TGI Friday! Our weekly round-up of recent research abstracts and articles | 16 November 2012

November 16, 2012

From the Proceedings of the Mayo Clinic, 8 November 2012.

Prevalence, Incidence, and Classification of Chronic Fatigue Syndrome in Olmsted County, Minnesota, as Estimated Using the Rochester Epidemiology Project

Ann Vincent, MD(a,b), Dana J. Brimmer, PhD, MPH(e,f), Mary O. Whipple, BA(a), James F. Jones, MD(e), Roumiana Boneva, MD, PhD(e), Brian D. Lahr, MS(c), Elizabeth Maloney, DrPH, MS(e), Jennifer L. St. Sauver, PhD(d), William C. Reeves, MD, MS)(†e)

(a) Fibromyalgia and Chronic Fatigue Clinic, Mayo Clinic, Rochester, MN
(b) Division of General Internal Medicine, Mayo Clinic, Rochester, MN
(c) Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN
(d) Division of Epidemiology, Mayo Clinic, Rochester, MN
(e) Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, GA
(f) McKing Consulting, Atlanta, GA



To estimate the prevalence and incidence of chronic fatigue syndrome in Olmsted County, Minnesota, using the 1994 case definition and describe exclusionary and comorbid conditions observed in patients who presented for evaluation of long-standing fatigue.


We conducted a retrospective medical record review of potential cases of chronic fatigue syndrome identified from January 1, 1998, through December 31, 2002, using the Rochester Epidemiology Project, a population-based database. Patients were classified as having chronic fatigue syndrome if the medical record review documented fatigue of 6 months' duration, at least 4 of 8 chronic fatigue syndrome–defining symptoms, and symptoms that interfered with daily work or activities. Patients not meeting all of the criteria were classified as having insufficient/idiopathic fatigue.


We identified 686 potential patients with chronic fatigue, 2 of whom declined consent for medical record review. Of the remaining 684 patients, 151 (22%) met criteria for chronic fatigue syndrome or insufficient/idiopathic fatigue. The overall prevalence and incidence of chronic fatigue syndrome and insufficient/idiopathic fatigue were 71.34 per 100,000 persons and 13.16 per 100,000 person-years vs 73.70 per 100,000 persons and 13.58 per 100,000 person-years, respectively. The potential cases included 482 patients (70%) who had an exclusionary condition, and almost half the patients who met either criterion had at least one nonexclusionary comorbid condition.


The incidence and prevalence of chronic fatigue syndrome and insufficient/idiopathic fatigue are relatively low in Olmsted County. Careful clinical evaluation to identify whether fatigue could be attributed to exclusionary or comorbid conditions rather than chronic fatigue syndrome itself will ensure appropriate assessment for patients without chronic fatigue syndrome.

From PLos|One (open access), 14 November 2012.

Antibody to Epstein-Barr Virus Deoxyuridine Triphosphate Nucleotidohydrolase and Deoxyribonucleotide Polymerase in a Chronic Fatigue Syndrome Subset

A. Martin Lerner(1*), Maria E. Ariza(2), Marshall Williams(2), Leonard Jason(3), Safedin Beqaj(4), James T. Fitzgerald(5), Stanley Lemeshow(6), Ronald Glaser(7)

(1) Department of Medicine, Oakland University William Beaumont School of Medicine, Rochester, Michigan, United States of America,
(2) Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, United States of America,
(3) Center for Community Research, DePaul University, Chicago, Illinois, United States of America,
(4) Pathology Inc, Torrance, California, United States of America,
(5) Department of Medical Education, University of Michigan School of Medicine, Ann Arbor, Michigan, United States of America,
(6) College of Public Health, The Ohio State University, Columbus, Ohio, United States of America,
(7) Institute for Behavioral Medicine Research, The Ohio State University, Columbus, Ohio, United States of America



A defined diagnostic panel differentiated patients who had been diagnosed with chronic fatigue syndrome (CFS), based upon Fukuda/Carruthers criteria. This diagnostic panel identified an Epstein-Barr virus (EBV) subset of patients (6), excluding for the first time other similar “clinical” conditions such as cytomegalovirus (CMV), human herpesvirus 6 (HHV6), babesiosis, ehrlichiosis, borreliosis, Mycoplasma pneumoniae, Chlamydia pneumoniae, and adult rheumatic fever, which may be mistakenly called CFS. CFS patients were treated with valacyclovir (14.3 mg/kg q6h) for ≥12 months. Each patient improved, based upon the Functional Activity Appraisal: Energy Index Score Healthcare Worker Assessment (EIPS), which is a validated (FSS-9), item scale with high degree of internal consistency measured by Cronbach's alpha.


Antibody to EBV viral capsid antigen (VCA) IgM, EBV Diffuse Early Antigen EA(D), and neutralizing antibodies against EBV-encoded DNA polymerase and EBV-encoded dUTPase were assayed serially approximately every three months for 13–16 months from sera obtained from patients with CFS (6) and from sera obtained from twenty patients who had no history of CFS.


