09-08-2004 In Dr. Lapp's words: This Cochrane review study is a sore subject! I obtained a copy of the entire review, and it is just horrible. The author examined 9 studies, accepted only 5, and none were from the USA. Here are some of the problems: 1. Fatigue was the main outcome measured; depression and quality of life were secondary outcome measurements. 2. Fukuda international criteria for Chronic Fatigue Syndrome (CFS) were used in only two studies, and it appears that the subjects were not terribly ill. 3. In two of the studies (Fulcher and Appleby), 80-92% of subjects were working at the time of the study; in Powell's study 35% were working. The others did not report. Obviously this was not a very sick cohort. 4. Of the 5 studies, the Appleby study was the only one with a rigorous exercise plan (70-75% of aerobic capacity for 30 minutes). This study did NOT show any improvement in subjects, and had the highest dropout rate. The 4 other studies used a low level of exercise (40% of aerobic capacity). 5. The so-called "experts' [plural] that were listed were Dr. Peter White [only], whom I believe works closely with Wessley and Sharpe. Read biased. 6. Even though the authors concluded "patients with CFS who are similar to those in the trials should be offered exercise therapy," the press did not make it clear that these CFS patients were rather high functioning, and that most CFS patients could not tolerate such exercise. 7. The authors also concluded from this same cohort that "exercise therapy may not worsen outcomes on average." This is very misleading since it is part of the Fukuda definition that exercise causes post-exertional malaise, and all Persons with Chronic Fatigue Syndrome (PWCs) may trigger prolonged relapses if they overexert. Sadly, this Cochrane review study once again sends the incorrect message to primary physicians -- that they should exercise all PWCs and not worry about post-exertional sequelae. Charles W. Lapp, M.D. HUNTER-HOPKINS CENTER, P.A. specializing in CFS, ME, FM, and related illnesses. Activity rhythm degrades after strenuous exercise in chronic fatigue syndrome. Physiol Behav 2002 Sep;77(1):39 Ohashi K, Yamamoto Y, Natelson B. Educational Physiology Laboratory, Graduate School of Education, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-0033, Tokyo, Japan NLM Citation: PMID: 12213500 Date sent: Sat, 7 Sep 2002 Post-exertional exacerbation of symptoms is one of the major characteristics of chronic fatigue syndrome (CFS). In this study, we evaluated the hypothesis that disturbances in circadian chronobiological regulation may play a role in generating this phenomenon. We recorded physical activity for 6-day periods in 16 women (10 CFS and 6 sedentary healthy controls, CON) before and after performing a maximal treadmill test. We calculated activity rhythms by computing autocorrelation coefficients by cutting 1 day apart from the data as a template and sliding it sequentially through each of the other days; all of 6 days were used as the templates. The peak value of autocorrelation coefficient (R) and the time between peak R's (circadian period, CP) were calculated. CFS patients had a lengthening (P<.05) of mean circadian period (MCP) that was longer than 24 h (P<.05), while MCP in CON remained unchanged. No difference was found in the standard error of each subject's MCP (circadian period variability, CPV) before and after exercise for both groups. We interpret this increase in circadian rest-activity period seen in CFS patients following exercise to indicate that exhaustive exercise interferes with normal entrainment to 24-h zeitgeber(s). This effect may be associated in part with the common patient complaint of symptom worsening following exertion. Respiratory symptoms and lung function testing in Chronic Fatigue Syndrome (CFS) patients P. De Becker, I. Campine, E. Van Steenberge, M. Noppen, A. Leysl, K. De Meirleir Objective: The purpose of this study is to report the prevalence of respiratory symptoms in a cohort of CFS patients and to assess the usefulness and importance of pulmonary function testing in the clinical management of these patients. Methods: A sample of 55 consecutive CFS patients, who met the CDC (1988) and Fukuda (1994) criteria, were recruited from a university-based fatigue clinic in Brussels, Belgium. The following respiratory symptoms were observed in 46 of these patients (9 CFS patients did not present any respiratory symptoms at all): cough (19/55), medical history of allergy (8/55), new onset of allergy (16/55), chest tightness (6/55) and the major respiratory complaint appeared to be a pronounced exercise induced dyspnea (39/55). A control group consisted of a community based sample of 39 age-and sex-matched individuals, not seeking medical care, and specifically denying any CFS related symptoms. Furthermore, they did not present any respiratory symptoms. Only 10 subjects showed a medical history of allergy (2 penicillin, 8 hayfever/house dust). All patients and controls underwent a standardized pulmonary function testing, measuring following parameters: forced vital capacity (FVC), forced expiratory volume in one second (FEV1), functional residual capacity (FRC), residual volume (RV), vital capacity (VC) and total lung capacity (TLC). In all CFS patients, a histamine broncho-provocation test was additionally performed to determine the presence of bronchial hyper-responsiveness (defined as PD20 his < 2 mg histamine). Statistical analysis was performed using descriptive statistics and a nonparametric Mann-Whitney test. Results: Compared to controls (A), CFS patients (B) do not show a significant difference in TLC (mean ± SD, A: 5.94 L ± 1.04 L; B: 5.72 L ± 1.005; p = 0.37). However, we found a significant difference between both groups in VC (A: 4.74 L ± 0.90 L; B: 4.255 ± 0.849; p < 0.01) and in RV (A: 1.19 L ± 0.33 L; B :1.479 ± 0.494; p < 0.01). In 33/55 (60%) patients a marked bronchial hyper-responsiveness was present. Conclusion: CFS patients show a significant decrease in VC, possibly due to a significant increase of RV. The incidence of bronchial hyper-responsiveness in this group is also remarkably high. These observations can, at least partially, explain the respiratory symptoms in these patients. Lung function test findings in patients with chronic fatigue syndrome (CFS). F De Lorenzo, J Hargreaves, W Kakkar. Aust NZ J Med 1996:26:563-4 Motor cortex excitability in chronic fatigue syndrome.Starr A, Scalise A, Gordon R, Michalewski HJ, Caramia MD Clin Neurophysiol 2000 Nov 1;111(11):2025-2031 Department of Neurology, University of California, CA 92697-4290, Irvine, USA PMID: 11068238 Abstract Objective: To use transcranial magnetic stimulation (TMS) to definene motor cortical excitability in chronic fatigue syndrome (CFS) subjects during a repetitive, bilateral finger movement task. Methods: A total of 14 CFS patients were tested and compared with 14 age-matched healthy control subjects. TMS of the motor cortex (5% above threshold) was used to elicit motor evoked potentials (MEPs). Subjects performed regular (3-4/s) repetitive bilateral opening-closing movements of the