Friday, November 12, 2004

Standing up for M.E.

Copy in full of a report at MERGE by Dr Vance Spence and Prof Julian Stewart - Published in Biologist 2004; 51(2): 65-70

The Summer 2004 issue of Biologist (volume 51(2), pages 65-70) — the prestigious journal of the Institute of Biology, which is the professional body for 14,000 UK biologists— contains the article "Standing up for ME" by Dr Vance Spence (Chairman of MERGE & Senior Fellow in Medicine, University of Dundee, UK), and Prof. Julian M. Stewart (Professor of Pediatrics and Physiology, New York Medical College, USA).

This stimulating and authoritative review article — which begins with the plea, "Data, data everywhere and no one stops to think", examines the problems of orthostatic intolerance in "CFS/ME". One of the key difficulties that ME patients face is standing (orthostasis), particularly standing still. Inability to remain standing because of subjective findings (symptoms) or objective findings (signs such as hypotension) is designated "orthostatic intolerance". Many ME patients are unaware that something as simple as being upright can trigger a cluster of symptoms, such as dizziness, altered vision, nausea, fatigue, neurocognitive difficulties, headache, sweating and pallor. Orthostatic intolerance is characteristic of so many of these patients that it may very well serve as a definable subset in its own right, and might even be seen as diagnostic if the underlying mechanisms could be understood.

For copyright reasons at the Institute of Biology, the full text of this review article cannot be made available. However, some paper reprints are available, and can be obtained from MERGE (small donation welcome).

MERGE comment

This article looks at the various definitions of orthostatic intolerance and the differences between them. It also sets out to explain the specific mechanisms that might underly the problems that CFS/ME patients have when they are upright. Standing upright provokes major shifts of blood volume in the human body. Without compensatory mechanisms, the pooling of blood in the lower body and the position of the human head well above the heart would combine to produce unconsciousness in us all. In order to maintain blood pressure and consciousness, there are effective compensatory mechanisms.

The article makes clear that what happens in CFS/ME has little to do with cardiovascular deconditioning; indeed, the problems associated with the illness are most likely to be found in peripheral rather than central mechanisms, although a mixture of both may be applicable to some patients. Much has been written about orthostatic intolerance in CFS/ME but most of this is qualitative; i.e., patients have been subjected to tilt-table testing, most have positive results of one form or other, but very little research has addressed the mechanisms of the problems associated with being upright. Both authors have been studying circulatory problems in CFS/ME patients from different perspectives and this article brings these separate disciplines together.

The central question is what causes orthostatic intolerance in CFS/ME? It is clear that all of the problems cannot be explained by central or autonomic nervous system irregularities, but if CFS/ME is not autonomic dysfunction then what is it? A number of specific yet disparate mechanisms have evolved over time to explain orthostatic intolerance, but vascular dysfunction appears to be best supported by the available data.

CFS/ME patients with chronic orthostatic intolerance/postural tachycardia syndrome (POTS) often (but not always) display significant blue discolouration and sometimes swelling (pooling) of the legs, most especially on getting up in the morning. This suggests that vascular abnormalities form the basis for many of the findings of CFS/POTS and fit in well with our knowledge of compensatory mechanisms for orthostatic stress. This has been termed the vascular hypothesis, which includes possible autonomic dysfunction as a subset. Current thinking about both CFS/ME and POTS has emphasized the importance of disturbed blood flow physiology, and some investigators have grouped patients by their patterns of altered blood flow into three groups: "high flow", "low flow" and "normal flow" POTS.

It should also be borne in mind that the onset of orthostatic symptoms in many CFS/ME patients is often predated by a viral infection. The involvement of inflammatory cytokines such as IL-1, IL-6 and tumour necrosis factor, and nitric oxide (NO) needs to be considered. NO is an obvious candidate for generating orthostatic symptoms, and since there is clearly a problem with local vasodilator and vasoconstrictor mechanisms in these patients, an imbalance between endothelial and immunological-derived NO is an area worthy of further study. Of further interest are potential autoimmune mechanisms and the recent finding that circulating self-antibodies against nicotinic receptors interfere with neurotransmission in patients with problems of the autonomic nervous system, including orthostatic intolerance.

The article concludes that treatment of orthostatic intolerance in CFS/ME will not be possible until the mechanisms underlying the problem are unravelled and quantified. Of specific interest to MERGE is the role of endothelial-dependent vasodilatation and the various pathways surrounding acetylcholine sensitivity in CFS/ME patients. MERGE is currently funding a project examining the relative contributions of endothelial-derived hyperpolarising factor, prostacyclin and NO that are associated with acetylcholine vasodilatation in CFS/ME patients, and the first results of this new research study should be available sometime in 2005.


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