Tag: Bateman

Chronic Fatigue Patients Show Lower Response To Placebos

Contrary to conventional wisdom, patients with chronic fatigue syndrome respond to placebos at a lower rate than people with many other illnesses, according to the first systematic review of the topic.

According to the new analysis by Dr. Hyong Jin Cho of King’s College London and colleagues, 19.6 percent of patients with chronic fatigue syndrome improved after receiving inactive treatments, compared with a widely accepted figure of about 30 percent for other conditions.

Because the placebo effect seems to be strongest in diseases with highly subjective symptoms, some medical professionals believed it could be as high as 50 percent among CFS patients.

The review, reported in the current issue of Psychosomatic Medicine, pooled data from 29 studies in which 1,016 people with CFS received various placebos.

CFS is a complex illness that has no known cause or cure. Myriad symptoms include severe malaise, muscle and joint pain, sleep and mood disturbances and headache. The symptoms continue for at least six months and cannot be explained by any other medical conditions. The Centers for Disease Control and Prevention estimate that as many as 500,000 Americans may have CFS or related conditions.

With so many mysteries surrounding CFS, a great deal of controversy exists among both doctors and patients as to whether its origins are primarily psychological or physiological. Current evidence suggests that emotional or social stresses such as bereavement or problems at work, combined with other triggers such as common viral infections, contribute to the disorder. Additional factors, such as avoidance of physical activity, may cause the symptoms to become chronic, says Cho.

The authors propose several possible explanations for the surprisingly low placebo response revealed in the analysis. Perhaps patients have low expectations due to the reality that CFS is very difficult to treat and often persists for many years. Alternatively, disconnects between how patients and doctors view the illness “may impede development of a collaborative therapeutic relationship,” reviewers suggest.

The study also showed that the placebo response is 24 percent for medical interventions but only 14 percent for psychiatric/psychological treatments. The authors say the reason may be that many CFS sufferers seen in specialist settings or self-help groups “have a firm conviction that their illness is of physical origin” and thus would have little faith in psychiatric/psychological treatments. This finding supports the idea that the placebo response is greatly influenced by patients’ expectations of improvement.

According to the review, behavioral therapy and graded exercise therapy have benefits, and if patients were more aware of them, says Cho, they might be “more open, more optimistic, and more collaborative with the professionals, and the overall outcome of the treatments could be enhanced.”

Dr. Lucinda Bateman, an internist who specializes in CFS and fibromyalgia and serves on the board of the American Association for Chronic Fatigue Syndrome, has worked with about 500 CFS patients over the past 15 years.

“In my clinical experience, I have found that CFS is among the most difficult conditions to improve at all, with either physical or psychological interventions.” This is true in part, she says, because there is a great deal of variation among patients diagnosed with CFS, and Bateman believes that ultimately CFS may be found to involve more than one disease.

In the absence of a cure, Bateman has found that the most effective treatment for CFS combines improving symptoms with medication, helping patients retain physical conditioning when possible and using psychological and psychiatric interventions to help patients adapt to living with chronic illness.

She doesn’t discount the placebo effect, however. “When you say to people, ‘I believe you, I will help you manage your symptoms, I will advocate for you,’ that hope and feeling of control over their disease could be considered placebo effect, but it’s an important part of delivering medical care.”‘

 

Source: Center For The Advancement Of Health. “Chronic Fatigue Patients Show Lower Response To Placebos.” ScienceDaily. ScienceDaily, 22 March 2005. https://www.sciencedaily.com/releases/2005/03/050322120639.htm

 

Distinct plasma immune signatures in ME/CFS are present early in the course of illness

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an unexplained incapacitating illness that may affect up to 4 million people in the United States alone. There are no validated laboratory tests for diagnosis or management despite global efforts to find biomarkers of disease. We considered the possibility that inability to identify such biomarkers reflected variations in diagnostic criteria and laboratory methods as well as the timing of sample collection during the course of the illness.