index finger onto the thumb. MEPs of the first dorsal interosseus (FDI) were measured before, immediately following exercise periods of 30, 60 and 90 s, and after 15 min of rest. Results: Performance, defined by rate of movement, was significantly slower in CFS subjects (3.5/s) than in controls (4.0/s) independent of the hand measured. The rate, however, was not significantly affected by the exercise duration for either group. The threshold of TMS to evoke MEPs from the FDI muscle was significantly higher in CFS than in control subjects, independent of the hemisphere tested. A transient post-exercise facilitation of MEP amplitudes immediately after the exercise periods was present in controls independent of the hemisphere tested, but was absent in CFS subjects. A delayed facilitation of MEPs after 15-30 min of rest was restricted to the non-dominant hemisphere in controls; delayed facilitation was absent in CFS subjects. Conclusions: Individuals with CFS do not show the normal fluctuations of motor cortical excitability that accompany and follow non-fatiguing repetitive bimanual finger movements. Physiological responses to incremental exercise in patients with chronic fatigue syndrome. Inbar O, Dlin R, Rotstein A, Whipp BJ.  Med Sci Sports Exerc 2001 Sep;33(9):1463-1470 Department of Life Sciences, Zinman College, Wingate Institute, ISRAEL; Links Clinic, Edmonton, CANADA; and Department of Physiology, St. George's Hospital Medical School, London, UNITED KINGDOM. PURPOSE: The purpose of this investigation was to characterize the physiological response profiles of patients with chronic fatigue syndrome (CFS), to an incremental exercise test, performed to the limit of tolerance. METHODS: Fifteen patients (12 women and three men) who fulfilled the case definition for chronic fatigue syndrome, and 15 healthy, sedentary, age- and sex-matched controls, performed an incremental progressive all-out treadmill test (cardiopulmonary exercise test). RESULTS: As a group, the CFS patients demonstrated significantly lower cardiovascular as well as ventilatory values at peak exercise, compared with the control group. At similar relative submaximal exercise levels (% peak VO2), the CFS patients portrayed response patterns (trending phenomenon) characterized, in most parameters, by similar intercepts, but either lower (VCO2, HR, O2pulse, VE, VT, PETCO2) or higher (Bf, VE/VCO2) trending kinetics in the CFS compared with the control group. It was found that the primary exercise-related physiological difference between the CFS and the control group was their significantly lower heart rate at any equal relative and at maximal work level. Assuming maximal effort by all (indicated by RER, PETCO2, and subjective exhaustion), these results could indicate either cardiac or peripheral insufficiency embedded in the pathology of CFS patients. CONCLUSION: We conclude that indexes from cardiopulmonary exercise testing may be used as objective discriminatory indicators for evaluation of patients complaining of chronic fatigue syndrome. Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise. Jammes Y, Steinberg JG, Mambrini O, Bregeon F, Delliaux S J Intern Med., 2005 Mar;257(3):299-310. From the Laboratoire de Physiopathologie Respiratoire (UPRES EA 2201), Faculte de Medecine, Institut Federatif de Recherche Jean Roche, and Service des Explorations Fonctionnelles Respiratoires, Hopital Nord, Assistance Publique-Hopitaux de Marseille, Marseille, France. NLM Citation: PMID: 15715687 Abstract. Objectives. Because the muscle response to incremental exercise is not well documented in patients suffering from chronic fatigue syndrome (CFS), we combined electrophysiological (compound-evoked muscle action potential, M wave), and biochemical (lactic acid production, oxidative stress) measurements to assess any muscle dysfunction in response to a routine cycling exercise. Design. This case-control study compared 15 CFS patients to a gender-, age- and weight-matched control group (n = 11) of healthy subjects. Interventions. All subjects performed an incremental cycling exercise continued until exhaustion. Main outcome measures. We measured the oxygen uptake (Vo(2)), heart rate (HR), systemic blood pressure, percutaneous O(2) saturation (SpO(2)), M-wave recording from vastus lateralis, and venous blood sampling allowing measurements of pH (pHv), PO(2) (PvO(2)), lactic acid (LA), and three markers of the oxidative stress (thiobarbituric acid-reactive substances, TBARS, reduced glutathione, GSH, and ascorbic acid, RAA). Results. Compared with control, in CFS patients (i) the slope of Vo(2) versus work load relationship did not differ from control subjects and there was a tendency for an accentuated PvO(2) fall at the same exercise intensity, indicating an increased oxygen uptake by the exercising muscles; (ii) the HR and blood pressure responses to exercise did not vary; (iii) the anaerobic pathways were not accentuated; (iv) the exercise-induced oxidative stress was enhanced with early changes in TBARS and RAA and enhanced maximal RAA consumption; and (v) the M-wave duration markedly increased during the recovery period. Conclusions. The response of CFS patients to incremental exercise associates a lengthened and accentuated oxidative stress together with marked alterations of the muscle membrane excitability. These two objective signs of muscle dysfunction are sufficient to explain muscle pain and postexertional malaise reported by our patients. *O* Increased daily physical activity and fatigue symptoms in chronic fatigue syndrome. Black CD, O'Connor PJ, McCully KK. Dynamic Medicine, 2005 Mar 3;4(1):3 The Department of Exercise Science, The University of Georgia, Athens, GA, USA NLM Citation: PMID: 15745455 Abstract: Individuals with chronic fatigue syndrome (CFS) have been shown to have reduced activity levels associated with heightened feelings of fatigue. Previous research has demonstrated that exercise training has beneficial effects on fatigue-related symptoms in individuals with CFS. PURPOSE: The aim of this study was to sustain an increase in daily physical activity in CFS patients for 4 weeks and assess the effects on fatigue, muscle pain and overall mood. METHOD: Six CFS and seven sedentary controls were studied. Daily activity was assessed by a CSA accelerometer. Following a two week baseline period, CFS subjects were asked to increase their daily physical activity by 30% over baseline by walking a prescribed amount each day for a period of four weeks. Fatigue, muscle pain and overall mood were reported daily using a 0 to 100 visual analog scale and weekly using the Profile of Mood States (Bipolar) questionnaire. RESULTS: CFS patients had significantly lower daily activity counts than controls (162.5 ± 51.7 x 103 counts/day vs. 267.2 ± 79.5 x 103 counts/day) during a 2-week baseline period. At baseline, the CFS patients reported significantly (P < 0.01) higher fatigue and muscle pain intensity compared to controls but the groups did not differ in overall mood. CFS subjects increased their daily activity by 28 ± 19.7% over a 4 week period. Overall mood and muscle pain worsened in