Human Tragedy & the Heart of the Matter

 

 

This document illustrates both the desperate human and the pressing scientific need for sub-grouping, as acknowledged in January 2002 in the CMO’s Report, which stated:

 “One highly heterogeneous disease might exist that encompasses CFS/ME or several related pathophysiological entities may exist; these distinct hypotheses should be studied.”[1]

 

 

 

 

 

PART ONE: Human Tragedy

 

Sadly, on July 4 2005, at the age of 23, Casey Fero died in his sleep. In September 2005, a forensic pathologist determined that Casey had Myocarditis, viral infection of the heart muscle. The pathologist was shocked at the state of Casey's heart, which showed fibrosis indicating the presence of a long-standing infection.

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The sudden and tragic death of a young man, Casey Fero, in the United States has highlighted the urgency for answers to be found as to the causes of ME and the desperate need for treatments.

Casey had been diagnosed with CFS at the age of 9 and then again at age 15. It caused him to feel weak, unable to think, and exhausted. He was plagued with headaches, stomach problems, and had major sleep disorder among a list of daily symptoms.   Early on, he knew that medical help was unavailable and furthermore, he was met with disbelief at school and in the doctor's office.

As a lasting tribute to Casey, the Fero family; the Wisconsin Chronic Fatigue Syndrome Association, inc.; and Mothers against Myalgic Encephalomyelitis, Inc. (MAME) created the first universal access blood and tissue bank for ME-CFS patients.   Many recognized illnesses, such as Alzheimer's, were poorly understood before the creation of tissue and blood banks.

Precious gifts of tissue and blood benefit all individuals and families living with illness. Please contact: Wisconsin CFS Association, 747 Lois Drive, Sun Prairie, WI 53590 for further details

 

NOTE: The above is a summary of information taken from the website of the Wisconsin CFS Association:  www.wicfs-me.org 


PART TWO: The Heart of the Matter



Some medical researchers believe there is a link between cardiac problems and chronic fatigue syndrome (CFS).   Indeed the research on the following pages supports this. Sadly, this research has had little bearing on medical and other official attitudes and approaches to patients.

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The following examples of research indicating cardiac problems are taken from the work of A. Martin Lerner in the USA. The research summaries presented below are heavily based on those found on Dr Lerner’s website - http://cfsviraltreatment.com/ - but have been edited here for ease of comprehension by a lay audience. Dr Lerner’s credentials are set out in the appended physician profile.

 

It should be noted that these examples are not exhaustive: other researchers have also identified indicators of cardiac abnormality. Some further examples of such research are summarised in the document ‘Is Graded Exercise Safe for People with ME?’.[2]

 

 

 

A. Martin Lerner, M.D.

“The work that we are doing suggests that the epidemic of Chronic Fatigue Syndrome is an ongoing herpes-virus infection caused by persisting incomplete virus multiplication of Epstein-Barr virus alone, Cytomegalovirus alone, or the two viruses in co-infection. Our work also suggests that specific anti-viral therapy leads to improvement in the ongoing, life-altering fatigue and associated symptoms.” [3]

 

 

 

DR LERNER’S RESEARCH FINDINGS: SUMMARIES OF PUBLISHED STUDIES

 

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

This research showed that the 24 CFS patients studied had abnormal cardiac electrical conduction when investigated by 24 hour electrocardiograph ECG testing (Holter monitoring), compared to 106 non-fatigued control patients. In 8 of the 24 CFS patients, MUGA testing – which measures muscle strength of the heart – revealed gross abnormal cardiac wall motion at exercise. Coronary artery disease was excluded by myocardial perfusion imaging in all CFS patients.

 

  1. Dworkin HJ, Lawrie C, Bohdiewicz P and Lerner AM. Abnormal left ventricular myocardial dynamics in eleven patients with the chronic fatigue syndrome. Clinical Nuclear Medicine 1994;19:675-677.

Here, 11 CFS patients were studied in detail by cardiac nuclear medicine MUGA test, which measures muscle strength of the heart. Abnormal cardiac wall motion both at rest and under stress, dilatation of the left ventricle, and segmental wall motion abnormalities were again observed.

