2013 – Page 14 – American ME and CFS Society

Relationship between autonomic cardiovascular control, case definition, clinical symptoms, and functional disability in adolescent chronic fatigue syndrome: an exploratory study

Abstract:

Chronic Fatigue Syndrome (CFS) is characterized by severe impairment and multiple symptoms. Autonomic dysregulation has been demonstrated in several studies. We aimed at exploring the relationship between indices of autonomic cardiovascular control, the case definition from Centers for Disease Control and Prevention (CDC criteria), important clinical symptoms, and disability in adolescent chronic fatigue syndrome.

38 CFS patients aged 12-18 years were recruited according to a wide case definition (ie. not requiring accompanying symptoms) and subjected to head-up tilt test (HUT) and a questionnaire. The relationships between variables were explored with multiple linear regression analyses. In the final models, disability was positively associated with symptoms of cognitive impairments (p<0.001), hypersensitivity (p<0.001), fatigue (p=0.003) and age (p=0.007).

Symptoms of cognitive impairments were associated with age (p=0.002), heart rate (HR) at baseline (p=0.01), and HR response during HUT (p=0.02). Hypersensitivity was associated with HR response during HUT (p=0.001), high-frequency variability of heart rate (HF-RRI) at baseline (p=0.05), and adherence to the CDC criteria (p=0.005). Fatigue was associated with gender (p=0.007) and adherence to the CDC criteria (p=0.04).

In conclusion, a) The disability of CFS patients is not only related to fatigue but to other symptoms as well; b) Altered cardiovascular autonomic control is associated with certain symptoms; c) The CDC criteria are poorly associated with disability, symptoms, and indices of altered autonomic nervous activity.

Source: Wyller VB, Helland IB. Relationship between autonomic cardiovascular control, case definition, clinical symptoms, and functional disability in adolescent chronic fatigue syndrome: an exploratory study. Biopsychosoc Med. 2013 Feb 7;7(1):5. doi: 10.1186/1751-0759-7-5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3570350/ (Full article)

Recovery from chronic fatigue syndrome after treatments given in the PACE trial

Abstract:

BACKGROUND: A multi-centre, four-arm trial (the PACE trial) found that rehabilitative cognitive behaviour therapy (CBT) and graded exercise therapy (GET) were more effective treatments for chronic fatigue syndrome (CFS) than specialist medical care (SMC) alone, when each was added to SMC, and more effective than adaptive pacing therapy (APT) when added to SMC. In this study we compared how many participants recovered after each treatment.

METHOD: We defined recovery operationally using multiple criteria, and compared the proportions of participants meeting each individual criterion along with two composite criteria, defined as (a) recovery in the context of the trial and (b) clinical recovery from the current episode of the illness, however defined, 52 weeks after randomization. We used logistic regression modelling to compare treatments.

RESULTS: The percentages (number/total) meeting trial criteria for recovery were 22% (32/143) after CBT, 22% (32/143) after GET, 8% (12/149) after APT and 7% (11/150) after SMC. Similar proportions met criteria for clinical recovery. The odds ratio (OR) for trial recovery after CBT was 3.36 [95% confidence interval (CI) 1.64–6.88] and for GET 3.38 (95% CI 1.65–6.93), when compared to APT, and after CBT 3.69 (95% CI 1.77–7.69) and GET 3.71 (95% CI 1.78–7.74), when compared to SMC (p values < or =0.001 for all comparisons). There was no significant difference between APT and SMC. Similar proportions recovered in trial subgroups meeting different definitions of the illness.

CONCLUSIONS: This study confirms that recovery from CFS is possible, and that CBT and GET are the therapies most likely to lead to recovery.

Comment in: Reports of recovery in chronic fatigue syndrome may present less than meets the eye. [Evid Based Ment Health. 2014]

Source: White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med. 2013 Oct;43(10):2227-35. doi: 10.1017/S0033291713000020. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776285/ (Full study)

Postural orthostatic tachycardia syndrome as a clinically important subgroup of chronic fatigue syndrome: further evidence for central nervous system dysfunctioning

In this issue of the Journal of Internal Medicine, Lewis and colleagues [1] provide compelling data for a novel subgroup within the chronic fatigue syndrome (CFS) population. They show that approximately 13% (24/179) of CFS patients have postural orthostatic tachycardia syndrome (POTS), a form of dysautonomia implying that when patients change their body position from supine to upright, their heart rate will increase abnormally (tachycardia). POTS is associated with several symptoms often seen in CFS patients: fatigue, lightheadedness, dizziness, neurocognitive deficits and exercise intolerance. Importantly, this was a confirmatory study of a previously published pilot study that found a prevalence rate for POTS of 29% in a smaller sample (n = 63) of CFS patients [2]. Another significant finding is the differences in fatigue severity, depressive thoughts and daytime hypersomnolence between CFS patients with and without POTS, providing evidence for the clinical importance of POTS in CFS.

