Newton JL, Okonkwo O, Sutcliffe K, Seth A, Shin J, Jones DE


Fatigue Interest Group and Liver Research Group, Institute of Cellular Medicine, University of Newcastle, Newcastle, UK


Funding provided by ME Research UK and the Medical Research Council.


Chronic fatigue syndrome (CFS) is common and its cause is unknown. The aim of this cross-sectional study with independent derivation and validation phases was to study the prevalence of autonomic dysfunction in CFS, and to develop diagnostic criteria.


Symptoms of autonomic dysfunction were assessed using the Composite Autonomic Symptom Scale (COMPASS). Fatigue was assessed using the Fatigue Impact Scale (FIS). Subjects were studied in two groups: phase 1 (derivation phase), 40 CFS patients and 40 age- and sex-matched controls; phase 2 (validation phase), 30 CFS patients, 37 normal controls and 60 patients with primary biliary cirrhosis.


Symptoms of autonomic dysfunction were strongly and reproducibly associated with the presence of CFS or primary biliary cirrhosis (PBC), and correlated with severity of fatigue. Total COMPASS score >32.5 was identified in phase 1 as a diagnostic criterion for autonomic dysfunction in CFS patients, and was shown in phase 2 to have a positive predictive value of 0.96 (95%CI 0.86–0.99) and a negative predictive value of 0.84 (0.70–0.93) for the diagnosis ofCFS.


Autonomic dysfunction is strongly associated with fatigue in some, but not all, CFS and PBC patients. We postulate the existence of a ‘cross-cutting’ aetiological process of dysautonomia-associated fatigue (DAF). COMPASS >32.5 is a valid diagnostic criterion for autonomic dysfunction in CFS and PBC, and can be used to identify patients for targeted intervention studies.


Quarterly Journal of Medicine, 2007 Aug; 100(8): 519–26
Download the full paper (pdf 120 KB)

Non-technical summary

The autonomic nervous system controls many important functions in the body, including circulation, digestion and breathing. One consequence of a problem with autonomic function is the inability to stand still for long without suffering ill effects, which is often reported as a symptom of ME/CFS.

The authors wanted to assess the prevalence of autonomic function in patients with ME/CFS, and investigate whether it has any relationship with fatigue. They found a strong association between autonomic dysfunction and the presence of ME/CFS, and also with the severity of fatigue.

Comment by ME Research UK

The autonomic nervous system controls cardiovascular, digestive and respiratory functions, as well as a range of other important roles. When it goes wrong, the consequences can be severe; for instance, one of the main consequences is orthostatic intolerance; i.e., the inability to remain standing for long without suffering ill effects. Since one of the key difficulties that CFS/ME patients face is standing, most especially standing still, without experiencing symptoms such as dizziness, altered vision, nausea, fatigue, etc., it has been speculated that a thorough assessment of autonomic function might be a way to identify a specific definable subset of patients, or might even be diagnostic if the underlying mechanisms could be understood.

Dr Julia Newton of the School of Clinical Medical Sciences, University of Newcastle, had been investigating fatigue in people with the autoimmune liver disease primary biliary cirrhosis. In this group of these patients, she has discovered that abnormalities of the autonomic nervous system contributed to their fatigue which was itself related to low blood pressure and abnormalities of sleep. In addition, the fatigue in these patients was associated with excess mortality, which could also be linked with autonomic abnormalities. Could, she wondered, these abnormalities also be found in ME/CFS patients who experienced many similar symptoms? With a grant from ME Research UK, and the support of the regional ME/CFS service and ME North East, Julia tested a large group of people with ME/CFS using a well-validated battery of autonomic function tests which, by assessing heart rate and blood pressure responses to a variety of manoeuvres, can test cardiovascular reflexes. The intention was to examine 100 ME/CFS patients initially, and — depending on the findings — to monitor their progress over time using further tests. The Cardiovascular Laboratory in which the tests were done is one of the largest autonomic testing labs in Europe with all the necessary equipment and expertise for comprehensive autonomic testing that is being done.

The scientific paper published in the Quarterly Journal of Medicine (August 2007) reports on the group’s comprehensive assessment of symptoms of autonomic dysfunction in a large and well characterised group of ME/CFS patients, and essentially combines two distinct study phases in one report. Phase 1 (derivation phase) involved 40 ME/CFS patients and 40 age- and sex-matched controls, and phase 2 (validation phase) attempted to replicate and confirm the phase 1 results in a mixed ME/CFS population of 30 patients, 37 normal controls and 60 patients with primary biliary cirrhosis (in whom there is a well-recognised association between autonomic dysfunction and fatigue). All were assessed using the Composite Autonomic Symptom Scale (COMPASS) which consists of 73 questions, grouped into domains relating to individual aspects of the autonomic nervous system, such as orthostatic intolerance (generalised adrenergic function), vasomotor function (peripheral adrenergic), gastrointestinal function, bladder, and syncope. Importantly, in 15 representative ME/CFS patients, COMPASS scores were compared with objective measurement of autonomic function (such as baroreflex sensitivity and heart rate variability, using continuous digital photoplethysmography) to test the validity of assessing autonomic function from patients’ reports.

The researchers found a clear and significant association between ME/CFS and the symptoms of autonomic dysfunction. In three-quarters of the patients, autonomic dysfunction was present, and it was found that a COMPASS score >32.5 (defined in phase 1 and confirmed in phase 2) appears to be a robust, reproducible and objective diagnostic tool for identifying that significant sub-population of ME/CFS patients in whom autonomic dysfunction is a prominent disease feature. Also, the strong relationship between COMPASS scores and heart rate variability (an objective measure of autonomic function) gave good confirmatory evidence that the COMPASS scores are indeed identifying autonomic dysfunction. The researchers stress, however, that a minority of patients did not have elevated COMPASS scores, suggesting that may have identified subgroups of CFS with potentially different origins for their illness.

A particularly strong association was seen with symptoms of orthostatic intolerance, suggesting that abnormality of dynamic blood pressure regulation is particularly associated with fatigue severity in ME/CFS, and confirming the conclusions of a previous review on the subject (see Spence and Stewart, Biologist 2004). This review from 2004 looked at the various definitions of orthostatic intolerance and the differences between them, and set out to explain the specific mechanisms that might underly the problems that ME/CFS patients have when they are upright. It made clear that what happens in ME/CFS 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.

The central question is what causes autonomic symptoms, such as orthostatic intolerance, in ME/CFS? It is clear that all of the problems cannot be explained by central or autonomic nervous system irregularities, but if ME/CFS 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. The discussion of Dr Newton’s paper mentions that the apparent autonomic dysfunction is unlikely to be simply a consequence of being ill, such as deconditioning, since if deconditioning was involved, a more prolonged experience of fatigue should be associated with increased autonomic dysfunction, and this was not the case in her study. It should also be borne in mind that the onset of orthostatic symptoms in many ME/CFS patients is often predated by a viral infection. The involvement of inflammatory cytokines such as interleukin-1, interleukin-6 and tumour necrosis factor, and nitric oxide needs to be considered.

The authors say that treatments for dysautonomia that have been used in previous small studies have proved disappointing, though the authors add the caveat that this may be in part related to poor selection of patients and the methods used to assess improvement — so the jury is out on whether suitable treatments might become available. It is likely, however, that treatment of orthostatic intolerance in ME/CFS will not be possible until the mechanisms underlying the problem are unravelled and quantified.

Read more (pdf 551 KB) in the Summer 2007 issue of Breakthrough.