 

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

This study compared the prevalence of abnormal Holter monitoring[4] in 67 CFS patients and 78 non-CFS patients matched for age, place and time and absence of other confouding medical diseases. 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. The prevalence of T-wave abnormalities by Holter monitoring was greater in CFS than in non-CFS patients: as such, the presence of abnormal T-waves was "a sensitive indicator of the presence of CFS". Conversely, the absence of these abnormal T-waves made the diagnosis of CFS unlikely. Light and electron micrographic studies of right ventricular endomyocardial biopsies in these CFS patients showed cardiomyopathic changes. However, Dr Lerner does not recommend further right ventricular cardiac biopsies, since the hearts of CFS patients may be friable and as such may have an increased likelihood of post-biopsy bleeding.

 

 

 

Summary of Publications 1-3 : Cardiac Involvement in CFS

 

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. The absence of abnormal Holter electrocardiograph (ECG) testing can be used as a criterion to identify fatigued patients who do not have CFS.

 

 

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

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

 

  1. Lerner AM, Zervos M, Dworkin HJ, Chang, CH and O'Neill W. A unified theory of the cause of chronic fatigue syndrome. Infectious Diseases in Clinical Practice 1997;6:230-243.

In this theoretical paper Dr Lerner and colleagues hypothesize that CFS is a prolonged infectious mononucleosis syndrome in previously healthy (immunocompetent) persons. He further suggests that prime candidates for cause of CFS are two herpesviruses which cause infectious mononucleosis i.e. Epstein-Barr virus (EBV) and cytomegalovirus (HCMV). On this basis, he notes 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’, and observes that such ‘negative’ studies have indeed been reported. He hypothesises that there may be three causes of CFS.

1)      single virus Epstein-Barr virus (EBV) CFS;

2)      single virus cytomegalovirus (HCMV) CFS; and

3)      EBV-HCMV co-infection CFS.

Finally, he outlines research studies to prove or disprove this new paradigm.

 

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

Here, Dr Lerner and colleagues emphasize the need of subset classification in the diagnosis and treatment of CFS illness. The subset of CFS patients in this study had significant IgG serum antibody titers to cytomegalovirus (HCMV), but little to no evidence of EBV infection by blood tests. Most of these patients - 13 out of 18 - were remarkably improved after 30 days of intravenous ganciclovir. Therefore, single virus HCMV CFS in this pilot study was improved by antiviral treatment. There were no side effects from this carefully monitored trial.

 

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

Twenty-five patients with CFS illness were treated orally for 6 months with doses of valacyclovir (valtrex) in a formulation to give continuous anti-EBV effective blood levels throughout the day. 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 of the 25 patients had single virus EBV infection and benefitted, but the remaining 9 - clinically similar - CFS patients with had EBV-HCMV co-infection and did not benefit. It is therefore concluded that valacyclovir (valtrex) in the laboratory is effective versus Epstein-Barr virus (EBV), but it is not effective (active) versus cytomegalovirus (HCMV). Therefore, the results strengthen the need for subset classification and appropriate subset-directed antiviral treatment for CFS illness.

 

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

Eleven CFS patients with EBV-HCMV co-infections were identified, and appropriately treated according to this 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.

 

 

Summary of Publications 5-8 : Treatment of CFS Illness with Anti-viral Drugs According to Subset Classification  

In these studies, CFS patients were safely treated with antiviral drugs, appropriately targeted according to the nature of the virus identified. They were remarkably improved.

 

 

9.      Lerner AM, Beqaj SH, Deeter RG and Fitzgerald JT. 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. In Vivo. 2002;16:153-160.

Dr Lerner’s prior work implies an Epstein-Barr virus (EBV), cytomegalovirus (HCMV), or EBV-HCMV (co-infection) cause for CFS illness, with the patient population divisible into these three subsets, depending on the viral culprit involved.  Yet in many such patients, normal means for diagnosis by blood tests or virus isolation are negative.[5] In this study, Dr Lerner and colleagues show a definitive new means of cytomegalovirus (HCMV) multiplication in the HCMV subset of CFS patients. Certain HCMV IgM antibodies -  p52 and CM2 - 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 were synthesized, but remained unassembled into complete virus. These data provide strong evidence for a virus etiology for CFS illness and provide a strong rationale for antiviral treatment of CFS patients.

 

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

Here Dr Lerner and colleagues present the evolution of their data, describing studies conducted over more 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.