You can read the full comment here: http://onlinelibrary.wiley.com/doi/10.1111/joim.12034/full

Comment on: Clinical characteristics of a novel subgroup of chronic fatigue syndrome patients with postural orthostatic tachycardia syndrome. [J Intern Med. 2013]

Source: Nijs J, Ickmans K. Postural orthostatic tachycardia syndrome as a clinically important subgroup of chronic fatigue syndrome: further evidence for central nervous system dysfunctioning. J Intern Med. 2013 May;273(5):498-500. doi: 10.1111/joim.12034. Epub 2013 Feb 8. http://onlinelibrary.wiley.com/doi/10.1111/joim.12034/full (Full article)

Cost-effectiveness of supported self-management for CFS/ME patients in primary care

Abstract:

BACKGROUND: Nurse led self-help treatments for people with chronic fatigue syndrome/myalgic encephalitis (CFS/ME) have been shown to be effective in reducing fatigue but their cost-effectiveness is unknown.

METHODS: Cost-effectiveness analysis conducted alongside a single blind randomised controlled trial comparing pragmatic rehabilitation (PR) and supportive listening (SL) delivered by primary care nurses, and treatment as usual (TAU) delivered by the general practitioner (GP) in North West England. A within trial analysis was conducted comparing the costs and quality adjusted life years (QALYs) measured within the time frame of the trial. 296 patients aged 18 and over with CFS/ME diagnosed using the Oxford criteria were included in the cost-effectiveness analysis.

RESULTS: Treatment as usual is less expensive and leads to better patient outcomes compared with Supportive Listening. Treatment as usual is also less expensive than Pragmatic Rehabilitation. PR was effective at reducing fatigue in the short term, but the impact of the intervention on QALYs was uncertain. However, based on the results of this trial, PR is unlikely to be cost-effective in this patient population.

CONCLUSIONS: This analysis does not support the introduction of SL. Any benefits generated by PR are unlikely to be of sufficient magnitude to warrant recommending PR for this patient group on cost-effectiveness grounds alone. However, dissatisfaction with current treatment options means simply continuing with ‘treatment as usual’ in primary care is unlikely to be acceptable to patients and practitioners.

TRIAL REGISTRATION: The trial registration number is IRCTN74156610.

Source: Richardson G, Epstein D, Chew-Graham C, Dowrick C, Bentall RP, Morriss RK, Peters S, Riste L, Lovell K, Dunn G, Wearden AJ; FINE Trial Writing group on behalf of the FINE Trial group. Collaborators (23). Cost-effectiveness of supported self-management for CFS/ME patients in primary care. BMC Fam Pract. 2013 Jan 18;14:12. doi: 10.1186/1471-2296-14-12. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3556109/ (Full article)

Acute psychosocial stress-mediated changes in the expression and methylation of perforin in chronic fatigue syndrome

Abstract:

Perforin (PRF1) is essential for immune surveillance and studies report decreased perforin in chronic fatigue syndrome (CFS), an illness potentially associated with stress and/or infection. We hypothesize that stress can influence regulation of PRF1 expression, and that this regulation will differ between CFS and non-fatigued (NF) controls.

We used the Trier Social Stress Test (TSST) as a standardized acute psychosocial stress, and evaluated its effect on PRF1 expression and methylation in CFS (n = 34) compared with NF (n = 47) participants. During the TSST, natural killer (NK) cells increased significantly in both CFS (P = <0.0001) and NF subjects (P = <0.0001). Unlike previous reports, there was no significant difference in PRF1 expression at baseline or during TSST between CFS and NF. However, whole blood PRF1 expression increased 1.6 fold during the TSST in both CFS (P = 0.0003) and NF (P = <0.0001). Further, the peak response immediately following the TSST was lower in CFS compared with NF (P = 0.04).

In addition, at 1.5 hours post TSST, PRF1 expression was elevated in CFS compared with NF (whole blood, P = 0.06; PBMC, P = 0.02). Methylation of seven CpG sites in the methylation sensitive region of the PRF1 promoter ranged from 38%-79% with no significant differences between CFS and NF. Although, the average baseline methylation of all seven CpG sites did not differ between CFS and NF groups, it showed a significant negative correlation with PRF1 expression at all TSST time points in both CFS (r = -0.56, P = <0.0001) and NF (r = -0.38, P = <0.0001). Among participants with high average methylation (≥65%), PRF1 expression was significantly lower in CFS than NF subjects immediately following TSST.

These findings suggest methylation could be an important epigenetic determinant of inter-individual differences in PRF1 expression and that the differences in PRF1 expression and methylation between CFS and NF in the acute stress response require further investigation.

