A Hummingbirds Guide to M.E.

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.

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.

*O* CFS severity is related to reduced stroke volume and diminished blood pressure responses to mental stress Arnold Peckerman, John J. LaManca, Sharon L. Smith, and Benjamin H. Natelson; NJ CFS Research Center, University of Medicine and Dentistry of New Jersey Objective:

One plausible hypothesis of the pathophysiology of chronic fatigue syndrome (CFS) is a disorder of circulation. The present study examined whether cardiovascular homeostasis at rest and centrally-mediated hemodynamic responses to behavioral challenges are altered in CFS. Methods: Twenty-one patients fulfilling CDC criteria for CFS (18 women and 3 men) and 25 matched sedentary controls were evaluated in supine, standing, and sitting postures (resting homeostasis), and during the cold pressor test and simulated public speaking (stress responsivity). The measured responses, in addition to blood pressure and heart rate, included impedance cardiography-derived stroke volume and cardiac output. Patients with CFS were rated for illness severity on a 6-point scale using the New Jersey CFS diagnostic system. Results: As a group, patients with CFS displayed a similar cardiovascular functional status on most of the parameters. However, an observation was made that in patients with CFS, a lower stroke volume was highly predictive (r = -.72, p < .001) of illness severity. When divided into severe (N = 11) and less-than-severe (N = 10) groups, the severe CFS patients were found to have a lower stroke volume and cardiac output (p < .05) relative to a more moderate CFS group across three different postures. In response to the speech task, the less severe CFS group displayed attenuated blood pressure responses relative to a healthy control group (p < .05). A reduced blood pressure response to speech stressor in less severe CFS patients was attributable to a smaller increase in total peripheral resistance. In contrast, cardiovascular responses to the cold pressor test were not significantly different Conclusion: These findings suggest the possibility of a low flow circulatory state in the most severe cases of CFS. In patients with a less severe form of CFS, a diminished blood pressure response to a cognitive-behavioral (speech presentation), but not to an aversive-sensory (the cold pressor test) stressor may indicate a defect in the higher cortical modulation of cardiovascular autonomic control. In this latter group, situations may arise where a demand for blood flow to the brain may exceed the supply with a possibility of ischemia and a decrement of function.

[Note that the 'severe' patients in this study are in reality only mildly or moderately ill]

*O* ME/CFS Post-Exertional Malaise / Fatigue and Exercise by Marjorie van de Sande B.Ed, Grad. Dip. Ed.

An excerpt:

Even though post-exertional malaise is a hallmark feature of ME/CFS, exercise programs are often prescribed with little thought to the effect they may have on patients. The panel of experts for the ME/CFS clinical consensus document(1) stressed that a thorough evaluation of patients and their total illness burden, optimizing medical management, and a careful evaluation of pain generators and risk factors must be done before even considering an exercise program. As much care must be taken in prescribing appropriate exercise for ME/CFS patients as in prescribing pharmaceuticals.(5)

[Note that recovery may be incomplete in some patients even after 'days or weeks' as this chart states. Symptom execerbation or progression may in fact persist for many months or years following exertion, or may be irreversible. This website also does not support use of the inadequate term 'fatigue' to describe the symptomatology of ME]

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 REE_TBK; 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 REE_TBK 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.

The two groups had similar resting ejection fraction (EF). During maximal exercise, EF increased in controls, but declined in CFS patients. The decreases in EF tended to be greater in patients with more severe symptoms. Using a decline in EF as a criterion, 13 CFS patients (81 percent) and 0 control subjects had positive tests. There were no group differences in levels of exertion, as indicated by similar cumulative work output, maximal heart rate, and increases in lactate levels. A similar patter of changes in EF (i.e., increases in controls and declines in CFS patients) was observed in response to postural stress. Conclusions This study provides a preliminary indication of reduced cardiac function in some patients with CFS. It raises the possibility that some CFS patients may have cardiac disorders that are subtle enough to escape the current net of clinical cardiological diagnoses, but may be significant enough in some patients -- perhaps in conjunction with other factors -- to lead to the clinical syndrome of CFS. The researchers note that their findings may also be explained by abnormalities other than those with the heart, including problems with the distribution of cardiac output, reduced blood volume, and neurogenic and endocrinologic abnormalities. Accordingly, further studies capable of defining more precisely the causes of altered cardiac stress responses are required.

