Biochemical and vascular aspects of pediatric chronic fatigue syndrome

Abstract:

OBJECTIVE: To evaluate the biochemical and vascular aspects of pediatric chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME).

DESIGN: Cross-sectional clinical study.

SETTING: Tayside, Scotland, United Kingdom.

PARTICIPANTS: Twenty-five children with CFS/ME and 23 healthy children recruited from throughout the United Kingdom.

INTERVENTIONS: Participants underwent a full clinical examination to establish a diagnosis of CFS/ME and were asked to describe and score their CFS/ME symptoms. Biochemical markers were measured. Arterial wave reflection was estimated to assess systemic arterial stiffness.

MAIN OUTCOME MEASURES: Markers of oxidative stress and free radicals, C-reactive protein level, white blood cell apoptosis, and arterial wave reflection.

RESULTS: Children with CFS/ME had increased oxidative stress compared with control individuals (isoprostanes: 252.30 vs 215.60 pg/mL, P = .007; vitamin C, mean [SD]: 0.84 [0.26] vs 1.15 [0.28] mg/dL, P < .001; vitamin E, 8.72 [2.39] vs 10.94 [3.46] microg/mL, P = .01) and increased white blood cell apoptosis (neutrophils: 53.7% vs 35.7%, P = .005; lymphocytes: 40.1% vs 24.6%, P = .009). Arterial stiffness variables did not differ significantly between groups (mean augmentation index, -0.57% vs -0.47%, P = .09); however, the derived variables significantly correlated with total (r = 0.543, P = .02) and low-density lipoprotein (r = 0.631, P = .004) cholesterol in patients with CFS/ME but not in controls.

CONCLUSIONS: Biomedical anomalies seen in adults with CFS/ME-increased oxidative stress and increased white blood cell apoptosis-can also be observed in children with clinically diagnosed CFS/ME compared with matched controls. Unlike in their adult counterparts, however, arterial stiffness remained within the reference range in these pediatric patients.

Comment in: Chronic fatigue syndrome in adolescence: where to from here? [Arch Pediatr Adolesc Med. 2010]

 

Source: Kennedy G, Khan F, Hill A, Underwood C, Belch JJ. Biochemical and vascular aspects of pediatric chronic fatigue syndrome. Arch Pediatr Adolesc Med. 2010 Sep;164(9):817-23. doi: 10.1001/archpediatrics.2010.157. https://www.ncbi.nlm.nih.gov/pubmed/20819963

 

Adolescent chronic fatigue syndrome: a follow-up study

Abstract:

OBJECTIVE: To describe the symptomatic and educational long-term outcomes, health care use, and risk factors of nonrecovery in adolescent chronic fatigue syndrome (CFS).

DESIGN: Follow-up study.

SETTING: Academic pediatric hospital.

PARTICIPANTS: Sixty adolescents with CFS.

INTERVENTIONS: Regular care.

OUTCOME MEASURES: The Checklist Individual Strength, Child Health Questionnaire, and a general questionnaire regarding further symptoms, school attendance, work attendance, and treatment.

RESULTS: Complete measurements were returned for 54 adolescents (90%). At initial assessment, their mean (SD) age was 16.0 (1.5) years and 20.4% were male. The mean follow-up duration was 2.2 years. At follow-up, the mean (SD) age was 18.2 (1.5) years; 28 adolescents (51.9%) had nearly complete improvement of symptoms but 26 (48.1%) did not experience improvement. Adolescents who attended school (n = 41) had missed an average of 33% of classes during the last month. The rest (n = 13) had worked an average of 38.7% of a full-time job during the last month. A total of 66.7% of subjects were treated by a physiotherapist, 38.9% were clinically treated in rehabilitation, 48.1% had received psychological support, and 53.7% had used alternative treatment.

CONCLUSIONS: About half of the adolescents had recovered from CFS at follow-up. The other half was still severely fatigued and physically impaired. Health care use had been high, and school and work attendance were low. Older age at inclusion was a risk factor, and pain, poor mental health, self-esteem, and general health perception at outcome were associated with an unfavorable outcome. Future research should focus on customizing existing treatment and studying additional treatment options.

 

Source: van Geelen SM, Bakker RJ, Kuis W, van de Putte EM. Adolescent chronic fatigue syndrome: a follow-up study. Arch Pediatr Adolesc Med. 2010 Sep;164(9):810-4. doi: 10.1001/archpediatrics.2010.145. https://www.ncbi.nlm.nih.gov/pubmed/20819962

 

Postinfectious fatigue in adolescents and physical activity

Abstract:

OBJECTIVE: To compare adolescents who do and do not recover from acute infectious mononucleosis in terms of fatigue severity and activity levels before, during, and in the 2 years following infection.