Source: Falkenberg VR, Whistler T, Murray JR, Unger ER, Rajeevan MS. Acute psychosocial stress-mediated changes in the expression and methylation of perforin in chronic fatigue syndrome. Genet Epigenet. 2013 Jan 28;5:1-9. doi: 10.4137/GEG.S10944. ECollection 2013. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4222335/ (Full article)

Inflammatory and oxidative and nitrosative stress cascades as new drug targets in myalgic encephalomyelitis and chronic fatigue syndrome

Abstract:

Myalgic encephalomyelitis (ME), chronic fatigue syndrome (CFS) and chronic fatigue (CF) are distinct diagnostic categories with regard to clinical symptoms, severity of illness and biomarkers. Patients with ME and CFS show higher scores on fatigue, neurocognitive disorders, hyperalgesia, autonomic symptoms, postexertional malaise and a subjective feeling of infection than patients with CF. ME is characterized by increased postexertional malaise, a subjective feeling of infection and neurocognitive disorders and is a more severe variant than CFS.

Fukuda’s 1994 CDC criteria are adequate to make a distinction between patients with ME/CFS and CF, while ME/CFS patients should be subdivided into those with and without postexertional malaise into ME and CFS, respectively. Different interrelated pathophysiological mechanisms play a role in ME/CFS, i.e. (1) inflammation and immune activation, (2) oxidative and nitrosative stress and lowered antioxidant defenses, (3) activation of cell signaling networks, e.g. nuclear factor ĸβ, the 2 9 ,5 9 -oligoadenylate/RNase-L and/or protein kinase R pathway, (4) a transition towards autoimmune reactions, and (5) bacterial translocation.

The inflammatory biomarkers are higher in ME/CFS than in CF and higher in ME than in CFS. The above-mentioned pathways may explain the onset of characteristic ME/CFS symptoms, such as fatigue, malaise, autonomic symptoms, hyperalgesia, and neurocognitive symptoms. Different etiological factors may trigger ME/CFS/CF, e.g. viral and bacterial infections, and (auto)immune and inflammatory disorders, while psychosocial and physical stressors act as modulating factors. New pathophysiologically driven drug candidates for ME and CFS are discussed which target the pathways that play a role in ME/CFS.

Source: Maes M. Inflammatory and oxidative and nitrosative stress cascades as new drug targets in myalgic encephalomyelitis and chronic fatigue syndrome. Mod Trends Pharmacopsychiatri. 2013;28:162-74. doi: 10.1159/000343982. Epub 2013 Feb 27. https://www.ncbi.nlm.nih.gov/pubmed/25224898

A review of hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome

Abstract:

Hypothalamic-pituitary-adrenal (HPA) axis dysfunction has been found in a high proportion of chronic fatigue syndrome (CFS) patients and includes enhanced corticosteroid-induced negative feedback, basal hypocortisolism, attenuated diurnal variation, and a reduced responsivity to challenge. A putative causal role for genetic profile, childhood trauma, and oxidative stress has been considered.

In addition, the impact of gender is demonstrated by the increased frequency of HPA axis dysregulation in females. Despite the temporal relationship, it is not yet established whether the endocrine dysregulation is causal, consequent, or an epiphenomenon of the disorder. Nonetheless, given the interindividual variation in the effectiveness of existing biological and psychological treatments, the need for novel treatment strategies such as those which target the HPA axis is clear.

Source: Tomas C, Newton J, Watson S. A review of hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome. ISRN Neurosci. 2013 Sep 30;2013:784520. doi: 10.1155/2013/784520. eCollection 2013. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4045534/ (Full article)

Chronic fatigue syndrome following infections in adolescents

Abstract:

PURPOSE OF REVIEW: To review the recent epidemiology, pathophysiology, and treatment of postinfectious chronic fatigue syndrome (CFS) in adolescents.

RECENT FINDINGS: Thirteen percent of adolescents (mainly women) met the criteria for CFS 6 months following infectious mononucleosis; the figure was 7% at 12 months and 4% at 24 months. Peak work capacity, activity level, orthostatic intolerance, salivary cortisol, and natural killer cell number and function were similar between adolescents with CFS following infectious mononucleosis and recovered controls. Autonomic system, oxygen consumption, peak oxygen pulse, psychological and cytokine network differences were documented between those who recovered and those who did not.

SUMMARY: The prognosis of CFS is better in adolescents than in adults. Activity level, exercise tolerance, and orthostatic testing could not distinguish patients with CFS from adolescents who have recovered from infectious mononucleosis (controls), while certain cytokine network analyses, life stress factors, and autonomic symptoms could.