"Now, do CFIDS patients prefer to stand up or lie down? Of course, they prefer to lie down. Do you know why? "Do you know what your cardiac output does when you stand up? It drops 30%. In all humans, without exception. So very critical to this technology is that it's the only one that could be done upright [again, four positions on the tilt table are best; standing up and laying down at a minimum]. And what they found is absolutely astonishing, truly astonishing. When [disabled CFIDS patients] stand up, [they're] on the edge of organ failure due to low cardiac output."

The Peckerman article Dr. Cheney refers to is available free online.

"Peckerman's research team at the VA Medical Center in East Orange, N.J., used a sophisticated test to measure how well the heart pumps blood. They gave the test to 16 chronic fatigue syndrome patients, both before and after they exercised. They also tested four non-athletic volunteers. All of the patients' and volunteers' hearts' pumped normally during rest. After exercise, however, 13 of the 16 chronic fatigue [syndrome] patients' hearts pumped less blood than they did at rest.

"Basically we are talking about heart failure," Peckerman tells WebMD. "But chronic fatigue syndrome is a progressive disease. If we were able to detect this in its early stages, it is quite possible there might be a way to treat it."

Peggy Munson’s book ‘Stricken: Voices from the Hidden Epidemic of CFIDS’ is available from this site which also features Peggy’s Awareness day letters from

2003. Dr. Paul Cheney explained how the bodies of CFIDS patients are choosing between lower energy and life, or higher energy and death. On a physiological level, CFIDS patients live in a near-death suspension, making patients feel much like they are dying, not tired.

Dr. David Bell has studied the near-death feeling as it relates to blood volume. "[T]he vast majority of Bell’s CFIDS patients had 'extraordinarily' low circulating blood volume (a combination of plasma and the red blood cells via which the plasma delivers oxygen throughout the body)," writes About.com columnist Joan Livingston. "While his average patients ran about 70 percent of normal, several patients with Chronic Fatigue Syndrome (PWCs) had only half the blood volume of a healthy person, an amount so low that it would ordinarily cause shock and prove fatal in a car accident."

*O* Circulating Blood Volume in Chronic Fatigue Syndrome David H. P. Streeten, MB, DPhil, FRCP, FACP David S. Be11, MD, FAAP

ABSTRACT. Chronic fatigue syndrome (CFS) is an illness associated with severe activity limitation and a characteristic pattern of symptoms despite a relatively normal physical examination and routine laboratory evaluation. The recent description of delayed orthostatic hypotension in patients with CFS, and previous findings of reduced red blood cell (RBC) mass in other patients with orthostatic hypotension not known to have CFS, led us to measure RBC mass and plasma volume in 19 individuals (15 female, four male) with well characterized, severe CFS. RBC mass was found to be significantly reduced (p < 0.001) below the published normal range in the 16 women, being subnormal in 15 (93.8%) of them as well as in two of the four men. Plasma volume was subnormal in 10 (52.6%) patients and total blood volume was below normal in 12 (63.2%). The high prevalence and frequent severity of the low RBC mass suggest that this abnormality might contribute to the symptoms of CFS by reducing the oxygen-carrying power of the blood reaching the brain in many of these patients.

Conclusion: Of the 19 patients reported here, abnormalities in blood volume were very common. The most common, found in 16 of 19 patients, was a reduction in red blood cell mass. Eleven subjects had low plasma volumes, and total circulating blood volume was subnormal in 12 of 19 subjects. In some individuals this abnormality was strikingly severe. Patient #15, for example, had an RBC mass of 12.9 mL/Kg, which is 46% of the expected normal, and a total blood volume of 35.8 mL/Kg, which represents 49.7% of the expected normal value (21). Her peripheral hematocrit was not impressively low at 33.8%, presumably because of the symmetrical reduction in both RBC mass and plasma volume. In other patients the plasma volume was normal or even elevated in the face of a low RBC mass, and in nqne of these patients was the RBC mass abnormality detected by conventional interpretation of the peripheral hematocrit.