Accordingly, we leveraged two large, multicenter cohort studies of ME/CFS to assess the relationship of immune signatures with diagnosis, illness duration, and other clinical variables. Controls were frequency-matched on key variables known to affect immune status, including season of sampling and geographic site, in addition to age and sex. We report here distinct alterations in plasma immune signatures early in the course of ME/CFS (n = 52) relative to healthy controls (n = 348) that are not present in subjects with longer duration of illness (n = 246).

Analyses based on disease duration revealed that early ME/CFS cases had a prominent activation of both pro- and anti-inflammatory cytokines as well as dissociation of intercytokine regulatory networks. We found a stronger correlation of cytokine alterations with illness duration than with measures of illness severity, suggesting that the immunopathology of ME/CFS is not static. These findings have critical implications for discovery of interventional strategies and early diagnosis of ME/CFS.

 

Source: Hornig M, Montoya JG, Klimas NG, Levine S, Felsenstein D, Bateman L, Peterson DL, Gottschalk CG, Schultz AF, Che X, Eddy ML, Komaroff AL, Lipkin WI. Distinct plasma immune signatures in ME/CFS are present early in the course of illness. Sci Adv. 2015 Feb;1(1). pii: e1400121. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465185/ (Full article)

 

Article on CFS does not reflect current best treatment practices

TO THE EDITOR: We feel that the overview of the diagnosis and treatment of chronic fatigue syndrome (CFS) was incomplete and did not reflect current best treatment practices. The discussion of current CFS research omitted key studies, such as evidence from prospective cohort studies indicating that up to 10 percent of patients with postinfectious syndromes develop CFS, regardless of the type of infectious agent.1 Biomarker research has shown distinct patterns of gene expression correlating with cytokine, adrenergic, and sensory receptor changes after modest exercise in patients with CFS compared with healthy sedentary patients.2 Indeed, many peer-reviewed publications support a physiologic etiology of CFS.

You can read the rest of this comment here: http://www.aafp.org/afp/2013/0401/ol1.html

Comment on: Chronic fatigue syndrome: diagnosis and treatment. [Am Fam Physician. 2012]

 

Source: Bateman L, Spotila J. Article on CFS does not reflect current best treatment practices. Am Fam Physician. 2013 Apr 1;87(7):Online. http://www.aafp.org/afp/2013/0401/ol1.html (Full article)

 

A multicenter blinded analysis indicates no association between chronic fatigue syndrome/myalgic encephalomyelitis and either xenotropic murine leukemia virus-related virus or polytropic murine leukemia virus

Abstract:

The disabling disorder known as chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) has been linked in two independent studies to infection with xenotropic murine leukemia virus-related virus (XMRV) and polytropic murine leukemia virus (pMLV). Although the associations were not confirmed in subsequent studies by other investigators, patients continue to question the consensus of the scientific community in rejecting the validity of the association. Here we report blinded analysis of peripheral blood from a rigorously characterized, geographically diverse population of 147 patients with CFS/ME and 146 healthy subjects by the investigators describing the original association. This analysis reveals no evidence of either XMRV or pMLV infection. I

MPORTANCE Chronic fatigue syndrome/myalgic encephalomyelitis has an estimated prevalence of 42/10,000 in the United States, with annual direct medical costs of $7 billion. Here, the original investigators who found XMRV and pMLV (polytropic murine leukemia virus) in blood of subjects with this disorder report that this association is not confirmed in a blinded analysis of samples from rigorously characterized subjects. The increasing frequency with which molecular methods are used for pathogen discovery poses new challenges to public health and support of science. It is imperative that strategies be developed to rapidly and coherently address discoveries so that they can be carried forward for translation to clinical medicine or abandoned to focus resource investment more productively. Our study provides a paradigm for pathogen discovery that may be helpful to others working in this field.