the CFS patients with increased activity. CONCLUSIONS: CFS patients were able to increase their daily physical activity for a period of four weeks. In contrast to previous studies fatigue, muscle pain, and overall mood did not improve with increased activity. Increased activity was not presented as a treatment which may account for the differential findings between this and previous studies. The results suggest that a daily "activity limit" may exist in this population. Future studies on the impact of physical activity on the symptoms of CFS patients are needed. Chronic fatigue syndrome: intracellular immune deregulations as a possible etiology for abnormal exercise response. Nijs J, De Meirleir K, Meeus M, McGregor NR, Englebienne P. Department of Human Physiology, Faculty of Physical Education and Physical Therapy Science, Vrije Universiteit Brussel, Brussel 1090, Belgium. jo.nijs@vub.ac.be The exacerbation of symptoms after exercise differentiates Chronic fatigue syndrome (CFS) from several other fatigue-associated disorders. Research data point to an abnormal response to exercise in patients with CFS compared to healthy sedentary controls, and to an increasing amount of evidence pointing to severe intracellular immune deregulations in CFS patients. This manuscript explores the hypothetical interactions between these two separately reported observations. First, it is explained that the deregulation of the 2-5A synthetase/RNase L pathway may be related to a channelopathy, capable of initiating both intracellular hypomagnesaemia in skeletal muscles and transient hypoglycemia. This might explain muscle weakness and the reduction of maximal oxygen uptake, as typically seen in CFS patients. Second, the activation of the protein kinase R enzyme, a characteristic feature in atleast subsets of CFS patients, might account for the observed excessive nitric oxide (NO) production in patients with CFS. Elevated NO is known to induce vasidilation, which may limit CFS patients to increase blood flow during exercise, and may even cause and enhanced postexercise hypotension. Finally, it is explored how several types of infections, frequently identified in CFS patients, fit into these hypothetical pathophysiological interactions. Exercise capacity and immune function in male and female patients with chronic fatigue syndrome (CFS). Snell CR, Vanness JM, Strayer DR, Stevens SR. University of the Pacific, Department of Sport Sciences, Stockton, CA 95211-0197, USA. snells@juno.com Hyperactivition of an unwanted cellular cascade by the immune-related protein RNase L has been linked to reduced exercise capacity in persons with chronic fatigue syndrome (CFS). This investigation compares exercise capacities of CFS patients with deregulation of the RNase L pathway and CFS patients with normal regulation, while controlling for potentially confounding gender effects. Thirty-five male and seventy-one female CFS patients performed graded exercise tests to voluntary exhaustion. Measures of peak VO2, peak heart rate, body mass index, perceived exertion, and respiratory quotient were entered into a two-way factorial analysis with gender and immune status as independent variables. A significant multivariate main effect was found for immune status (p < 0.01), with no gender effect or interaction. Follow-up analyses identified VO2(peak) as contributing most to the difference. These results implicate abnormal immune activity in the pathology of exercise intolerance in CFS and are consistent with a channelopathy involving oxidative stress and nitric oxide-related toxicity. *O* Chronic Fatigue Syndrome May Be An Infectious Cardiomyopathy Of Single Or Multiple Viral Etiology by Maryann Spurgin, Ph.D. The most acutely perceptive and pioneering work on CFS these days is happening in a quiet corner of the country, out of the CFS limelight. The work is being conducted by A. Martin Lerner, M.D., an infectious-disease specialist at Wayne State University, along with his colleagues in cardiology. The basic thesis of their well-documented research is that CFS is an infectious cardiomyopathy of single or multiple viral etiology -- a cardiomyopathy that in many cases is progressive and degenerative. According to the theory, CFS results when an initial infection with a virus, or a reactivation of a latent virus -- for example, EBV or CMV -- attacks cardiac tissue, producing exercise intolerance, the hallmark of CFS. The human cardiac myofiber becomes the site of persistent viral infection. The infection flares up when the infected person physically exerts him or herself. In a normal subject, an ejection fraction will rise during exercise. They note that a stationary or falling ejection fraction is abnormal. Their work cites studies showing that declining ejection fractions are not seen in normal persons leading a sedentary life. Deconditioning and a sedentary lifestyle in normal subjects are not causes of decreasing or falling left ventricular ejection fractions. On the contrary, these cardiac abnormalities are likely virally induced: in some of the CMV patients, ejection fractions reverted to normal after anti-viral therapy with ganciclovir. Elevated Peroxynitrite as the cause of chronic fatigue syndrome: Other Inducers and Mechanisms of Symptom Generation Martin L Pall School of Molecular Biosciences, Washington State University, Pullman, WA. Source: J Chronic Fatigue Syndrome 2000; 7(4):45-58. Abstract: In an earlier paper, I proposed that chronic fatigue syndrome (CFS) is caused by a response to infection, involving the induction of inflammatory cytokines which induce, in turn, the inducible nitric oxide synthase, producing elevated nitric oxide. Nitric oxide reacts with superoxide to form the potent oxidant, peroxynitrite. Six positive feedback loops were proposed by which peroxynitrite may stay elevated, acting to increase levels of both nitric oxide and superoxide, which react to form more peroxynitrite. This vicious cycle based on known biochemistry is proposed to be the central cause of CFS. The current paper discusses additional inducers which may act by increasing nitric oxide (physical or psychological trauma) or increasing superoxide (hypoxia) and the role of orthostatic intolerance, Ehlers-Danlos syndrome, excessive exercise, exercise intolerance and carbon monoxide in inducing hypoxia and consequently superoxide and peroxynitrite. The major symptoms of CFS can all be interpreted as relatively direct consequences of the pathophysiology predicted by the elevated peroxynitrite theory of CFS. Attractive mechanisms are proposed by which elevated peroxynitrite, nitric oxide and/or related physiological changes may induce CFS symptoms including fatigue, immune dysfunction, learning and memory dysfunction, multi-organ pain, exercise intolerance/postexertional malaise and orthostatic intolerance. Roles are discussed for six factors likely to influence the frequency of CFS induction in response to infection or other inducing events. Physical performance and prediction of 2-5A synthetase/RNase L antiviral pathway activity in patients with chronic fatigue syndrome. CR Snell, JM Vanness, DR