All of the subjects in this study had symptoms of orthostatic intolerance which probably contributed to their activity restriction, but tilt table and autonomic nervous system testing was not carried out systematically in these individuals. Normal sitting blood pressures were recorded in all patients under office visit circumstances, except for relatively low values in three and a mildly elevated blood pressure in one. Some of these patients have been tested subsequently and found to have delayed orthostatic hypotension (12), which may be characteristic for CFS (11,12). In general, blood pressure measurements were not predictive of the results of circulating blood volume measurements.

Cardiac function at rest and with exercise in the chronic fatigue syndrome. Montague TJ, Marrie TJ, Klassen GA. Chest 1989; 95: 779-84.

Abstract: To evaluate a possible cardiac pathophysiology of the chronic fatigue syndrome, we compared the resting cardiac function and exercise performance of 41 patients to those of an age-matched and sex-matched normal control group. Persistent fatigue following an acute apparently viral illness was the major complaint of all patients; none had specific cardiac symptoms nor abnormal physical findings. Electrocardiographic spatial patterns were normal in the patients, and there were no differences in the body surface sum of positive T-wave integrals between the patients (240 microV.x 10(2) ± 107 microV.s x10(2)) and control (244 microV.x 10(2) ± 108 microV.s x 10(2) subjects. Twenty-four hour ambulatory ECGs revealed no differences in sinus rates and incidences of ventricular dysrhythmias in the two populations. Left ventricular dimensions and systolic fractional shortening values were also similar in both groups; moreover none of the patients had segmental wall motion abnormalities. On graded exercise testing, 20 of 32 normal subjects achieved target (85 percent of age-maximum) heart rates, compared to four of 31 patients (p less than 0.001). The duration of exercise averaged 12 ± 4 minutes for the normal subjects and 9± 4 minutes for the patients (p less than 0.01). The temporal profile of exercise heart rates was dissimilar in the two groups, with patients' rates consistently and progressively less than those of normal subjects. Peak heart rate averaged 152 ± 16 beats per minute for the normal group vs 124 ± 19 beats per minute for the patients (p less than 0.0001); in age-related terms, respectively, 82 ± 6 percent of the maximum heart rate vs 66 ± 10 percent (p less than 0.0001). Thus, patients with chronic fatigue syndrome have normal resting cardiac function but a markedly abbreviated exercise capacity characterized by slow acceleration of heart rate and fatigue of exercising muscles long before peak heart rate is achieved.

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.

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.

Abnormal Heart Pumping After Exercise Linked to Chronic Fatigue Syndrome

Peckerman's research team at the VA Medical Center in East Orange, N.J., used a sophisticated test to measure how well the heart pumps blood. They gave the test to 16 chronic fatigue syndrome patients, both before and after they exercised. They also tested four non-athletic volunteers. All of the patients' and volunteers' hearts' pumped normally during rest. After exercise, however, 13 of the 16 chronic fatigue patients' hearts pumped less blood than they did at rest.

"Basically we are talking about heart failure," Peckerman tells WebMD. "But chronic fatigue syndrome is a progressive disease. If we were able to detect this in its early stages, it is quite possible there might be a way to treat it."

Emory University cardiologist Joseph I. Miller III, MD, says Peckerman's findings on a potential cause of chronic fatigue syndrome are very interesting. He agrees that these patients have serious heart problems. "Typically we see this in people with three-vessel heart disease," Miller tells WebMD. "A drop in [blood pumped by the heart] during exercise is not a typical response. It is actually a marker of significant coronary artery obstruction."