 

Source: Alter HJ, Mikovits JA, Switzer WM, Ruscetti FW, Lo SC, Klimas N, Komaroff AL, Montoya JG, Bateman L, Levine S, Peterson D, Levin B, Hanson MR, Genfi A, Bhat M, Zheng H, Wang R, Li B, Hung GC, Lee LL, Sameroff S, Heneine W, Coffin J, Hornig M, Lipkin WI. A multicenter blinded analysis indicates no association between chronic fatigue syndrome/myalgic encephalomyelitis and either xenotropic murine leukemia virus-related virus or polytropic murine leukemia virus. MBio. 2012 Sep 18;3(5). pii: e00266-12. doi: 10.1128/mBio.00266-12. Print 2012. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448165/ (Full article)

 

A double-blind, placebo-controlled, randomized, clinical trial of the TLR-3 agonist rintatolimod in severe cases of chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a severely debilitating disease of unknown pathogenesis consisting of a variety of symptoms including severe fatigue. The objective of the study was to examine the efficacy and safety of a TLR-3 agonist, rintatolimod (Poly I: C(12)U), in patients with debilitating CFS/ME.

METHODS AND FINDINGS: A Phase III prospective, double-blind, randomized, placebo-controlled trial comparing twice weekly IV rintatolimod versus placebo was conducted in 234 subjects with long-standing, debilitating CFS/ME at 12 sites. The primary endpoint was the intra-patient change from baseline at Week 40 in exercise tolerance (ET). Secondary endpoints included concomitant drug usage, the Karnofsky Performance Score (KPS), Activities of Daily Living (ADL), and Vitality Score (SF 36). Subjects receiving rintatolimod for 40 weeks improved intra-patient placebo-adjusted ET 21.3% (p = 0.047) from baseline in an intention-to-treat analysis. Correction for subjects with reduced dosing compliance increased placebo-adjusted ET improvement to 28% (p = 0.022). The improvement observed represents approximately twice the minimum considered medically significant by regulatory agencies. The rintatolimod cohort vs. placebo also reduced dependence on drugs commonly used by patients in an attempt to alleviate the symptoms of CFS/ME (p = 0.048). Placebo subjects crossed-over to receive rintatolimod demonstrated an intra-patient improvement in ET performance at 24 weeks of 39% (p = 0.04). Rintatolimod at 400 mg twice weekly was generally well-tolerated.

CONCLUSIONS/SIGNIFICANCE: Rintatolimod produced objective improvement in ET and a reduction in CFS/ME related concomitant medication usage as well as other secondary outcomes.

TRIAL REGISTRATION: ClinicalTrials.gov NCT00215800.

 

Source: Strayer DR, Carter WA, Stouch BC, Stevens SR, Bateman L, Cimoch PJ, Lapp CW, Peterson DL; Chronic Fatigue Syndrome AMP-516 Study Group, Mitchell WM.Collaborators (12). A double-blind, placebo-controlled, randomized, clinical trial of the TLR-3 agonist rintatolimod in severe cases of chronic fatigue syndrome. PLoS One. 2012;7(3):e31334. doi: 10.1371/journal.pone.0031334. Epub 2012 Mar 14.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3303772/ (Full article)

 

Myalgic encephalomyelitis: International Consensus Criteria

Abstract:

The label ‘chronic fatigue syndrome’ (CFS) has persisted for many years because of the lack of knowledge of the aetiological agents and the disease process. In view of more recent research and clinical experience that strongly point to widespread inflammation and multisystemic neuropathology, it is more appropriate and correct to use the term ‘myalgic encephalomyelitis’ (ME) because it indicates an underlying pathophysiology. It is also consistent with the neurological classification of ME in the World Health Organization’s International Classification of Diseases (ICD G93.3).

Consequently, an International Consensus Panel consisting of clinicians, researchers, teaching faculty and an independent patient advocate was formed with the purpose of developing criteria based on current knowledge. Thirteen countries and a wide range of specialties were represented. Collectively, members have approximately 400 years of both clinical and teaching experience, authored hundreds of peer-reviewed publications, diagnosed or treated approximately 50 000 patients with ME, and several members coauthored previous criteria. The expertise and experience of the panel members as well as PubMed and other medical sources were utilized in a progression of suggestions/drafts/reviews/revisions.

The authors, free of any sponsoring organization, achieved 100% consensus through a Delphi-type process. The scope of this paper is limited to criteria of ME and their application. Accordingly, the criteria reflect the complex symptomatology. Operational notes enhance clarity and specificity by providing guidance in the expression and interpretation of symptoms. Clinical and research application guidelines promote optimal recognition of ME by primary physicians and other healthcare providers, improve the consistency of diagnoses in adult and paediatric patients internationally and facilitate clearer identification of patients for research studies.