Source: Katz BZ, Jason LA. Chronic fatigue syndrome following infections in adolescents. Curr Opin Pediatr. 2013 Feb;25(1):95-102. doi: 10.1097/MOP.0b013e32835c1108. https://www.ncbi.nlm.nih.gov/pubmed/23263024

Clinical characteristics of a novel subgroup of chronic fatigue syndrome patients with postural orthostatic tachycardia syndrome

Abstract:

OBJECTIVES: A significant proportion of patients with chronic fatigue syndrome (CFS) also have postural orthostatic tachycardia syndrome (POTS). We aimed to characterize these patients and differentiate them from CFS patients without POTS in terms of clinical and autonomic features.

METHODS: A total of 179 patients with CFS (1994 Centers for Disease Control and Prevention criteria) attending one of the largest Department of Health-funded CFS clinical services were included in this study. Outcome measures were as follows: (i) symptom assessment tools including the fatigue impact scale, Chalder fatigue scale, Epworth sleepiness scale (ESS), orthostatic grading scale (OGS) and hospital anxiety and depression scale (HADS-A and -D, respectively), (ii) autonomic function analysis including heart rate variability and (iii) haemodynamic responses including left ventricular ejection time and systolic blood pressure drop upon standing.

RESULTS: CFS patients with POTS (13%, n = 24) were younger (29 ± 12 vs. 42 ± 13 years, P < 0.0001), less fatigued (Chalder fatigue scale, 8 ± 4 vs. 10 ± 2, P = 0.002), less depressed (HADS-D, 6 ± 4 vs. 9 ± 4, P = 0.01) and had reduced daytime hypersomnolence (ESS, 7 ± 6 vs. 10 ± 5, P = 0.02), compared with patients without POTS. In addition, they exhibited greater orthostatic intolerance (OGS, 11 ± 5; P < 0.0001) and autonomic dysfunction. A combined clinical assessment tool of ESS ≤9 and OGS ≥9 identifies accurately CFS patients with POTS with 100% positive and negative predictive values.

CONCLUSIONS: The presence of POTS marks a distinct clinical group of CFS patents, with phenotypic features differentiating them from those without POTS. A combination of validated clinical assessment tools can determine which CFS patients have POTS with a high degree of accuracy, and thus potentially identify those who require further investigation and consideration for therapy to control heart rate.

Comment in: Postural orthostatic tachycardia syndrome as a clinically important subgroup of chronic fatigue syndrome: further evidence for central nervous system dysfunctioning. [J Intern Med. 2013]

Source: Lewis I, Pairman J, Spickett G, Newton JL. Clinical characteristics of a novel subgroup of chronic fatigue syndrome patients with postural orthostatic tachycardia syndrome. J Intern Med. 2013 May;273(5):501-10. doi: 10.1111/joim.12022. Epub 2013 Jan 7. http://onlinelibrary.wiley.com/doi/10.1111/joim.12022/full (Full article)

Prevalence of DSM-IV personality disorders in patients with chronic fatigue syndrome: a controlled study

Abstract:

BACKGROUND: It is not yet clear whether chronic fatigue syndrome (CFS) is associated with elevated levels of personality disorders.

PURPOSE: This study aims to determine the prevalence of DSM-IV axis II personality disorders among patients with CFS.

METHODS: We examined the prevalence of personality disorders in a sample of 92 female CFS patients and in two well-matched control groups, i.e., normal community individuals (N = 92) and psychiatric patients (N = 92). Participants completed the assessment of DSM-IV personality disorders questionnaire (ADP-IV), which yields a categorical and dimensional evaluation of personality disorder features.

RESULTS: The prevalence of personality disorders in CFS patients (16.3 %) was significantly lower than in psychiatric patients (58.7 %) and was similar to that in the community sample (16.3 %). Similar results were found for dimensional and pseudodimensional scores, except for the Depressive (DE) and Obsessive-Compulsive Personality Disorder (O-C) subscales. Patients with CFS had significantly higher levels of DE features compared to normal controls and similar dimensional scores on the O-C scale compared to psychiatric controls.

CONCLUSIONS: Although the CFS sample was characterized by depressive and obsessive-compulsive personality features, this study provides no evidence for the assumption that these patients generally show a higher prevalence of axis II pathology. Given the conflicting findings in this area, future studies using multiple measures to assess personality disorders in CFS are needed to substantiate these findings.

Source: Kempke S, Van Den Eede F, Schotte C, Claes S, Van Wambeke P, Van Houdenhove B, Luyten P. Prevalence of DSM-IV personality disorders in patients with chronic fatigue syndrome: a controlled study. Int J Behav Med. 2013 Jun;20(2):219-28. doi: 10.1007/s12529-012-9273-y. https://www.ncbi.nlm.nih.gov/pubmed/23065435