What's happening to the hearts of people with chronic fatigue syndrome? It's too soon to tell, but Peckerman has a theory. "There is some indication that chronic fatigue syndrome is precipitated by a viral infection," he says. "Some of the viruses that have been suspected have an affinity for the heart."

Repetitively negative changing T-waves at 24-h electrocardiographic monitors in patients with the chronic fatigue syndrome (left ventricular dysfunction in a cohort). Lerner AM, Lawrie C, Dworkin HJ. Chest. 1993;104:1417-1421.

Here, we showed that 24 CFS patients have abnormal cardiac electrical conduction by 24-Hr. ECG testing (Holter monitoring) compared to 106 non-fatigued control patients (p<0.03). In 8 of the 24 CFS patients, gross abnormal cardiac wall motion at exercise MUGA testing was seen. Coronary artery disease was excluded by myocardial perfusion imaging in all CFS patients.

This was our first publication in continuing studies of the chronic fatigue syndrome. Here, for the first time, cardiac abnormalities in CFS illness were recognized.

"Cardiac involvement in patients with chronic fatigue syndrome as documented with Holter and biopsy data in Birmingham, Michigan, 1991-1993." Lerner AM, Goldstein J, Chang CH et al.  Infectious Diseases in Clinical Practice 1997;6:327-33.

Here, the prevalence of abnormal Holter monitoring in 67 CFS patients and 78 non-CFS patients matched for age, place and time and absence of other confouding medical diseases were compared. Holter monitors in both CFS and control groups were read by two non-involved cardiologists without clinical knowledge about the patient or place in the study. Dr. Lerner was not a reader of Holter monitors in this study. The prevalence of T-wave abnormalities by Holter monitoring was greater in CFS than in non-CFS patients (p<0.01). The presence of abnormal T-waves at Holter monitoring was "a sensitive indicator of the presence of CFS." The "absence" of these abnormal T-waves made the diagnosis of CFS unlikely (statistical sensitivity 0.96). Light and electron micrographic studies of right ventricular endomyocardial biopsies in these CFS patients showed cardiomyopathic changes. We do not recommend further right ventricular cardiac biopsies in CFS patients since the hearts of CFS patients may be friable and may have an increased likelihood of post-biopsy bleeding.

This work shows that rapid heart rates at rest, and in some cases, abnormal cardiac wall motion contribute to the light-headedness that many CFS patients experience. Uniformly, abnormal Holter monitoring is present in CFS patients. This additional criterion for diagnosis of CFS illness, namely abnormal Holter monitoring, to the CDC criteria for the diagnosis of CFS does not exclude any CFS patients included in the original CDC definition. The absence of abnormal Holter ECG testing excludes fatigued patients who do not have CFS.A unified theory of the cause of chronic fatigue syndrome. Lerner AM, Zervos M, Dworkin HJ, Chang, CH and O'Neill W. Infectious Diseases in Clinical Practice 1997;6:230-243.

Here, we hypothesize that CFS is a prolonged infectious mononucleosis syndrome in previously healthy (immunocompetent) persons. We further speculate in this early study that prime candidates for cause of CFS are two herpesviruses which cause infectious mononucleosis, Epstein-Barr virus (EBV) and cytomegalovirus (HCMV). We further suggest that studies seeking a single virus cause of CFS, even those studies searching for single-virus EBV or single virus HCMV would conclude in a result of "no cause". Indeed, such negative studies have been done. We suggest that (1997) there may be three causes of CFS, 1) single virus, EBV CFS; 2) single virus HCMV CFS; and 3) EBV-HCMV co-infection CFS. We outline research studies to prove or disprove this new paradigm.\

Editorial response: microbial persistence and idiopathic dilated cardiomyopathy. Lerner AM. Clinical Infectious Diseases. 1999;29:526-7.

Here, Dr. Lerner discusses the possible relationship between long-standing cardiomyopathy, heart muscle disease not associated with coronary artery disease, and CFS.

"New cardiomyopathy: a pilot study of intravenous gancyclovir in a subset of the chronic fatigue syndrome." Lerner AM, Zervos M and Dworkin HJ et al. Infectious Diseases In Clinical Practice 1997;6:110-117.