Strayer, SR Stevens. Department of Sport Sciences, University of the Pacific, Stockton, CA. Source: In Vivo 2002; 16(2):107-9. Abstract: The elevated RNase L enzyme activity observed in some Chronic Fatigue Syndrome (CFS) patients may be linked to the low exercise tolerance and functional impairment that typify this disease. The purpose of this investigation was to determine if specific indicators of physical performance can predict abnormal RNase L activity in CFS patients. Seventy-three CFS patients performed a graded exercise test to voluntary exhaustion. Forty-six patients had elevated RNase L levels. This measure was employed as the dependent variable in a discriminant function analysis, with peak V02, exercise duration and Karnofsky Performance Scores (KPS) serving as the independent variables. All three variables entered the single significant function (p < 0.001). The elevated RNase L group had a lower peak V02 and duration than the normal group, but a higher KPS. The results suggest that both exercise testing and the RNase L biomarker have potential to aid in the diagnosis of CFS. *O* The symptoms of Chronic Fatigue Syndrome are related to abnormal ion channel function Peter O. Behan*, Abhijit Chaudhuri*, Walter S. Watson**, John Pearn*** *University Department of Neurology, Institute of Neurological Sciences and **Department of Nuclear Medicine, Southern General Hospital, Glasgow (UK), ***Department of Child Health, University of Queensland, Brisbane (Australia).Presented at the American Association for Chronic Fatigue Syndrome Research Conference October 10-11, 1998 -- Cambridge, Massachusetts Objective: Many symptoms of chronic fatigue syndrome (CFS), including severity of fatigue, are periodic, fluctuant and are inducible by physical and mental activities. Chest pain is a common symptom of CFS, like patients with syndrome X, an ion channel disorder. Symptoms in CFS such as fatigue, myalgia and headache bear striking resemblance with neurological disorders that affect ion channel function, such as periodic paralysis and familial hemiplegic migraine. Maintenance of normal transmembrane ionic equilibrium is an active, energy-dependent process, and constitutes an important share of the resting energy expenditure (REE). We wanted to compare and contrast the clinical profile of CFS patients with other neurological disorders that are known to affect ion channel function, and estimate REE in CFS. We also studied the myocardial perfusion in CFS by thallium201 SPECT scans to compare the results with Syndrome X. Methods: All patients who fulfilled the modified CDC criteria for CFS were included in our studies. For investigations that required the administration of radiopharmaceuticals (e.g. cardiac-thallium201 SPECT scans), patients between the age of 18 - 65 years were recruited after informed consent. A comparable group of healthy, sedentary volunteers were tested as controls in the REE study. Results: Fatigue was fluctuant in most patients with CFS. This was induced or worsened by physical activities (exercise), mental stress and chemicals that affect ion channel function (e.g. alcohol, quinine and anaesthetics). Significant perfusion defects were observed in the cardiac-thallium201 SPECT scans in 70% of CFS patients, similar to that described in patients with syndrome X. In a separate study, a significant number of CFS patients were found to have elevated REE as compared to the controls using total body potassium (TBK) as the refererence (REE TBK).4 Conclusion: Abnormal thallium201-cardiac SPECT scans in CFS similar to those described in syndrome X suggest a common mechanism for both these conditions. An abnormality of membrane ion channel function is considered the underlying mechanism in syndrome X. Increased REETBK; in a subgroup of CFS patients suggests that some CFS patients spend more energy in maintaining essential body function at the expense of the energy available for other physical activities. Since 30% of REE is expended to maintain physiological ion gradients in normal health, cell membranes that leak ions increase REETBK Elevated REE and abnormal cardiac perfusion scans in CFS provide the first objective and indirect support to our hypothesis that symptoms in CFS could be the result of an acquired abnormality of the voltage or ligand-gated ion channels. It is possible that such alteration of transmembrane ion traffic could affect normal receptor sensitivity to neurochemicals and neurohormones such as acetylcholine, serotonin or other monoamines, accounting for the neuroendocrine abnormalities previously documented in CFS. Exercise capacity and immune function in male and female patients with chronic fatigue syndrome (CFS)     Muscle fibre characteristics and lactate responses to exercise in chronic fatigue syndrome Russell J M Lane,a Michael C Barrett,b David Woodrow,b Jill Moss,b Robert Fletcher,b Leonard C Archardc a Division of Neuroscience and Psychological Medicine, b Division of Diagnostic and Investigative Sciences, c Division of Biochemical Sciences, Imperial College School of Medicine, Charing Cross Hospital, London, UKJ Neurol Neurosurg Psychiatry 1998;64:362-367 OBJECTIVES To examine the proportions of type 1 and type 2 muscle fibres and the degree of muscle fibre atrophy and hypertrophy in patients with chronic fatigue syndrome in relation to lactate responses to exercise, and to determine to what extent any abnormalities found might be due to inactivity. METHODS Quadriceps needle muscle biopsies were obtained from 105 patients with chronic fatigue syndrome and the proportions of type 1 and 2 fibres and fibre atrophy and hypertrophy factors were determined from histochemical preparations, using a semiautomated image analysis system. Forty one randomly selected biopsies were also examined by electron microscopy. Lactate responses to exercise were measured in the subanaerobic threshold exercise test (SATET). RESULTS Inactivity would be expected to result in a shift to type 2 fibre predominance and fibre atrophy, but type 1 predominance (23%) was more common than type 2 predominance (3%), and fibre atrophy was found in only 10.4% of cases. Patients with increased lactate responses to exercise did have significantly fewer type 1 muscle fibres (p<0.043 males, p<0.0003 females), but there was no evidence that this group was less active than the patients with normal lactate responses. No significant ultrastructural abnormalities were found. CONCLUSION Muscle histometry in patients with chronic fatigue syndrome generally did not show the changes expected as a result of inactivity. However, patients with abnormal lactate responses to exercise had a significantly lower proportion of mitochondria rich type 1 muscle fibres.   Nurse, is it ME? Understanding myalgic encephalomyelitis. Dale S.  Prof Nurse. 1991 Mar;6(6):339-40. Ignored or dismissed for years, myalgic encephalomyelitis (ME) is now recognised as a genuine illness, and sufferers are recommended strict rest until the symptoms of the virus subside. Public understanding of ME is still uncertain, and nurses are ideally placed to provide practical information and support.