Antibodies to EBV EA(D) and neutralizing antibodies against the encoded-proteins EBV DNA polymerase and deoxyuridine triphosphate nucleotidohydrolase (dUTPase) were present in the EBV subset CFS patients. Of the sera samples obtained from patients with CFS 93.9% were positive for EA(D), while 31.6% of the control patients were positive for EBV EA(D). Serum samples were positive for neutralizing antibodies against the EBV-encoded dUTPase (23/52; 44.2%) and DNA polymerase (41/52; 78.8%) in EBV subset CFS patients, but negative in sera of controls.


There is prolonged elevated antibody level against the encoded proteins EBV dUTPase and EBV DNA polymerase in a subset of CFS patients, suggesting that this antibody panel could be used to identify these patients, if these preliminary findings are corroborated by studies with a larger number of EBV subset CFS patients.

From Virus Adaptation and Treatment, November 2012.

Abortive lytic Epstein–Barr virus replication in tonsil-B lymphocytes in infectious mononucleosis and a subset of the chronic fatigue syndrome

A Martin Lerner(1), Safedin Beqaj(2)

(1) Department of Medicine, Oakland University William Beaumont School of Medicine, Rochester, MI, USA;
(2) Pathology Inc, Torrance, CA, USA


A systematic 2001–2007 review of 142 chronic fatigue syndrome (CFS) patients identified 106 CFS patients with elevated serum IgG antibodies to the herpesviruses Epstein–Barr virus (EBV), cytomegalovirus, or human herpesvirus (HHV) 6 in single or multiple infections, with no other co-infections detected.

We named these 106 patients group-A CFS. Eighty-six of these 106 group-A CFS patients (81%) had elevated EBV early antibody, early antigen (diffuse), serum titers. A small group of six patients in the group-A EBV subset of CFS, additionally, had repetitive elevated-serum titers of antibody to the early lytic replication-encoded proteins, EBV dUTPase, and EBV DNA polymerase.

The presence of these serum antibodies to EBV dUTPase and EBV DNA polymerase indicated EBV abortive lytic replication in these 6 CFS patients. None of 20 random control people (age- and sex-matched, with blood drawn at a commercial laboratory) had elevated serum titers of antibody to EBV dUTPase or EBV DNA polymerase (P < 0.01).This finding needs verification in a larger group of EBV CFS subset patients, but if corroborated, it may represent a molecular marker for diagnosing the EBV subset of CFS.We review evidence that EBV abortive lytic replication with unassembled viral proteins in the blood may be the same in infectious mononucleosis (IM) and a subset of CFS. EBV-abortive lytic replication in tonsil plasma cells is dominant in IM. No complete lytic virion is in the blood of IM or CFS patients.Complications of CFS and IM include cardiomyopathy and encephalopathy. Circulating abortive lytic-encoded EBV proteins (eg, EBV dUTPase, EBV DNA polymerase, and others) may be common to IM and CFS. The intensity and duration of the circulating EBV-encoded proteins might differentiate the IM and EBV subsets of CFS.Abortive lytic replication may be a pathogenic mechanism for EBV disease. EBV (HHV4) is a gamma herpesvirus composed of dsDNA about 170 Kb in length. For this discussion, there are early genes (including expressions of encoded proteins EBV dUTPase, DNA polymerase, and nuclear proteins) and late genes (including expressions of capsid and membrane proteins).Abortive infection infers incomplete virion expressions of either early or late proteins, but the virion is incomplete. The lytic virus infers a complete virion. The pathologic consequences of EBV abortive replication are currently being investigated by authors.

From PLoS|One (open access), 14 November 2012.

Reduced Cardiac Vagal Modulation Impacts on Cognitive Performance in Chronic Fatigue Syndrome

Alison Beaumont(1), Alexander R. Burton(1), Jim Lemon(1), Barbara K.Bennett(2,3), Andrew Lloyd(4), Uté Vollmer-Conna1(1,*)

(1) School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia,
(2) School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia,
(3) Department of Medical Oncology, Prince of Wales Hospital, Sydney, New South Wales, Australia,
(4) Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Sydney, New South
Wales, Australia



Cognitive difficulties and autonomic dysfunction have been reported separately in patients with chronic fatigue syndrome (CFS). A role for heart rate variability (HRV) in cognitive flexibility has been demonstrated in healthy individuals, but this relationship has not as yet been examined in CFS. The objective of this study was to examine the relationship between HRV and cognitive performance in patients with CFS.


Participants were 30 patients with CFS and 40 healthy controls; the groups were matched for age, sex, education, body mass index, and hours of moderate exercise/week. Questionnaires were used to obtain relevant medical and demographic information, and assess current symptoms and functional impairment. Electrocardiograms, perceived fatigue/effort and performance data were recorded during cognitive tasks. Between–group differences in autonomic reactivity and associations with cognitive performance were analysed.


Patients with CFS showed no deficits in performance accuracy, but were significantly slower than healthy controls. CFS was further characterized by low and unresponsive HRV; greater heart rate (HR) reactivity and prolonged HR-recovery after cognitive challenge. Fatigue levels, perceived effort and distress did not affect cognitive performance. HRV was consistently associated with performance indices and significantly predicted variance in cognitive outcomes.