DESIGN: Prospective case-control study.

SETTING: The baseline and 12- and 24-month evaluations occurred in the subjects’ homes. The 6-month outpatient visit occurred at Children’s Memorial Hospital in Chicago, Illinois.

PARTICIPANTS: Three hundred one adolescents (aged 12-18 years) with acute infectious mononucleosis.

MAIN EXPOSURES: All participants were evaluated at baseline (during active infection). Six months following infection, 39 of them met criteria for chronic fatigue syndrome. These subjects were matched by sex and Tanner stage to 39 randomly selected screened-negative subjects. Both groups were reevaluated at 12- and 24-month follow-ups.

OUTCOME MEASURES: Scores from the Fatigue Severity Scale and the Modifiable Activity Questionnaire.

RESULTS: For both groups, physical activity levels declined and sleep increased as a result of having mononucleosis. Compared with their matched controls, adolescents with chronic fatigue syndrome reported significantly higher levels of fatigue at all points and spent significantly more time sleeping during the day 6 and 12 months following infection. The 2 groups did not differ significantly in terms of physical activity levels before, during, or after infection. There was a consistent trend for decreased physical activity in the chronic fatigue syndrome group.

CONCLUSIONS: Adolescents with chronic fatigue syndrome appear to be pushing themselves in an attempt to maintain similar activity levels as their peers, but paying for it in terms of fatigue severity and an increased need for sleep, particularly during the day.

Comment in: Chronic fatigue syndrome in adolescence: where to from here? [Arch Pediatr Adolesc Med. 2010]

 

Source: Huang Y, Katz BZ, Mears C, Kielhofner GW, Taylor R. Postinfectious fatigue in adolescents and physical activity. Arch Pediatr Adolesc Med. 2010 Sep;164(9):803-9. doi: 10.1001/archpediatrics.2010.144. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3050621/ (Full article)

 

Mouse retroviruses and chronic fatigue syndrome: Does X (or P) mark the spot?

Five years ago, a retrovirus resembling a murine leukemia virus (MLV) was found in patients with prostate cancer (1), and last year, a similar gammaretrovirus was identified in patients with chronic fatigue syndrome (CFS) (2). The agent was named xenotropic MLV-related virus (XMRV), because its env gene was nearly identical to that of xenotropic MLV, an infectious endogenous MLV that preferentially infects cells from foreign species, including humans (Fig. 1A) (3). The two reports struck a common chord, because the viral sequences found in prostate cancer and CFS were nearly identical. A second common theme emerged in reports from Europe that XMRV was rarely found, if at all, in prostate-cancer samples or patients with CFS; however, other investigators confirmed the presence of XMRV in prostate-cancer samples from North America (4). Although a recent report from the Centers for Disease Control and Prevention (CDC) did not find a link between XMRV and CFS (5), distinct MLV-related sequences are found in serial samples collected from the mid-1990s to 2010 from patients with CFS reported in the study by Lo et al. (6) in PNAS. However, the reasons for the current geographical restriction and the source of the infection are baffling.

You can read the rest of this comment here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936611/

Comment on: Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors. [Proc Natl Acad Sci U S A. 2010]

 

Source: Courgnaud V1, Battini JL, Sitbon M, Mason AL. Mouse retroviruses and chronic fatigue syndrome: Does X (or P) mark the spot? Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15666-7. doi: 10.1073/pnas.1007944107. Epub 2010 Aug 23. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936611/ (Full article)

 

Psychomotor function and response inhibition in chronic fatigue syndrome

Abstract:

Most research points to cognitive slowing in chronic fatigue syndrome (CFS), although there have been negative reports. The present study is one of few that examines fine motor processing and the inhibition of automatic responses in a well-characterised CFS population.

A total of 35 female CFS patients without current major depression and 25 female controls performed two computerised figure-copying tasks. The cognitive and fine motor processing of visual-spatial information was measured by recording reaction time (RT) and movement time (MT), respectively. The inhibition of automatic responses was assessed by introducing ‘conflicting patterns’ (i.e., patterns that were difficult to draw from the preferred left to right).

A multivariate general linear model was adopted for the statistical analysis of the movement recordings. As a result, CFS was significantly associated with longer RT and MT in the pooled and in the task-specific analyses. However, there was no interaction between disease status and conflicting character of the patterns.