Exercise a health risk for chronic fatigue [syndrome] sufferers

Adelaide scientists have found evidence that exercise programs commonly undertaken by patients with chronic fatigue syndrome (CFS), may actually make the condition worse.

Exercise Capacity in Chronic Fatigue Syndrome.

RESULTS: The resting heart rate of the patient group was higher, but the maximal heart rate at exhaustion was lower, relative to the control subjects. The maximal workload and maximal oxygen uptake attained by the patients with CFS were almost half those achieved by the control subjects. Analyzing only those persons who performed a maximal exercise test, similar findings were observed.

CONCLUSIONS: When compared with healthy sedentary women, female patients with CFS show a significantly decreased exercise capacity. This could affect their physical abilities to a moderate or severe extent. Reaching the age-predicted target heart rate seemed to be a limiting factor of the patients with CFS in achieving maximal effort, which could be due to autonomic disturbances.

Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome.

The authors attempted to confirm the consistent report by patients with the CFS of delay in recovery of peripheral muscle function after exercise. They tested the quadriceps muscle group of 10 patients and 10 controls. Recovery was prolonged in the patient group, with a significant difference between the two groups after exercise and after 24 hours. These findings support the clinical complaint of delayed recovery after exercise in patients with CFS.

Effects of exercise on cognitive and motor function in chronic fatigue syndrome and depression.

The authors theorized that cognitive and motor responses to vigorous exercise in patients with chronic fatigue syndrome would differ from those in depressed and healthy control, and following their study they made the following conclusions: "patients with CFS show a specific sensitivity to the effects of exertion on effortful cognitive functioning. This occurs despite subjective and objective evidence of effort allocation in chronic fatigue syndrome, suggesting that patients have reduced working memory capacity, or a greater demand to monitor cognitive processes, or both."

Activity rhythm degrades after strenuous exercise in chronic fatigue syndrome.

We interpret this increase in circadian rest-activity period seen in CFS patients following exercise to indicate that exhaustive exercise interferes with normal entrainment to 24-h zeitgeber(s). This effect may be associated in part with the common patient complaint of symptom worsening following exertion.

Chronic fatigue syndrome: intracellular immune deregulations as a possible etiology for abnormal exercise response.

Second, the activation of the protein kinase R enzyme, a characteristic feature in at least subsets of CFS patients, might account for the observed excessive nitric oxide (NO) production in patients with CFS. Elevated NO is known to induce vasidilation, which may limit CFS patients to increase blood flow during exercise, and may even cause and enhance postexercise hypotension.