© 2011 The Association for the Publication of the Journal of Internal Medicine.

Comment in: A controversial consensus–comment on article by Broderick et al. [J Intern Med. 2012]

 

Source: Carruthers BM, van de Sande MI, De Meirleir KL, Klimas NG, Broderick G, Mitchell T, Staines D, Powles AC, Speight N, Vallings R, Bateman L, Baumgarten-Austrheim B, Bell DS, Carlo-Stella N, Chia J, Darragh A, Jo D, Lewis D, Light AR, Marshall-Gradisbik S, Mena I, Mikovits JA, Miwa K, Murovska M, Pall ML, Stevens S. Myalgic encephalomyelitis: International Consensus Criteria. J Intern Med. 2011 Oct;270(4):327-38. doi: 10.1111/j.1365-2796.2011.02428.x. Epub 2011 Aug 22. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3427890/ (Full article)

 

Evidence for a heritable predisposition to Chronic Fatigue Syndrome

Abstract:

BACKGROUND: Chronic Fatigue Syndrome (CFS) came to attention in the 1980s, but initial investigations did not find organic causes. Now decades later, the etiology of CFS has yet to be understood, and the role of genetic predisposition in CFS remains controversial. Recent reports of CFS association with the retrovirus xenotropic murine leukemic virus-related virus (XMRV) or other murine leukemia related retroviruses (MLV) might also suggest underlying genetic implications within the host immune system.

METHODS: We present analyses of familial clustering of CFS in a computerized genealogical resource linking multiple generations of genealogy data with medical diagnosis data of a large Utah health care system. We compare pair-wise relatedness among cases to expected relatedness in the Utah population, and we estimate risk for CFS for first, second, and third degree relatives of CFS cases.

RESULTS: We observed significant excess relatedness of CFS cases compared to that expected in this population. Significant excess relatedness was observed for both close (p <0.001) and distant relationships (p = 0.010). We also observed significant excess CFS relative risk among first (2.70, 95% CI: 1.56-4.66), second (2.34, 95% CI: 1.31-4.19), and third degree relatives (1.93, 95% CI: 1.21-3.07).

CONCLUSIONS: These analyses provide strong support for a heritable contribution to predisposition to Chronic Fatigue Syndrome. A population of high-risk CFS pedigrees has been identified, the study of which may provide additional understanding.

 

Source: Albright F, Light K, Light A, Bateman L, Cannon-Albright LA. Evidence for a heritable predisposition to Chronic Fatigue Syndrome. BMC Neurol. 2011 May 27;11:62. doi: 10.1186/1471-2377-11-62. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3128000/ (Full article)

 

Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome

Abstract:

OBJECTIVES: To determine mRNA expression differences in genes involved in signalling and modulating sensory fatigue, and muscle pain in patients with chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FM) at baseline, and following moderate exercise.

DESIGN: Forty-eight patients with CFS only, or CFS with comorbid FM, 18 patients with FM that did not meet criteria for CFS, and 49 healthy controls underwent moderate exercise (25 min at 70% maximum age-predicted heart rate). Visual-analogue measures of fatigue and pain were taken before, during and after exercise. Blood samples were taken before and 0.5, 8, 24 and 48 h after exercise. Leucocytes were immediately isolated from blood, number coded for blind processing and analyses and flash frozen. Using real-time, quantitative PCR, the amount of mRNA for 13 genes (relative to control genes) involved in sensory, adrenergic and immune functions was compared between groups at baseline and following exercise. Changes in amounts of mRNA were correlated with behavioural measures and functional clinical assessments.