In conclusion, these performance data on the figure-copying tasks provide confirmatory evidence for psychomotor slowing in CFS, but not for a disturbed inhibition of automatic responses. Computerised figure-copying tasks may be promising tools for use in neurobiological research and clinical trials in CFS.

Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

 

Source: Van Den Eede F, Moorkens G, Hulstijn W, Maas Y, Schrijvers D, Stevens SR, Cosyns P, Claes SJ, Sabbe BG. Psychomotor function and response inhibition in chronic fatigue syndrome. Psychiatry Res. 2011 Apr 30;186(2-3):367-72. doi: 10.1016/j.psychres.2010.07.022. Epub 2010 Aug 24. https://www.ncbi.nlm.nih.gov/pubmed/20797797

 

The increase of alpha-melanocyte-stimulating hormone in the plasma of chronic fatigue syndrome patients

Abstract:

BACKGROUND: Despite extensive research, no reliable biological marker for chronic fatigue syndrome (CFS) has yet been identified. However, hyperactivation of melanotrophs in the pituitary gland and increased levels of plasma alpha-melanocyte-stimulating hormone (alpha-MSH) have recently been detected in an animal model of chronic stress. Because CFS is considered to be caused partly by chronic stress events, increased alpha-MSH plasma levels may also occur in CFS patients. We therefore examined alpha-MSH levels in CFS patients.

METHODS: Fifty-five CFS patients, who were previously diagnosed within 10 years of with the disease, were enrolled in this study. Thirty healthy volunteers were studied as controls. Fasting bloods samples were collected in the morning and evaluated for their plasma levels of alpha-MSH, adrenocorticotropic hormone (ACTH), serum cortisol and dehydroepiandrosterone sulfate (DHEA-S). Mean levels of alpha-MSH were compared between the CFS and control groups using Welch’s t test.

RESULTS: The mean plasma alpha-MSH concentration in the CFS group (17.9 +/- 1.0 pg/mL) was significantly higher than that in healthy controls (14.5 +/- 1.0 pg/mL, p = 0.02). However, there was a wide range of values in the CFS group. The factors correlated with the plasma alpha-MSH values were analyzed using Spearman’s rank correlation. A negative correlation was found between the duration of the CFS and the plasma alpha-MSH values (p = 0.04, rs = -0.28), but no correlations with ACTH, cortisol or DHEA-S levels were identified (p = 0.55, 0.26, 0.33, respectively). The CFS patients were divided into two groups: patients diagnosed for <or= 5 years’ duration, and those diagnosed for 5-10 years’ duration. They were compared with the healthy controls using one-way ANOVA and Tukey-Kramer multiple comparison tests. The mean alpha-MSH concentration in the <or= 5 years group was 20.8 +/- 1.2 pg/mL, which was significantly higher than that in the healthy controls (p < 0.01). There was no significant difference between the 5-10 year group (15.6 +/- 1.4 pg/mL) and the healthy controls.

CONCLUSIONS:CFS patients with a disease duration of <or= 5 years had significantly higher levels of alpha-MSH in their peripheral blood. alpha-MSH could be a potent biological marker for the diagnosis of CFS, at least during the first 5 years after onset of the disease.

 

Source: Shishioh-Ikejima N, Ogawa T, Yamaguti K, Watanabe Y, Kuratsune H, Kiyama H. The increase of alpha-melanocyte-stimulating hormone in the plasma of chronic fatigue syndrome patients. BMC Neurol. 2010 Aug 23;10:73. doi: 10.1186/1471-2377-10-73. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2933583/ (Full article)

 

Tired with all those supplements?

A 37 year-old patient, who had a history of chronic fatigue syndrome (CFS), was referred to the Clinical Immunology clinic by her general practitioner (GP). Her chief complaint was of severe fatigue following a viral illness 3 months previously. Concerned by her slow recovery she had sought the advice of a private health professional, who performed a series of blood tests and told her that she had insufficient levels of several vitamins and recommended a variety of supplements. In addition to sertraline prescribed by her GP, she was taking eight nutritional supplements. Her weight was stable and she had no history of cough, night sweats, lymphadenopathy, abdominal pain, joint pain, skin rashes or change in bowel habit. Physical examination was unremarkable.

