Chronic Fatigue Syndrome
Review by Ellie Stein, MD, FRCPC
This small hardcover volume is a landmark publication on the topic of chronic fatigue syndrome (CFS). In a field where speculation and unproven hypotheses have run rampant, this book offers a welcome reprieve. Every argument is extensively referenced with original research. The evidence-based molecular model of CFS, which is argued in this book, will provide information that could radically change attitudes toward and treatment of this serious but controversial disorder.
The editors, Patrick Englebienne, PhD, and Kenny De Meirleir, MD, PhD, from the Free University of Brussels and RED Laboratories, head the world’s leading research group in the field of molecular biology of CFS. The authors are gathered from several independent research groups: the editors’ own group, Lebleu and others from France, Suhadolnik and others and Nicolson and others from the US, and McGregor and others from Australia. Despite different authorship in each chapter, the book is tightly edited and reads smoothly. One drawback, however, is that several figures require additional explanation to ease understanding. In addition, the book is filled with abbreviations for various molecules and receptors that are difficult to remember without more frequent reference to the full text. Reader beware! This volume is a technical book, requiring moderate knowledge of biochemistry and molecular genetics.
The core argument, to which the first 6 chapters are dedicated, is that dysregulation of the antiviral RNase-L pathway plays a central role in CFS etiology and symptom development. RNase-L is a phylogenetically preserved molecule that, when activated, degrades single- and double-stranded RNA of both viral and cellular origin. It is central to the control of viral replication and apoptosis (programmed cell death). Usually, RNase-L activation is tightly controlled by a series of regulating molecules. However, in patients with CFS, the native 83 KDalton human RNase-L molecule is degraded to a 37 KDalton molecule that, because of conformational changes, can escape the influence of RNase-L inhibitor (RLI) and other regulators of the antiviral pathway. Disinhibition results in cleavage of vital intracellular proteins such as G-actin.
Further, RLI is a member of the ATP-binding cassette (ABC) protein-channel superfamily. Other members of this family include drug and toxin transporters, the sulfonylurea receptor, the cystic fibrosis regulator, monoamine transporters, and proteins controlling antigen presentation. When the RNase-L is degraded to the 37 KDalton form, fragments that interfere with the function of RLI and other ABC family members are released. This interference with ABC functions is posited to explain many of the physiological abnormalities and clinical symptoms found in patients with CFS; specifically, electrolyte imbalance and thyroid-receptor resistance.
The second portion of the book attempts to integrate the basic research presented in the first portion with clinical findings. Chapter 7 summarizes the findings from a factor analysis of a group of over 1500 Belgian patients who are studied in detail by Dr De Becker and Dr De Meirleir. The analysis shows that there are in fact 4 major symptom groupings in CFS: general infective symptoms, neurocognitive symptoms, musculoskeletal symptoms, and mood and psychiatric symptoms. The first 3 of these subjective symptom groups correlate strongly with various biochemical markers, including the ration between concentrations of 37 KDalton and 83 KDalton RNAse-L. The psychiatric symptom group shows far less correlation, suggesting that it is not a core feature of CFS. By analyzing the correlational patterns between infective, immune, biochemical, and clinical measures, Dr Neil McGregor hypothesizes which CFS symptom clusters are due to acute infectious comorbidity, which correlate with host defence mechanisms, and which are secondary illness, caused by the accumulation or depletion of nutrients and pathway intermediates. Although many of these hypotheses have yet to be proven, they provide a new and exciting framework for understanding CFS and perhaps other chronic, ill-defined syndromes.
Chapter 8 reviews the evidence for and against the involvement of various individual pathogens in CFS, with specific mention of the role of chronic intracellular infection (viral, Mycoplasma spp, and Chlamydia spp) in an environment of impaired cellular toxicity (Th1-to-Th2 immune shift) and impaired apoptosis.
Chapter 9 provides a brief but comprehensive summary of clinical treatment trials in CFS, including several substances not often reported in reviews, such as dehydroepiandrosterone (DHEA), transfer factor, and Kutapressin. The largest section is devoted to the 4 clinical trials of the controversial drug Ampligen, a synthetic, mismatched, double-stranded RNA. Ampligen is the only drug or supplement to show consistent positive results in patients who are severely ill with CFS. Ampligen acts directly on the RNase-L pathway and has been shown to inhibit a wide variety of viruses in vivo. Phase 3 trials are ongoing worldwide.
The final chapter is the reader’s digest version of the most comprehensive hypothesis of CFS etiology and symptom formation published to date. Based on this hypothesis, the authors suggest a multilevel workup for CFS patients, including history, physical exam, and laboratory tests. Time and further research will reveal whether the treatments this elegant hypothesis hints at will change the currently bleak outlook for long-term CFS sufferers.
The research presented in this book is compelling, is well referenced, and is already changing attitudes toward CFS diagnosis and treatment. The book is especially recommended to those who have been looking for some solid evidence of biological abnormalities in CFS and are willing to wade through 170 pages of detailed molecular biochemistry. This book, though groundbreaking, is not a panacea. The editors have aptly titled the book “a biological approach.” They outline their biological theory of CFS exclusively and do not include commentary on the history, natural history, epidemiology, or psychosocial aspects of CFS. Nor do they fully examine evidence that does not support their hypothesis. A recent publication by Gow and others is evidence of ongoing debate, not addressed in this volume (1). The price tag, US$99.95 (Amazon.com price), is high, and despite the importance of the material, some readers may prefer to wait for the clinical implications to be more fully elaborated.
1.Gow JW, Simpson K, Behan PO, Chaudhuri A, McKay IC, Behan WM. Antiviral pathway activation in patients with chronic fatigue syndrome and acute infection. Clin Infect Dis 2001;33:2080-1.
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