RESEARCH BREAKTHROUGH: ME/CFS AN INFECTIOUS CARDIOMYOPATHY? by: Philipa D. Corning, Ph.D., B.Sc. (Reviewed and approved by Dr. A. Martin Lerner)

In this study, 100% of the ME/CFS participants showed abnormal oscillating T-waves at 24 hr. holter monitoring and 24% showed weakened function on the left side of the heart (abnormal cardiac dynamics). This is the side of the heart that pumps oxygenated blood to all of the body, except the lungs. Data, gathered from biopsies and a 24-hour electrocardiogram (EKG) Holter monitor, showed that patients exhibited evidence of cardiomyopathy or disease of muscle in the heart.

These researchers tracked EKGs over a 24-hour period with a Holter monitor device and documented abnormal T-waves. This wave measures electrical recovery after contraction of the left ventricle. A normal T-wave should be shaped like the rolling crest of a wave in water. In 100% of ME/CFS patients, Lerner and his associates documented T-wave Inversions and/or T-wave flattenings. This finding is so consistent, they suggest that the Holter results should be included as part of the CDC case definition; it distinguishes ME/CFS patients from those with fatigue or unexplained origin. This research holds the potential to distinguish ME/CFS patients from FM patients, from those with other pain syndromes who do not relapse with exertion, and from those with fatigue associated with depression, which is a group that also does not suffer relapse with exertion. This work offers hard evidence to back up ME/CFS patients' much disbelieved claim that exercise is harmful and causes disease progression in ME/CFS.

In Dr. Lerner's model, the weakened heart is aggravated by physical activity, accounting for the post-exertional sickness and accounting for the post-exertional sickness so common in this disease - including flu symptoms, chills, fevers and increasing weakness. Indeed, the cardiac connection is what is so ground-breaking about this research.

In experiments with mice, Dr. Lerner has shown that raised myocardial coxsackie viral titers accompany physical exertion in the mice. When the heart muscle tissue is infected, overactivity causes death of cardiac tissue and disease progression. This is in direct conflict with the U.S. government research conclusions that ME/CFS disease symptoms are caused by underactivity due to a sedentary lifestyle. Dr. Lerner advises resting the heart in order to "do no harm" and to prevent death of cardiac tissue.

Dr. Lerner and associates also have documented abnormal ejection fractions in ME/CFS. Normally, over half of the blood in the left ventricle is ejected when the left ventricle contracts (part of the heart that pumps oxygenated blood out to the body). In Dr. Lerner's ME/CFS subjects, the ejection fraction is sometimes decreased, an indication that not all the normally-expelled blood leaves the ventricle. Some patients had reduced ejection fractions at rest while others had an ejection fraction that decreased during exercise from 51% to 36%. In a normal subject, the ejection fraction will rise over 5% during exercise. Stationary or falling ejection fraction is abnormal in coronary artery disease or cardiac muscle disease. Declining ejection fractions are not seen in normal persons leading sedentary lives.

These cardiac abnormalities are hypothesized to be virally induced.

This model explains the John Hopkins' finding of Rowe et al in which ME/CFS patients exhibited abnormal response to upright tilt. Lerner argues that it is abnormal cardiac response of cardiomyopathy instead of abnormal neural response. Indeed, Dr. Lerner's thesis explains a myriad of phenomenon that other research has not. For example, it explains why patients relapse with exertion and why only physically active young persons may acquire the disease. It also explains why stress is a major aggravator in this disorder. Stress may aggravate both herpes viruses and heart conditions. It also explains the anti-viral lymphocyte enzyme system, the 2-5 A pathway, suggesting the presence of a chronic infection.

In short, Dr. Lerner's work explains why previously healthy, vigorous young adults fall ill with chronic cardiomyopathy due to viral infection and cannot exercise for fear of causing further heart damage. This is directly opposite to the work of Dr. Stephen Straus at National Institute of Health (NIH) whose theory states that ME/CFS is a psychiatric disorder. This new research of Dr. Lerner et al is both refreshing and insightful. Needless to say, it has also been long awaited.

Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise.

Plus a discussion of the text.

Thus, as in inherited muscular dystrophy in which a variety of cellular abnormalities can be accounted for by free radical-mediated damages including abnormal functions of the sarcolemma and an altered activity of membrane-bound enzymes involved in excitation-contraction coupling, an increased level of free radical damage in CFS may be a contributor to the underlying functional defects and symptom presentation. This should promote further researches towards the goal of an effective treatment of CFS-suffering patients.

On the pathophysiology of ME/CFS by Les Simpson, MD

The significance of the concept of 'mean capillary diameter' is that it explains why individuals with similar values for altered red cell shapes do or do not evince symptoms. While the effects on red cell shape of a change in the environment is the same, only those with small capillaries will develop symptoms. As overexertion changes red cell shape in an additive fashion, there will be an accompanying exacerbation of symptoms. It is worth noting that in a CFS patient with SPECT-demonstrated reduced cerebral blood flow in a pre-exercise sample, the cerebral blood flow was further reduced in a post-exercise SPECT scan.

Medical Neurobiology of CFS & FM: May May 7-9, 1993 by Jay Goldstein

It is widely documented that exercise is an exacerbator of CFIDS symptoms. Drs. Mena and Goldstein presented a series of SPECT scans which showed extreme hypoperfusion (reduced blood flow) in the brain following exercise. There appeared to be "holes" where blood would normally be flowing -- the degree of hypoperfusion was astonishing. Even 24 hours later, cerebral blood flow was severely reduced.

Cerebral hypoperfusion is not the only result of exercise intolerance. Drs. Lapp and Goldstein referenced irregular tidal volume rates common in PWCs. Hyperventilation and shallow breathing are frequent results of exertion. Normal controls breathe irregularly at the start of exercise, but respiration becomes regular over time. Dr. Lapp reported that PWCs breathed more regularly than controls at the outset, but during exercise their breathing was more variable. Dr. Goldstein concurred, "This phenomenon has never been described before in any population and, as of now anyway, we think that it's a diagnostic marker for CFS."

