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Autonomic Function in CFS
Cognitive Function in CFS
Cardiovascular function and exercise in CFS

Prepared by Ellie Stein MD FRCP(C) from the medical literature
July 2001

Autonomic Function in CFS

The autonomic nervous system affects virtually every aspect of body functioning. It regulates most involuntary functions such as heart rate (HR), blood pressure (BP) and gut and bladder function. Autonomic symptoms are not included in the diagnostic criteria of CFS. Never the less many CFS patients have clinical symptoms which suggest autonomic dysfunction. These include: increases heart rate, dizziness, fainting, delayed gastric emptying, urinary frequency and orthostatic intolerance.

Orthostatic intolerance refers to symptoms caused or worsened by standing. There are two types of OI. Neurally Mediated Hypotension (NMH) is a neurally mediated sudden drop in BP which causes fainting upon standing. Postural Orthostatic Tachycardia Syndrome (POTS) is an increase in HR of over 30 bpm from sitting to standing without loss of consciousness. The gold standard of diagnosis for OI is the onset of dizziness or fainting during tilt table testing.

Bou Holaigah et al from Johns Hopkins in 1995 were the first to note the connection between CFS and OI. They found that 22/23 CFS patients had abnormal responses on tilt table testing (Bou-Holaigah et al, 1995). Since then the finding of autonomic dysfunction has been validated as occurring in a subset of CFS patients.

Research findings include:

• increased incidence of abnormal tilt table response in CFS (30 - 95%) (Bou-Holaigah et al, 1995;Freeman & Komaroff, 1997;Gibson et al, 1993;Stewart et al, 1999;De Lorenzo et al, 1997) Not all agree (Duprez et al, 1998)
• increased resting heart rate (Duprez et al, 1998;LaManca et al, 1999)
• decreased vagal power (parasympathetic activity) (Freeman & Komaroff, 1997)
• decreased sympathetic activity response to physical stress (Stewart et al, 1999;Freeman & Komaroff, 1997;Duprez et al, 1998) and mental stress (Soetekouw et al, 1999)
• decreased nighttime systolic BP (van deLuit et al, 1998)
• increased postural drop in BP (Soetekouw et al, 1999)
• increased HR and sympathetic activity after tilt table testing (De Becker et al, 1998)
• improvement of CFS symptoms by treating the autonomic dysfunction (Bou-Holaigah et al, 1995;De Lorenzo et al, 1997)
• some studies show no abnormalities (Yataco et al, 1997)

Possible mechanisms of orthostatic intolerance: The most likely mechanism for OI is decreased vascular tone in the periphery. Rowe has reported several cases of CFS in persons with Erlans Danlos syndrome a disorder of connective tissue elasticity associated with neurally mediated hypotension (NMH) as measured by tilt table testing (Rowe et al, 1999). Poor elasticity causes blood pooling in the peripheries and orthostatic intolerance.

The autonomic parasympathetic nervous system decreases vascular tone by through a cascade of events. The vagal signals activate muscarinic acetylcholine receptors on the endothelial cell surface. This activates G proteins, promoting the conversion of L-arginine to nitric oxide, which diffuses into the smooth muscle cells and stimulates guanylate cyclase to produce cyclic GMP, thereby causing relaxation. In the presence of excess NO vascular tone will be decreased and OI (either NMH or POTS) may result. Therefore the abnormality could occur at any point on this cascade

Most researchers are currently hypothesizing the problem lies with the cholinergic system. A recent report shows cholinergic supersensitivity in CFS (Spence et al, 2000). Work from the University of Newcastle (Australia) shows increases in serum concentrations of the amino acid ornithine in the serum of CFS patients. Ornithine varies with NO production (Dunstan et al, 2000). Therefore, increased ornithine correlates with increased NO activity. A recent report from the Mayo Clinic shows that some people with OI have antibodies which block the function of the ganglionic cholinergic receptors (Vernino et al, 2000).