Here, we emphasize the need of subset classification in the diagnosis and treatment of CFS illness. CFS patients in this study had significant IgG serum antibody titers to cytomegalovirus, but little to no evidence of EBV infection by blood tests. In this study 13 of 18 CFS patients were remarkably improved after 30 days of intravenous ganciclovir (p<0.05). Single virus HCMV CFS in this pilot study was improved by antiviral treatment. There were no side effects from this carefully monitored trial.

A six-month trial of valacyclovir in the Epstein-Barr virus subset of chronic fatigue syndrome: improvement in left ventricular function. Lerner AM, Beqaj SH, and Deeter RG et al.  Drugs of Today. 2002;38:549-561.Drugs of Today. 2002;38:549-561.

Twenty-five patients with CFS illness were treated orally for 6 months with pharmacokinetic doses of valacyclovir (valtrex) in a formulation to give continuous anti-EBV effective blood levels throughout the day. This is the first time such valacyclovir dosing was given. The trial was approved by the U.S. Food and Drug Administration. Patients were carefully monitored for safety by repeated appropriate blood tests. There were no adverse side effects. Sixteen patients with single virus EBV infection were benefitted, but 9 clinically similar CFS patients with EBV-HCMV co-infection were not benefitted. Valacyclovir (valtrex) in the laboratory is effective versus EBV, but it is NOT effective (active) versus HCMV. Therefore, the results strengthen the need for subset classification and appropriate subset-directed antiviral treatment for CFS illness. This, to our knowledge, is the first successful report of valacyclovir treatment for EBV infection.

A small, randomized, placebo-controlled trial of the use of antiviral therapy for patients with chronic fatigue syndrome. Lerner AM, Zervos M and Chang CH et al. Clinical Infectious Diseases. 2001;32:1657-58.

Eleven CFS patients with EBV-HCMV co-infections were appropriately treated according to their prior subset classification over an 18-month period with antiviral drug treatments. All patients were carefully monitored for safety every 4-6 weeks. Valacyclovir for EBV infection and ganciclovir for HCMV infection were used. There were no significant side effects in CFS patients. All 11 CFS patients in this study were significantly improved.

In these studies, 40 CFS patients were safely treated with antiviral drugs. They were remarkably improved.

IgM serum antibodies to human cytomegalovirus nonstructural gene products p52 and CM₂ (UL44 and UL57) are uniquely present in a subset of patients with chronic fatigue syndrome. Lerner AM, Beqaj SH, Deeter RG and Fitzgerald JT.  In Vivo. 2002;16:153-160.

This is an especially enlightening study. In many CFS patients in whom our work implies an A) EBV; B) HCMV; or C) EBV-HCMV (co-infection) cause for CFS illness, normal means for diagnosis by blood tests or virus isolation (including those using polymerase chain reactions) are negative, both in our work, reviewed here, and in the careful work of others. In this study, we show a definitive new means of HCMV multiplication in this HCMV subset of CFS patients. The p52 and CM2 HCMV IgM antibodies were present in 16 CFS patients, but were not present in 77 various control patients. In these CFS patients, portions of the HCMV genetic material are synthesized, but remain unassembled into complete virus. These data provide strong evidence for a virus etiology for CFS illness and provide a strong rational for antiviral treatment of CFS patients.

"Cardiac and virologic issues" pp 304-330 from Handbook of Chronic Fatigue Syndrome. Lerner AM, Deeter RG, O’Neill W, Dworkin HJ, Zervos M, Beqaj SH, Chang CH, and Fitzgerald JT. Jason LA, Fennell PA, and Taylor RR. John Wiley & Sons, Inc. 2003.