Neuroendocrine responses were often reversed or blunted in the Cheney-Lapp study. Cortisol, epinephrine, norepinephrine, DHEA levels and body temperature normally rise with exercise, but PWCs were found to have lower than expected measures of all of the above. Dr. Goldstein related this phenomenon to limbic dysfunction, as altered levels of interleukins and nitric oxide (NO) can result in altered neuroendocrine responses to exercise.

Dr. Lapp and Dr. Kathy Sietsema reported that PWCs reached anaerobic threshold much sooner than predicted. Anaerobic threshold (AT) is the point at which a healthy person becomes completely fatigued and cannot exercise any longer (commonly called "hitting the wall"). In the Cheney-Lapp study, PWCs continued exercising beyond the point of AT. Dr. Cheney has hypothesized that PWCs normally perform above AT in everyday activity due to a metabolic injury, and therefore are more accustomed to performing at this level than controls.

Dr. Les Simpson – Rethinking the Pathogenesis of CFIDS By Craig Maupin at http:///www.cfidsreport.com

Simpson continues, "I found that ME blood filtered poorly - implying that they had a problem with blood flow, particularly at capillary level. In a paper published by New Jersey Medicine, I suggested that ME people might have the anatomical feature of smaller than usual capillary diameters. Such a proposal would help to explain the great variety and variation in distribution of the symptoms reported by ME people."

Other models for the illness have struggled to fit the distinct features of CFIDS, such as exertion intolerance and circulatory dysfunction. Simpson feels impaired blood flow offers a unifying thesis that can explain many of these distinct symptoms. He vividly recalls the unique response to exercise of a patient referred to him. "Two scans were done [SPECT scans] -- pre and post exercise. While the pre-exercise scan showed reduced cerebral blood flow, this was much worse in the post-exercise scan. At that time, the effects of physical activity on red cell shape had not been reported. This shows the extent of ignoring blood rheology factors as determinants of blood flow."

*O* CRITICAL CONSIDERATIONS by Margaret Williams

Since as long ago as 1996 it has been known that those with ME / CFS have abnormal lung function tests, with a significant reduction in all lung function parameters tested (see "Lung function test findings in patients with chronic fatigue syndrome" De Lorenzo et al. Australia and New Zealand Journal of Medicine 1996:26:4:563-564), and Jo Nijs from Belgium presented evidence at the Wisconsin international conference of underlying lung damage in ME / CFS through intracellular immune dysregulation with impairment of cardiopulmonary function.

How can forced aerobic exercise regimes be guaranteed to be harmless where there is existing underlying lung damage?

Montague/Hooper paper by Sally Montague, Malcolm Hooper

Tests of exercise capacity

Investigation of exercise capacity (VO₂ max) ie. measurement of maximal oxygen uptake and investigation of oxygen delivery to muscle are essential in patients with ME/CFS; oxidative metabolism is known to be reduced in ME/CFS. (78) This could affect patients’ physical abilities to a severe degree. ME/CFS patients have recovery rates for oxygen saturation that are 60% lower than normal controls. (79) It is imperative to ascertain oxygen delivery status before insisting on inappropriate interventions eg. CBT / graded exercise.

Exercise limits in chronic fatigue syndrome [Letter]. Lapp CW. American Journal of Medicine 1997; 103(1): 83-84.

Abstract: This study surveys the occurrence of repetitively negative to flat T waves, alternating with normal upright T waves in 24-h electrocardiographic recordings from a subspecialty infectious diseases outpatient practice during the years 1982 to 1990. Patients with normal resting electrocardiogram in the assayed leads, but with repetitively inverted to isoelectric abnormal T waves at Holter monitors, were considered to have abnormal readings. A total of 300 patients had undergone a 24-h Holter monitor. This group included 24 individuals with chronic fatigue syndrome (CFS). This population was restricted to individuals 50 years old or younger, and the patients with CFS are compared with the patients without CFS. One of the more striking differences between the two groups was the difference in abnormal Holter readings. The patients with CFS all had abnormal Holter readings, while 22.4 percent patients without CFS had abnormal readings (p < 0.01). We further report the occurrence of mild left ventricular dysfunction in 8 of 60 patients in continuing studies of this population with CFS, younger than 50 years old, and with no risk factors for coronary artery disease. All 60 patients with CFS showed repetitively flat to inverted T waves alternating with normal T waves. Stress multiple gated acquisitions (MUGAs) (labeled erythrocytes with stannous pyrophosphate) were abnormal in eight patients with CFS. Although resting ejection fractions (EFs) were normal (mean, 60 percent), with increasing work loads (Kilopon meters [Kpms]), gross left ventricular dysfunction occurred. The fatigue of patients with CFS may be related to subtle cardiac dysfunction occurring at work loads common to ordinary living.

The relationship between neurally mediated hypotension and the chronic fatigue syndrome. Bou-Holaigah I, Rowe PC, Kan J, Calkins H. Journal of the American Medical Association 1995; 274(12): 961-7.