Treatment: The treatment of choice for CFS patients with orthostatic intolerance is added salt and water. The amount of salt and water taken daily should be titrated to best health and blood pressure must be monitored during this treatment. The second line treatments for OI are florinef a salt saving hormone and midodrine a peripheral alpha (sympathetic) agonist. In some cases beta blockers or calcium channel blockers are helpful. Unfortunately all of the drug treatments for OI have side effects which can limit their use in CFS patients.

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Cognitive Function in CFS

Subjective cognitive dysfunction is a complaint of over 80% of patients with CFS and is a diagnostic criteria in all 4 of the extant working definitions.

What we know: Based on a thorough literature review it is agreed that persons with CFS (various definitions) show:

1. normal global intellectual functioning
2. normal receptive functioning
3. normal ability to focus and sustain attention for low effort tasks but reaction times and information processing are slowed
4. impaired concentration and memory for tasks requiring greater mental effort, less benefit from cueing, increased sensitivity to interference and slowed processing which limits elaboration of information during encoding
5. normal ability for verbal and non verbal conceptualization.

The cognitive deficit in CFS is not a structural one in any particular part of the brain. It is a functional disorder of information processing speed and efficiency. Emotional factors influence subjective report of cognitive difficulty, whereas their effect on objective performance remains uncertain. (Moss-Morris & Petrie, 1996;Tiersky et al, 1997)

Neuropsychological Findings:

• Cognitive deficits can be elicited more easily after aerobic exercise (LaManca et al, 1998;Blackwood et al, 1998).
• Cognitive changes are not due to psychiatric comorbidity (Johnson et al, 1996;Kane et al, 1997;Blackwood et al, 1998;Vercoulen et al, 1998;Michiels et al, 1996;Joyce et al, 1996;Michiels et al, 1999). DeLuca et al have found that cognitive impairment is greater in the absence of psychiatric diagnosis (DeLuca et al, 1997).
• Even groups who in other papers posit a psychological cause for CFS have found objective cognitive changes. eg. Vercoulen et al found that 80% of test subjects could be correctly classified as CFS or control based on the cognitive test results. Joyce et al (Wessely's group) found deficits in many aspects of function.
• Cognitive dysfunction in CFS is not due to lack of effort during testing (Blackwood et al, 1998) (Schmaling et al, 1994).
• Congitive dysfunction in CFS is not due to somatic overconcern (Vercoulen et al, 1998).
• Christodoulou et al report that CFS patients with failing scores (> 2SD below the mean) on verbal memory were more functionally disabled however the correlation between subjective and objective disability is still debated (Christodoulou et al, 1998).

Brain Imaging Findings:

• SPECT cerebral blood flow studies of persons with CFS show decreased blood flow in several key areas such as frontal lobes and brain stem which are different from both healthy controls (Barnden et al, 2001;Costa et al, 1995) and depressed subjects (Schwartz et al, 1994;Fischler et al, 1996). PET scan studies have reached similar conclusions (Tirelli et al, 1998).
• QEEG has also shown several abnormalities in brain function in CFS and neurophysiological differences between subjects with CFS and depression (Flor Henry et al, 2001).

Tests which most commonly discriminate CFS from controls:

• Any test measuring functioning before and after exertion
• Psychomotor speed - Finger Tapping Test (Halstead 1947), slower and decreasing speed across trials
• Memory - Selective Reminding Task (Rey 1964) delayed recall and long term storage
• Auditory processing speed - PASAT (Stuss et al 1987)
• Attention - Digit span forwards and backwards (Wechsler 1955), Trail making test parts A&B (Reitan & Davidson 1974)

Conclusions: As a group persons with CFS have measurable cognitive impairment which is made worse by physical exertion and cannot be attributed to comorbid conditions or attitudes. In individual patients cognitive deficits are difficult to prove with neuropsychiatric testing since there are rarely premorbid test results with which to compare. Never the less, findings which are out of keeping with known levels of premorbid functioning and decreased functioning after aerobic exercise are consistent with a diagnosis of CFS. Healthy controls and persons with depression generally do better on neuropsychiatric tests after exercise.