A worsening of her CFS was considered the likely reason for her increased fatigue, but a range of blood tests were requested to exclude other causes (Table 1). These showed a grossly elevated adjusted calcium (3.93 mmol/l), elevated phosphate (1.65 mmol/l) and high urea and creatinine (10.6 and 162 µmol/l, respectively) with normal alkaline phosphatase (48 u/l), and reduced parathyroid hormone (<5 pmol/l). Calcium and creatinine had been normal in blood processed by the laboratory 10 months previously (2.25 and 77 µmol/l, respectively). The patient was admitted under the care of the acute medical team and treated with intravenous fluids and 90 mg of intravenous pamidronate. Her creatinine normalized within a few days and serum calcium over 3 weeks (Figure 1).

You can read the rest of this report here: http://qjmed.oxfordjournals.org/content/104/6/531.long

 

Source: Manson AL1, Chapman N, Wedatilake Y, Balic M, Marway H, Seneviratne SL, Holloway P. Tired with all those supplements? QJM. 2011 Jun;104(6):531-4. doi: 10.1093/qjmed/hcq140. Epub 2010 Aug 13. http://qjmed.oxfordjournals.org/content/104/6/531.long (Full article)

 

Chronic fatigue syndrome reflects loss of adaptability

In this issue, Van Oosterwijck et al. [1] report that physical exercise lowered pain thresholds and was associated with exacerbation of symptoms in patients with myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) whereas, on the other hand, postexercise activity levels did not significantly decrease. Based on these and similar findings in patients with CFS, we present a conceptual framework that might provide a better understanding of the key features and pathophysiological mechanisms of CFS, and thus improve its diagnosis and treatment.

CFS as a failure of allostasis?

Van Oosterwijck et al. [1] correctly note the frequent cooccurrence of a chronic ‘fatigue–pain’ symptom cluster, usually diagnosed as CFS and/or fibromyalgia. Recently, it has been proposed that this cluster should be classified under the unifying label of ‘central sensitivity syndromes’– a broad range of functional somatic disorders mainly characterized by common sensory abnormalities (i.e. widespread pain, hyperalgesia, allodynia and hypersensitivity to noise, bright light and certain chemical substances) [2].

However, ‘stress intolerance and pain hypersensitivity syndromes’ may be a more appropriate umbrella term for these syndromes because it reflects these patients’ inability to adequately adapt to all kinds of physical and mental stressors, including pathological pain processing [3]. Within the innovative neurobiological stress paradigm of ‘allostasis’– the need for stability through continuous change [4] – this general loss of adaptability may be understood as a failure of allostasis.

Although the mechanisms underlying this failure are still unclear, they may include complex and interrelated disturbances of different components of the stress system, (i.e. the hypothalamic–pituitary–adrenal (HPA) axis), the sympathetic nervous system and various neurotransmitters that modulate perceptual–cognitive and affective brain circuits, all of which operate in intimate connection with the immune system and central pain mechanisms [5].

We and others have hypothesized that the pathophysiology of CFS might include a ‘switch’ from HPA axis hyperfunction to hypofunction following a period of chronic physical and/or psychosocial stress in vulnerable persons resulting in inadequate cortisol reactivity which may in turn, via low glucocorticoid signalling, increase inflammatory activity [5]. This assumption is consistent with the relatively low basal cortisol levels and blunted diurnal cortisol rhythm frequently observed in CFS patients [5], but recent data suggest that a decrease in glucocorticoid receptor sensitivity might play a role as well [6].

Abnormal activation of innate immunity involves the release of pro-inflammatory cytokines that influence the brain and give rise to ‘sickness behaviour’. This evolutionary, physiological and behavioural reaction normally occurs during infection or severe injury and its purpose is to optimally fight bodily threats by reorganizing priorities, saving energy and promoting healing and recovery. Characteristic symptoms are profound lethargy, feelings of malaise, concentration difficulties, headache, mild fever, sensory hypersensitivity and generalized pain. In CFS patients, however, this ‘flu-like’ symptom complex may be typically provoked by any kind of stressor (e.g. physical effort, mental pressure, strong emotions) and lead to a motivational shift by urging the patient to withdraw from activities [7].

Yet, the situation may be more complex. Not only is there evidence for basal hyperfunction of the sympathetic nervous system in CFS [8] and fibromyalgia [9], but dysfunctional descending pain-inhibiting pathways [10] and various psychological mechanisms may also contribute to abnormal pain perception [11].