 

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

This research builds on the work of an earlier study,[6] in which Dr Lerner and colleagues identificatied a unique subset of patients with chronic fatigue syndrome and specific diagnostic serum antibodies to certain cytomegalovirus (HCMV) non-structural gene products, indicating incomplete HCMV persistent multiplication in these specific patients. The results suggested that specific antiviral (HCMV) treatment in these patients may be beneficial.

In this study, a second distinct subset of CFS was defined, based on Epstein-Barr Virus (EBV). Fifty-eight CFS patients and 68 non-CFS matched controls were studied. Various immunological parameters were analysed. Serum Epstein-Barr Virus EBV viral capsid[7] antigen (VCA) IgM positive antibody titers were identified in 33 of the CFS patients (Group A) but were not present in the remaining 25 CFS patients (Group B) or in the controls. This finding was highly statistically significant, with a one in ten thousand probability of such a difference occuring by chance. The 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. It is concluded that it is therefore essential to identify which specific virus is involved. Preliminary studies suggest that the patient-specific pharmacokinetically directed antiviral therapy described by Dr Lerner 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 every 4-6 weeks for safety.

 

  1. Lerner AM, Dworkin HJ, Sayyed T, Chang CH, Fitzgerald JT, Beqaj S, Deeter RG, Goldstein J, Gottipolu P and O'Neill W. 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. In Vivo. 2004;18:417-424.

Here, Dr Lerner and colleagues report a prospective case control study – conducted over  more than a decade (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. Distinct cardiac abnormalities were found in a number of the CFS patients, but were not characteristic of the control group. For example:

·        The prevalence of abnormal cardiac wall motion (ACWM) at rest in CFS patients was 10 of 87 patients (11.5%), as compared to just 4 of 191 patients (2.1%) in the control group with malignancies.

·        With stress exercise, a greater number of CFS patients (21 patients; 24.1%) demonstrated ACWM.

·        Cardiac biopsies in 3 CFS patients with ACWM showed a cardiomyopathy.

It is concluded that a progressive cardiomyopathy often associated with EBV and/or HCMV incomplete virus multiplication is present in CFS patients.

 


Appendix – Martin Lerner MD:  physician profile[8]

 

Martin Lerner, M.D. is certified by the American Board of Internal Medicine.

 

A graduate of Washington University School of Medicine in St. Louis, Missouri, Dr. Lerner completed a one-year internship at Barnes Hospital in St. Louis. After serving two years as a laboratory investigator at the National Institutes of Health in Bethesda, Maryland, Dr. Lerner completed a residency in internal medicine at Harvard Medical Services at the Boston City Hospital and at Barnes Hospital in St. Louis.

After residency training, Dr. Lerner spent three years as a research fellow in medicine at the Thorndike Memorial Library, Boston City Hospital and Harvard Medical School in Boston, and one year as a research associate in biology at the Massachusetts Institute of Technology in Boston.

Dr. Lerner was chief of the Division of Infectious Diseases and a professor of internal medicine at Wayne State University School of Medicine from 1963-1982. Currently, Dr. Lerner is in private practice and is on staff at William Beaumont Hospital in Royal Oak, Michigan.

Among his professional memberships, Dr. Lerner was governor for the Michigan chapter of the American College of Physicians (ACP) from 1990-1994 and in 2001 was awarded a mastership from the ACP. He is a member of the American Society of Clinical Investigation and the Association of American Physicians. Dr. Lerner received the 1994 Alumni Achievement Award from Washington University School of Medicine, St. Louis.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

scotme@ntlworld.com

Submission to Gibson Inquiry January 2006

 



[1] A Report of the CFS/ME Working Group: Report to the Chief Medical Officer of an Independent Working Group. London: Department of Health, 2002. Chapter 3: Nature and impact of CFS/ME,  page 19.

[2] Also submitted by ScotME’s to the inquiry. See, for example, the research study from 2000 by P De Becker et al. featured on page 3 of this document.

[3] This quote is taken from Dr Lerner’s website : http://cfsviraltreatment.com/ .

[4] ‘Holter monitoring’ is a form of electrocardiograph (ECG) testing.

[5] Including those using polymerase chain reactions. This applies both to Dr Lerner’s own work, and the work of others.

[6] Study number 9 above.

[7] The outer protein coat of a mature virus is called a ‘capsid’.

[8] Taken from Dr Lerner’s website: http://cfsviraltreatment.com/