We present the evolution of data describing studies over greater than a decade which support the paradigm that CFS is a prolonged infectious mononucleosis due to Epstein-Barr virus, cytomegalovirus or the two viruses in co-infection undergoing incomplete virus multiplication. The paradigm suggests that the immunocompetent (otherwise healthy) CFS patients' immune defenses do not allow complete virus formation, but only parts of the virus(es) genetic material is expressed. Cardiac involvement of this newly hypothesized method of virus infection leads to rapid heart pumping at rest (tachycardia) and eventually cardiac muscle pump weakening. Specific antiviral treatment has led to remarkable sustained improvement in patient well being so that criteria for the diagnosis of CFS are no longer present. Medical testing by Holter monitoring, MUGA, nuclear stress testing, cardiac biopsy, virus serologic tests and disappearance of symptoms of CFS support this theory.

IgM serum antibodies to Epstein-Barr Virus are uniquely present in a subset of patients with the chronic fatigue syndrome. Lerner AM, Beqaj S, Deeter RG, and Fitzgerald JT.  In Vivo. 2004;18:101-106.

A first unique subset of patients with chronic fatigue syndrome (CFS) and specific diagnostic serum antibodies to cytomegalovirus (HCMV) non-structural gene products p 52 and CM₂ (UL 44 and UL 57) indicates incomplete HCMV persistent multiplication in these specific patients with CFS. The results suggest that specific antiviral (HCMV) treatment in these patients may be beneficial. A second Epstein-Barr Virus (EBV) distinct subset of CFS is now defined. Fifty-eight CFS patients and 68 non-CFS matched controls were studied. Serum antibodies to EBV viral capsid antigen (VCA) IgM and EBV Early Antigen, diffuse (EA, D) as well as HCMV (V), IgM and IgG; VP (sucrose density purified V); p 52 and CM₂, IgM serum antibodies were assayed. Serum EBV VCA IgM positive antibody titers were identified in 33 CFS patients (Group A subset EBV VCA IgM 62.3 ± 8.3, neg < 20), but were not present in other CFS patients (Group B subset EBV VCA IgM 6.8 ± 0.7) or controls (p < 0.0001). EBV VCA IgM titers remained positive in CFS patients from Group A for 24-42 months. Anti-viral medicines effective in HCMV and EBV infections are different, and preliminary studies suggest that this patient-specific pharmacokinetically directed antiviral therapy should be continued for 6-12 months. Trials of antiviral therapy must be individually monitored by complete blood counts, creatinine and tests of liver function (AST, ALT) every 4-6 weeks for safety. (reference publication #7)

Prevalence of abnormal cardiac wall motion in the cardiomyopathy associated with incomplete multiplication of Epstein-Barr Virus and/or cytomegalovirus in patients with chronic fatigue syndrome. Lerner AM, Dworkin HJ, Sayyed T, Chang CH, Fitzgerald JT, Beqaj S, Deeter RG, Goldstein J, Gottipolu P and O'Neill W.  In Vivo. 2004;18:417-424.

Here, we report a prospective consecutive case control study from 1987-1999 of cardiac dynamics as measured by radionuclide, ventriculography in 98 CFS patients. Controls were 191 patients with various malignancies who were evaluated in protocols requiring radionuclide ventriculography before initiation of cardiotoxic chemotherapeutic agents. The prevalence of abnormal cardiac wall motion (ACWM) at rest in CFS patients was 10 of 87 patients (11.5%). With stress exercise, 21 CFS patients (24.1%) demonstrated ACWM. Cardiac biopsies in 3 CFS patients with ACWM showed a cardiomyopathy. Among the controls, ACWM at rest was present in 4 of 191 patients (2%) (p=0.0018). A progressive cardiomyopathy often associated with EBV and/or HCMV incomplete virus multiplication is present in CFS patients.

Nondiscocytic erythrocytes in myalgic encephalomyelitis. Simpson LO. New Zealand Medical Journal 1989; 102: 126-7.