Abstract: OBJECTIVE-To compare the clinical symptoms and response evoked by upright tilt-table testing in healthy individuals and in a sample of those satisfying strict criteria for chronic fatigue syndrome. DESIGN-Case-comparison study with mean (SD) follow-up of 24 (5) weeks. SETTING-Tertiary care hospital. PATIENTS AND OTHER PARTICIPANTS-A sample of 23 patients with chronic fatigue syndrome (five men and 18 women; mean age, 34 years), each of whom fulfilled the strict diagnostic criteria of the Centers for Disease Control and Prevention, was recruited from regional chronic fatigue support groups and from the investigators' clinical practices. There were 14 healthy controls (four men and 10 women; mean age, 36 years). INTERVENTIONS-Each subject completed a symptom questionnaire and underwent a three-stage upright tilt-table test (stage 1, 45 minutes at 70 degrees tilt; stage 2, 15 minutes at 70 degrees tilt with 1 to 2 micrograms/min of isoproterenol; and stage 3, 10 minutes at 70 degrees with 3 to 4 micrograms/min of isoproterenol). Patients were offered therapy with fludrocortisone, beta-adrenergic blocking agents, and disopyramide, alone or in combination, directed at neurally mediated hypotension. MAIN OUTCOME MEASURES-Response to upright tilt and scores on symptom questionnaires prior to and during follow-up. RESULTS-An abnormal response to upright tilt was observed in 22 of 23 patients with chronic fatigue syndrome vs four of 14 controls (P < .001). Seventy percent of chronic fatigue syndrome patients, but no controls, had an abnormal response during stage 1 (P < .001). Nine patients reported complete or nearly complete resolution of chronic fatigue syndrome symptoms after therapy directed at neurally mediated hypotension. CONCLUSIONS-We conclude that chronic fatigue syndrome is associated with neurally mediated hypotension and that its symptoms may be improved in a subset of patients by therapy directed at this abnormal cardiovascular reflex.

Pathogenesis and management of delayed orthostatic hypotension in patients with chronic fatigue syndrome. De Lorenzo F, Hargreaves J, Kakkar VV. Clinical Autonomic Research 1997; 7(4): 185-90.

Abstract: The relationship between orthostatic hypotension and chronic fatigue syndrome (CFS) has been reported previously. To study the pathogenesis and management of delayed orthostatic hypotension in patients with CFS, a case comparison study with follow-up of 8 weeks has been designed. A group of 78 patients with CFS (mean age 40 years; 49% men and 51% women), who fulfilled the Centre for Disease Control and Prevention criteria were studied. There were 38 healthy controls (mean age 43 years; 47% men and 53% women). At entry to the study each subject underwent an upright tilt-table test, and clinical and laboratory evaluation. Patients with orthostatic hypotension were offered therapy with sodium chloride (1200 mg) in a sustained-release formulation for 3 weeks, prior to resubmission to the tilt-table testing, and clinical and laboratory evaluation. An abnormal response to upright tilt was observed in 22 of 78 patients with CFS. After sodium chloride therapy for 8 weeks, tilt-table testing was repeated on the 22 patients with an abnormal response at baseline. Of these 22 patients, 10 redeveloped orthostatic hypotension, while 11 did not show an abnormal response to the test and reported an improvement of CFS symptoms. However, those CFS patients who again developed an abnormal response to tilt-test had a significantly reduced plasma renin activity (0.79 pmol/ml per h) compared both with healthy controls (1.29 pmol/ml per h) and with those 11 chronic fatigue patients (1.0 pmol/ml per h) who improved after sodium chloride therapy (p = 0.04). In conclusion, in our study CFS patients who did not respond to sodium chloride therapy were found to have low plasma renin activity. In these patients an abnormal renin-angiotensin-aldosterone system could explain the pathogenesis of orthostatic hypotension and the abnormal response to treatment.

Possible relationship between chronic fatigue and postural tachycardia syndromes. De Lorenzo F, Hargreaves J, Kakkar VV. Clinical Autonomic Research 1996; 6: 263-264.

Abstract: Postural tachycardia syndrome refers to the development of symptoms such as light-headedness, visual blurring, palpitations and weakness on assuming an upright posture; these symptoms are relieved by resuming a supine posture. This syndrome is occasionally associated with idiopathic hypovolemia, impaired vasomotor tone, deconditioning and autonomic neuropathy, but has not been reported in association with chronic fatigue syndrome (CFS). We describe five patients who satisfied the CFS criteria of the Centres for Disease Control and Prevention. Upright tilt-table testing induced significant hypotension and increased heart rate in all five patients, consistent with clinical and autonomic manifestation of postural tachycardia syndrome.

Is physical deconditioning a perpetuating factor in chronic fatigue syndrome? A controlled study on maximal exercise performance and relations with fatigue, impairment and physical activity. Bazelmans E, Bleijenberg G, Van Der Meer JW, Folgering H. Department of Medical Psychology, University of Nijmegen, The Netherlands.

BACKGROUND: Chronic fatigue syndrome (CFS) patients often complain that physical exertion produces an increase of complaints, leading to a greater need for rest and more time spent in bed. It has been suggested that this is due to a bad physical fitness and that physical deconditioning is a perpetuating factor in CFS. Until now, studies on physical deconditioning in CFS have shown inconsistent results. METHODS: Twenty CFS patients and 20 matched neighbourhood controls performed a maximal exercise test with incremental load. Heart rate, blood pressure, respiratory tidal volume, O2 saturation, O2 consumption, CO2 production, and blood-gas values of arterialized capillary blood were measured. Physical fitness was quantified as the difference between the actual and predicted ratios of maximal workload versus increase of heart rate. Fatigue, impairment and physical activity were assessed to study its relationship with physical fitness. RESULTS: There were no statistically significant differences in physical fitness between CFS patients and their controls. Nine CFS patients had a better fitness than their control. A negative relationship between physical fitness and fatigue was found in both groups. For CFS patients a negative correlation between fitness and impairment and a positive correlation between fitness and physical activity was found as well. Finally, it was found that more CFS patients than controls did not achieve a physiological limitation at maximal exercise. CONCLUSIONS: Physical deconditioning does not seem a perpetuating factor in CFS.