These findings reveal for the first time an association between reduced cardiac vagal tone and cognitive impairment in CFS and confirm previous reports of diminished vagal activity.

From Archives of Medical Science (open access), 5 October 2012.

Lipid and protein oxidation in female patients with chronic fatigue syndrome

Slavica Tomic(1), Snezana Brkic(1), Daniela Maric(1), Aleksandra Novakov Mikic(2)

(1) Clinic for Infectious Diseases, Clinical Center Vojvodina, Novi Sad, Serbia
(2) Clinic for Gynecology and Obstetrics, Clinical Center Vojvodina, Novi Sad, Serbia



Chronic fatigue syndrome (CFS) is a widely recognized problem, characterized by prolonged, debilitating fatigue and a characteristic group of accompanying symptoms, that occurs four times more frequently in women than in men. The aim of the study was to determine the existence of oxidative stress and its possible consequences in female patients with CFS.


Twenty-four women aged 15-45 who fulfilled the diag- nostic criteria for CFS with no comorbidities were recruited and were age matched to a control group of 19 healthy women. After conducting the routine laboratory tests, levels of the lipid oxidation product malondialdehyde (MDA) and protein oxidation protein carbonyl (CO) were determined.


The CFS group had higher levels of triglycerides (p = 0.03), MDA (p = 0.03) and CO (p = 0.002) and lower levels of HDL cholesterol (p = 0.001) than the con- trol group. There were no significant differences in the levels of total protein, total cholesterol or LDL cholesterol.


The CFS group had an unfavorable lipid profile and signs of oxida- tive stress induced damage to lipids and proteins. These results might be indicative of early proatherogenic processes in this group of patients who are other- wise at low risk for atherosclerosis. Antioxidant treatment and life style changes are indicated for women with CFS, as well as closer observation in order to assess the degree of atherosclerosis.

MEA note An inquiry about the drug Dilmapimod to our ME Connect helpline took us the website below. Our medical adviser, Dr Charles Shepherd, comments: “This is an interesting new drug that is being assessed for use in neuropathic pain. The fact that it is an anti-inflammatory drug that suppresses cytokine activity means that it could have a role in ME/CFS.”

From the Imperial College London Faculty of Medicine website, 10 June 2011.

New drug treatment for chronic nerve pain shows promise in first trial

A new drug has been shown to reduce chronic pain caused by nerve injury in a trial conducted by clinician scientists from Imperial College London and GlaxoSmithKline, published in the European Journal of Pain on 14 May.

Chronic neuropathic pain is thought to affect around three in 100 people in the UK. It can result from injury or compression of a nerve e.g. sciatica, or from diseases that affect nerves such as diabetes and (shingles). Various treatments are currently used but they are only partially effective and only help a minority of patients. They also have a number of common side effects, which restricts their use.

Dilmapimod is a novel class of cytokine-suppressive anti-inflammatory drug (CSAID). In a randomised double-blind trial of 50 patients with chronic neuropathic pain, researchers compared the effects on pain relief of dilmapimod with a placebo. Each patient received either dilmapimod or a placebo for two weeks, then received the other treatment in a second period of two weeks. The patients rated the pain that they felt each day on an 11-point scale.

The results showed a significant reduction in the patients’ pain scores in the second week of treatment with dilmapimod compared with the placebo. Furthermore, the study found no side effects associated with the new drug.

Professor Praveen Anand, Principal Investigator from the Centre for Neuroscience at Imperial College London, said: “There is an urgent need for effective treatments for chronic neuropathic pain which are not being met by drugs available now. We have shown that dilmapimod significantly reduced chronic pain following nerve injury and was well tolerated. This is the first demonstration that this novel CSAID class of drugs has the potential to be developed as a treatment for clinical neuropathic pain.

“This finding offers new hope for chronic nerve pain sufferers. The study is also a great example of successful collaboration between academia and industry in translating new mechanisms and drug targets into advanced medicines.”

The team are now conducting larger trials to test the new drug further.

Journal reference: European Journal of Pain. P. Anand et al. Clinical trial of the p38 MAP kinase inhibitor dilmapimod in neuropathic pain following nerve injury. Published online 25 May 2011.

2 thoughts on “TGI Friday! Our weekly round-up of recent research abstracts and articles | 16 November 2012”

  1. The Australian research looks promising as it confirms a measurable performance impairment – both in terms of cardiac (nervous system) responsiveness and cognitively.

  2. Does Martin Lerner’s research bring us any closer to recognising a small subgroup of so-called “CFS” patients who are in fact suffering from chronic mononucleuosis? If so, when will his blood test ever be available in the UK? When will there be a trial of his antivirals on patients with chronic epstein-barr, and when will the Stanford gancylcovir trial he did some years ago be developed and put into clinical practice? Or do we have to wait another 20 years of young lives wasted unnecessarily? Isn’t it time to sort out patients with constantly swollen lymph nodes and chronic glandular fever symptoms from those without, and recognise there is a difference? I wonder if anyone has the courage to do this or whether they’ll be shot down in flames from the start?

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