Abstract: Blood samples from 102 volunteers who believed they suffered from myalgic encephalomyelitis were photographed in a scanning electron microscope at 500x. All identifiable cells were counted and classified on the basis of their shape. The frequency of each cell shape was expressed as a percentage of the total number of cells counted in the sample. The resulting data were compared with that from 52 healthy controls and 99 cases of multiple sclerosis which had been selected randomly by a computer from a panel of 229 cases in a concurrent study. Samples from subjects with myalgic encephalomyelitis had the lowest percentages of normal red cells and the highest incidence of cup forms. The results provide evidence that myalgic encephalomyelitis has an organic cause. Quantitative analysis of red cell shape may assist in the diagnosis of myalgic encephalomyelitis.

MYCOPLASMA
Extracted from Nexus Magazine, Volume 8, Number 5 (August-September 2001)
PO Box 30, Mapleton Qld 4560 Australia. editor@nexusmagazine.com
Telephone: +61 (0)7 5442 9280; Fax: +61 (0)7 5442 9381
From our web page at: www.nexusmagazine.com

© by Donald W. Scott, MA, MSc © 2001

You can also ask your doctor for a blood volume test. Every human being requires a certain amount of blood per pound of body weight, and it has been observed that people with fibromyalgia, chronic fatigue syndrome, multiple sclerosis and other illnesses do not have the normal blood volume their body needs to function properly. Doctors aren't normally aware of this.

This test measures the amount of blood in the human body by taking out 5 cc, putting a tracer in it and then putting it back into the body. One hour later, take out 5 cc again and look for the tracer. The thicker the blood and the lower the blood volume, the more tracer you will find.

The analysis of one of my clients stated: "This patient was referred for red cell mass study. The red cell volume is 16.9 ml per kg of body weight. The normal range is 25 to 35 ml per kg. This guy has 36% less blood in his body than the body needs to function." And the doctor hadn't even known the test existed.

If you lost 36% of your blood in an accident, do you think your doctor would tell you that you are alright and should just take up line dancing and get over it? They would rush you to the nearest hospital and start transfusing you with blood. These tragic people with these awful diseases are functioning with anywhere from 7% to 50% less blood than their body needs to function.

*O* Red Blood Cells and Chronic Fatigue Syndrome By Jule Klotter (Townsend Letter, issue: November 2001)

According to an article by Maryann Spurgin, Ph.D., New Zealand researcher Dr. L.O. Simpson has theorized that myalgic encephalomyelitis (ME), also known as Chronic Fatigue Immune Deficiency Syndrome (CFIDS), results from "insufficient oxygen availability due to impaired capillary blood flow."

Simpson attributes the impaired capillary blood flow to smaller-than-usual capillaries and to the presence of abnormal red blood cells (nondiscocytes).

In healthy people, most red blood cells are smooth-surfaced and concave-shaped with a donut-like appearance. These discocytes have extra membranes in the concave area that give them the flexibility needed to move through capillary beds, delivering oxygen, nutrients, and chemical messengers to tissue and removing metabolic waste, such as carbon dioxide and lactic acid

"The Role of Red Blood Cell Morphology in the Pathogenesis of ME/CFIDS" by Maryann Spurgin, Ph.D., The CFIDS Chronicle, Summer 1995 discocytes have extra membranes in the concave area that give them the flexibility needed to move through capillary, beds, delivering oxygen, nutrients, and chemical messengers to tissue and removing metabolic waste, such as carbon dioxide and lactic acid. Abnormal red blood cells lack flexibility that allow them to enter tiny capillaries. These nondiscocytes are characterized by a variety of irregularities, including surface bumps or ridges, a cup or basin shape, and altered margins instead of the round shape found in discocytes.

Simpson found that people with ME/CFIDS have higher percentages of nondiscocytes than people' with other chronic illnesses, such as Lupus, multiple sclerosis, Huntington's disease, malaria, and diabetes. In addition, the percentages of cup-shaped somatocytes in ME/CFIDS patients can remain high for months, inhibiting blood flow.

Simpson believes that, in ME/CFIDS, either the mechanism whereby red blood cells revert to the discocyte form is hampered for some reason or that whatever triggered the red blood cells to transform into nondiscocytes remains in effect, albeit unidentified.

*O* 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."

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.

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.

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.

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.