scores (anxiety, depression, health related quality of life) but not fatigue and regional reductions in glucose metabolism.

CONCLUSIONS: Although abnormalities in FDG-PET were only detectable in approximately half the CFS patients examined, and no specific pattern for CFS could be identified, PET may provide valuable information in helping to separate CFS patients into subpopulations with and without apparent alterations in the central nervous system.

 

Source: Siessmeier T, Nix WA, Hardt J, Schreckenberger M, Egle UT, Bartenstein P. Observer independent analysis of cerebral glucose metabolism in patients with chronic fatigue syndrome. J Neurol Neurosurg Psychiatry. 2003 Jul;74(7):922-8. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1738575/ (Full article)

 

 

Experimental evidence for interpretive but not attention biases towards somatic information in patients with chronic fatigue syndrome

Abstract:

OBJECTIVE: This study tested whether CFS patients have an attentional information processing bias for illness-related information and a tendency to interpret ambiguous information in a somatic fashion.

DESIGN: 25 patients meeting research criteria for a diagnosis of CFS were compared to 24 healthy matched controls on a modified Stroop task and an ambiguous cues task.

METHOD: In the modified Stroop task, participants colour named a series of somatic, depressed and neutral words in order to ascertain whether the somatic words were more distracting to the CFS patients than the depressed and neutral words when compared to controls. In the ambiguous cues task, participants were presented with a tape-recorded list of 30 words including 15 ambiguous illness words (e.g., vein/vain) and 15 unambiguous words. For each word, they were asked to write down the first word that came into their head. A somatic bias score was obtained for each subject by summing the number of somatic responses to the ambiguous word cues.

RESULTS: Although CFS patients were significantly slower in colour naming all of the Stroop word categories than controls, there was no evidence for illness or depressed words creating greater interference than neutral words. However, on the ambiguous cues task, CFS patients made significantly more somatic interpretations than controls and this bias was significantly associated with the extent to which they currently reported symptoms.

CONCLUSION: CFS patients have an interpretive bias for somatic information which may play a part in the maintenance of the disorder by heightening patients’ experience of physical symptoms and helping to maintain their negative illness schemas. Although patients did not show an attentional bias in this study, this may be related to the methodology employed.

 

Source: Moss-Morris R, Petrie KJ. Experimental evidence for interpretive but not attention biases towards somatic information in patients with chronic fatigue syndrome. Br J Health Psychol. 2003 May;8(Pt 2):195-208. http://www.ncbi.nlm.nih.gov/pubmed/12804333

 

Deficit in motor performance correlates with changed corticospinal excitability in patients with chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is characterised by fatigue and musculosketetal pain, the severity of which is variable. Simple reaction times (SRTs) and movement times (SMTs) are slowed in CFS. Our objective is to correlate the day-to-day changes in symptomatology with any change in SRT, SMT or corticospinal excitability.

Ten CFS patients were tested on two occasions up to two years apart. Motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) of the motor cortex were recorded from the thenar muscles. Threshold TMS strength to evoke MEPs was measured to index corticospinal excitability. SRTs and SMTs were measured.

The percentage change in both SRTs and SMTs between the two test sessions correlated with the percentage change in corticospinal excitability assessed according to threshold TMS intensity required to produce MEPs. This study provides evidence that changing motor deficits in CFS have a neurophysiological basis. The slowness of SRTs supports the notion of a deficit in motor preparatory areas of the brain.

 

Source: Davey NJ, Puri BK, Catley M, Main J, Nowicky AV, Zaman R. Deficit in motor performance correlates with changed corticospinal excitability in patients with chronic fatigue syndrome. Int J Clin Pract. 2003 May;57(4):262-4. http://www.ncbi.nlm.nih.gov/pubmed/12800454