The data presented by Van Oosterwijck et al. [1] fit within the stress adaptability hypothesis, which includes immune-related central pain sensitization, and thus make a strong case for refining current diagnostic criteria of CFS [12] to incorporate – as a mandatory criterion –patients’ maladaptive postexertional response. Novel clinical diagnostic criteria have meanwhile been developed [13] but it remains to be seen whether these criteria will empirically prove to be appropriate in identifying the key features of the illness.

You can read the rest of this comment here: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2010.02240.x/full

Comment on: Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: an experimental study. [J Intern Med. 2010]

 

Source: Van Houdenhove B, Luyten P. Chronic fatigue syndrome reflects loss of adaptability. J Intern Med. 2010 Sep;268(3):249-51. doi: 10.1111/j.1365-2796.2010.02240.x. http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2010.02240.x/full (Full article)

 

Pain physiology education improves pain beliefs in patients with chronic fatigue syndrome compared with pacing and self-management education: a double-blind randomized controlled trial

Abstract:

OBJECTIVE: To examine whether pain physiology education was capable of changing pain cognitions and pain thresholds in patients with chronic fatigue syndrome (CFS) and chronic widespread pain.

DESIGN: Double-blind randomized controlled trial.

SETTING: Specialized chronic fatigue clinic in university hospital.

PARTICIPANTS: A random sample of patients (N=48) with CFS patients (8 men, 40 women) experiencing chronic pain, randomly allocated to the control group (n=24) or experimental group (n=24). Two women in the experimental group did not complete the study because of practical issues (lack of time and restricted mobility).

INTERVENTIONS: One individual pain physiology education session (experimental) or 1 pacing and self-management education session (control).

MAIN OUTCOME MEASURES: Algometry, the Neurophysiology of Pain Test, and questionnaires evaluating pain cognitions-the Pain Coping Inventory, the Pain Catastrophizing Scale, and the Tampa Scale for Kinesiophobia-version CFS-were completed immediately before and immediately after the intervention.

RESULTS: After the intervention, the experimental group demonstrated a significantly better understanding of the neurophysiology of pain (P<.001) and a reduction of the Pain Catastrophizing Scale subscale “ruminating” (P=.009) compared with controls. For these variables, moderate to large Cohen d effect sizes were revealed (.79-2.53).

CONCLUSIONS: A 30-minute educational session on pain physiology imparts a better understanding of pain and brings about less rumination in the short term. Pain physiology education can be an important therapeutic modality in the approach of patients with CFS and chronic pain, given the clinical relevance of inappropriate pain cognitions.

Comment in: Educational programs for chronic fatigue syndrome need to take cognizance of the condition’s abnormal response to exercise. [Arch Phys Med Rehabil. 2011]

 

Source: Meeus M, Nijs J, Van Oosterwijck J, Van Alsenoy V, Truijen S. Pain physiology education improves pain beliefs in patients with chronic fatigue syndrome compared with pacing and self-management education: a double-blind randomized controlled trial. Arch Phys Med Rehabil. 2010 Aug;91(8):1153-9. doi: 10.1016/j.apmr.2010.04.020. https://www.ncbi.nlm.nih.gov/pubmed/20684894

 

Autonomic hyper-vigilance in post-infective fatigue syndrome

Abstract:

This study examined whether post-infective fatigue syndrome (PIFS) is associated with a disturbance in bidirectional autonomic signalling resulting in heightened perception of symptoms and sensations from the body in conjunction with autonomic hyper-reactivity to perceived challenges.

We studied 23 patients with PIFS and 25 healthy matched control subjects. A heartbeat discrimination task and a pressure pain threshold test were used to assess interoceptive sensitivity. Cardiac response was assessed over a 4-min Stroop task. PIFS was associated with higher accuracy in heartbeat discrimination and a lower pressure pain threshold. Increased interoceptive sensitivity correlated strongly with current symptoms and potentiated differences in the cardiac response to the Stroop task, which in PIFS was characterized by insensitivity to task difficulty and lack of habituation.

Our results provide the first evidence of heightened interoceptive sensitivity in PIFS. Together with the distinct pattern in cardiac responsivity these findings present a picture of physiological hyper-vigilance and response inflexibility.

Copyright (c) 2010 Elsevier B.V. All rights reserved.

 

Source: Kadota Y, Cooper G, Burton AR, Lemon J, Schall U, Lloyd A, Vollmer-Conna U/ Autonomic hyper-vigilance in post-infective fatigue syndrome. Biol Psychol. 2010 Sep;85(1):97-103. doi: 10.1016/j.biopsycho.2010.05.009. Epub 2010 Jun 2. https://www.ncbi.nlm.nih.gov/pubmed/20678991