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Cardiovascular function and exercise in CFS

An Overview of Exercise Physiology

Most patients with CFS complain of decreased exercise tolerance compared to their premorbid condition. As well they report prolonged fatigue after exercise that was previously well within their ability. Using a standard treadmill or bicycle model subjects are asked to slowly increase exertion to their maximum level. During this time measures of cardiovascular, pulmonary and metabolic function can be taken.

Oxygen ventilation rates per minute per kg body weight (VO2max) is the most commonly used indicator of oxidative capacity/fitness. VO2max depends upon cardiac output, pulmonary function and the muscle's ability to extract O2. In healthy people the cardiac output (CO) is the limiting factor. O2 uptake increases linearly with increasing exercise until a plateau is reached this is maximal work intensity. VO2max can also be estimated by peak HR (220 - age). The VO2max in healthy adults ranges from 25-35ml/min/kg (Lewis & Haller, 1991). At < 50% VO2max fatty acids are the predominant fuel, above 50% VO2max glycogen is the dominant fuel.

At a VO2max of 70-80% anaerobic metabolism is required to maintain activity level. This is marked by lactic acid accumulation which can be measured in the venous blood and a decrease in intracellular pH which can be measured by magnetic spectroscopy.

Exercise Findings in CFS 

Most well designed, large studies show that PWCs have significantly lower fitness level than well matched sedentary controls (De Becker et al, 2000;Fulcher & White, 2000;Sisto et al, 1996; Rowbottom et al, 1998;Riley et al, 1990). PWCs tolerate a shorter duration of exercise and some cannot finish the protocol. Specific findings include:

• increased resting heart rate
• decreased VO2max
• decreased maximum HR during exercise
• decreased maximum work
• increased perceived effort
• PWCs reach the anaerobic threshold sooner than controls

Related Findings:

• Decreased O2 resaturation of hemoglobin post exercise or post ischemia (McCully & Natelson, 1999)
• Some studies suggest oxidative dysfunction eg. slower ATP recovery after exercise (Wong et al, 1992) but there is conflicting evidence
• Cognitive function declines immediately and 24 hours after exhausting exercise (Levine et al, 1997; Blackwood et al, 1998)
• Although resting EKGs are normal in CFS 24 hour Holter monitors show T-wave changes in subjects with no cardiac history (Lerner et al, 1993).

Of Note:

• One author suggests that subjects with CFS failed to make a maximal effort (Gibson et al, 1993), most others state the opposite
• There is no study supporting the hypothesis of hyperventillation in CFS
• There is no study showing similar exercise results in subjects with depression.

Is Deconditioning an Etiological Factor in CFS?

There is substantial evidence that PWCs are deconditioned compared with their premorbid conditions. What remains controversial is whether deconditioning is a normal and expected response to decreased activity due to chronic illness or whether deconditioning is in fact causes or perpetuates CFS. Proponents of the first hypothesis note that PWCs are already functioning at their maximal energy ability (Friedberg & Krupp, 1994;Lapp, 1997). They note that both physical and mental exertion cause a temporary decline in functioning in persons with CFS (Paul et al, 1999;Levine et al, 1997;Blackwood et al, 1998).

The proponents of the deconditioning theory of CFS conclude that because PWCs are out of shape, that deconditioning is a causal factor. A recent study disproved this hypothesis (Bazelmans et al, 2001). There are two studies specifically assessing the effects of graded exercise in CFS. One with highly selected, mild and moderately ill patients showed improvement in fatigue levels with mild graduated exercise but the outcome was unrelated to increasing fitness. Like many treatment studies in CFS, the authors did not report on any physical symptoms of CFS (Fulcher & White, 1997). The other study had a high drop out rate in the exercise group and equivocal findings (Wearden et al, 1998). Despite the lack of evidence of benefit, several official bodies recommend graded exercise as a treatment of choice for CFS.

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Eleanor Stein MD FRCP(C)
Psychiatrist

Burke Institute for the Rehabilitation of Chronic Illness
Suite G100 Holy Cross Centre
2210 - 2nd St. SW
Calgary Alberta
T2S 3C3 Canada

Phone (403) 802-1772
FAX (not yet installed) (403) 802-1762
email: cdnpsych@telusplanet.net

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