RESULTS: No gene expression changes occurred following exercise in controls. In 71% of patients with CFS, moderate exercise increased most sensory and adrenergic receptor’s and one cytokine gene’s transcription for 48 h. These postexercise increases correlated with behavioural measures of fatigue and pain. In contrast, for the other 29% of patients with CFS, adrenergic α-2A receptor’s transcription was decreased at all time-points after exercise; other genes were not altered. History of orthostatic intolerance was significantly more common in the α-2A decrease subgroup. FM-only patients showed no postexercise alterations in gene expression, but their pre-exercise baseline mRNA for two sensory ion channels and one cytokine were significantly higher than controls.

CONCLUSIONS: At least two subgroups of patients with CFS can be identified by gene expression changes following exercise. The larger subgroup showed increases in mRNA for sensory and adrenergic receptors and a cytokine. The smaller subgroup contained most of the patients with CFS with orthostatic intolerance, showed no postexercise increases in any gene and was defined by decreases in mRNA for α-2A. FM-only patients can be identified by baseline increases in three genes. Postexercise increases for four genes meet published criteria as an objective biomarker for CFS and could be useful in guiding treatment selection for different subgroups.

© 2011 The Association for the Publication of the Journal of Internal Medicine.

 

Source: Light AR, Bateman L, Jo D, Hughen RW, Vanhaitsma TA, White AT, Light KC. Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome. J Intern Med. 2012 Jan;271(1):64-81. doi: 10.1111/j.1365-2796.2011.02405.x. Epub 2011 Jul 13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3175315/ (Full article)

 

Absence of XMRV retrovirus and other murine leukemia virus-related viruses in patients with chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a multisystem disorder characterized by prolonged and severe fatigue that is not relieved by rest. Attempts to treat CFS have been largely ineffective primarily because the etiology of the disorder is unknown. Recently, CFS has been associated with xenotropic murine leukemia virus-related virus (XMRV) as well as other murine leukemia virus (MLV)-related viruses, though not all studies have found these associations. We collected blood samples from 100 CFS patients and 200 self-reported healthy volunteers from the same geographical area. We analyzed these in a blind manner using molecular, serological, and viral replication assays. We also analyzed samples from patients in the original study that reported XMRV in CFS patients. We did not find XMRV or related MLVs either as viral sequences or infectious viruses, nor did we find antibodies to these viruses in any of the patient samples, including those from the original study. We show that at least some of the discrepancy with previous studies is due to the presence of trace amounts of mouse DNA in the Taq polymerase enzymes used in these previous studies. Our findings do not support an association between CFS and MLV-related viruses, including XMRV, and the off-label use of antiretrovirals for the treatment of CFS does not seem justified at present.

 

Source: Shin CH, Bateman L, Schlaberg R, Bunker AM, Leonard CJ, Hughen RW, Light AR, Light KC, Singh IR. Absence of XMRV retrovirus and other murine leukemia virus-related viruses in patients with chronic fatigue syndrome. J Virol. 2011 Jul;85(14):7195-202. doi: 10.1128/JVI.00693-11. Epub 2011 May 4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3126563/ (Full article)

 

Severity of symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) patients often report symptom flare (SF) for >24 h after moderate exercise (post-ex). We hypothesized that SF is linked to increases in circulating cytokines and CD40 Ligand (CD40L). In 19 CFS patients and 17 controls, mental and physical fatigue and pain symptom ratings were obtained together with serum for 11 cytokines and CD40L before and at 0.5, 8, 24, and 48 h post-ex.

Before exercise, CFS had lower CD40L (p<.05) but similar cytokines versus controls. In subgroups based on SF at 48 h, high SF patients (n=11) increased in IL-1beta, IL-12, IL-6, IL-8, IL-10, and IL-13 (p<.05) 8 h post-ex. Low SF patients (n=8) showed post-ex decreases in IL-10, IL-13, and CD40L, and controls decreased in IL-10, CD40L, and TNFalpha (p<.05). Thus, in CFS, cytokine activity may vary directly with SF, which may explain prior inconsistent findings.

 

Source: White AT, Light AR, Hughen RW, Bateman L, Martins TB, Hill HR, Light KC. Severity of symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome. Psychophysiology. 2010 Jul 1;47(4):615-24. doi: 10.1111/j.1469-8986.2010.00978.x. Epub 2010 Mar 4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4378647/ (Full article)