The Hummingbirds' Foundation for M.E.

The Hummingbirds' Foundation for M.E. (HFME) is fighting for the recognition of M.E.,
and for patients to be accorded the same basic human rights as those with similar
disabling and potentially fatal neurological diseases such as M.S.

An important note:

Before reading the research/advocacy information given in the links below, please be aware of the following facts:

1. Myalgic Encephalomyelitis and ‘Chronic Fatigue Syndrome’ are not synonymous terms. The overwhelming majority of research on ‘CFS’ or ‘CFIDS’ or ‘ME/CFS’ or ‘CFS/ME’ or ‘ICD-CFS’ does not involve M.E. patients and is not relevant in any way to M.E. patients. If the M.E. community were to reject all ‘CFS’ labelled research as ‘only relating to ‘CFS’ patients’ (including research which describes those abnormalities/characteristics unique to M.E. patients), however, this would seem to support the myth that ‘CFS’ is just a ‘watered down’ definition of M.E. and that M.E. and ‘CFS’ are virtually the same thing and share many characteristics.

A very small number of ‘CFS’ studies refer in part to people with M.E. but it may not always be clear which parts refer to M.E. The
A warning on ‘CFS’ and ‘ME/CFS’ research and advocacy paper is recommended reading and includes a checklist to help readers assess the relevance of individual ‘CFS’ studies to M.E. (if any) and explains some of the problems with this heterogeneous and skewed research.

In future, it is essential that M.E. research again be conducted using only M.E. defined patients and using only the term M.E. The bogus, financially-motivated disease category of ‘CFS’ must be abandoned.

2. The research referred to on this website varies considerably in quality. Some is of a high scientific standard and relates wholly to M.E. and uses the correct terminology. Other studies are included which may only have partial or minor possible relevance to M.E., use unscientific terms/concepts such as ‘CFS,’ ‘ME/CFS,’ ‘CFS/ME,’ ‘CFIDS’ or Myalgic ‘Encephalopathy’ and also include a significant amount of misinformation. Before reading this research it is also essential that the reader be aware of the most commonly used ‘CFS’ propaganda, as explained in A warning on ‘CFS’ and ‘ME/CFS’ research and advocacy and in more detail in Putting research and articles on Myalgic Encephalomyelitis into context.

Metabolic research

This section is closely related with the section on muscle abnormalities, specifically mitochondrial abnormalities. A small selection of articles and abstracts are given here, see the Mitochondrial Muscle Research and General Muscle Research section for more information. 

Because the metabolic abnormalities of M.E. are primarily responsible for much of the symptomatology and disability associated with the illness, this section is also relevant to many of the other sections including: Cardiac Research, Exercise Research, Muscle Research, Neurological and Cognitive Research, etc.

 *O*  The Complexities of Diagnosis by Byron Hyde MD

(Taken from: Handbook of Chronic Fatigue Syndrome by Leonard A. Jason, Patricia A. Fennell and Renée R. Taylor)

'In some cases of MRI spectography of arm muscle of ME patients, it has been shown that because of an abnormal buildup of normal metabolites, the muscle cell actually shuts down to prevent cell death. This cell field shutdown is probably what is happening to the true ME patient's cell physiology in the brain. It probably explains in part the so-called brain fog and the dysfunction after the brain is stressed. It probably also explains muscle dysfunction. In legal cases, I also attempt to send the patient for xenon scan, which demonstrates the significant shutdown of the brain after exercise. I also send the patient for PET scans to obtain confirmatory changes in this completely different technology. Neither xenon SPECT nor PET is necessary except for research or legal cases, but both give a great deal of information about the pathophysiology of this disease to the knowledgeable physician. Xenon SPECT scans are almost impossible to find.'

*O*O* A New and Simple Definition of Myalgic Encephalomyelitis and a New Simple Definition of Chronic Fatigue Syndrome & A Brief History of Myalgic Encephalomyelitis & An Irreverent History of Chronic Fatigue Syndrome by Dr Byron Hyde

‘Do not for one minute believe that CFS is simply another name for Myalgic Encephalomyelitis (M.E.). It is not. Though CFS is based upon a typical M.E. epidemic, in my opinion it has always been a confused and distorted view of reality. The invention of Chronic Fatigue Syndrome has to be one of the most curious cases of inventive American scientific imperialism that one could imagine. It is my opinion that the CDC 1988 definition of CFS describes a non-existing chimera based upon inexperienced individuals who lack any historical knowledge of this disease process. The CDC definition is not a disease process.’

'Muscle Dysfunction [in authentic M.E.]: This feature may be due to vascular dysfunction or peripheral nervous or spinal dysfunction and includes both pain and rapid loss of strength of muscle function after moderate physical or mental activity.'

'This epidemic started in a local residential school that was located a few hundred feet north of the hospital refuge dump. The epidemic started shortly after the return to school for the autumn session and probably followed significant immunization. Since the epidemic started among school children before it spread to the adults and then to neighbouring towns, there should be no controversy that this type of illness effects children. As in the LA epidemic, the disease manifested both diffuse central and peripheral nervous system symptoms. It was termed an "itis" or an inflammation of the nervous system. This was the first epidemic to demonstrate that we were dealing with a diffuse brain injury and specifically in the area that affected normal sleep and normal muscle physiology. Almost no patients died but all were left disabled and in many cases the disability persists until today, 55 years later.'


How Serious is ME The Committee for Justice and Recognition of Myalgic Encephalomyelitis

The complete answer to this question is clearly important and not yet fully established. However the families of patients that have succumb to this disease may hold a different opinion. These few brief reports on this page will help demonstrate the diverse course and consequence of infection with Myalgic Encephalomyelitis. ME has a variety of manifestations and outcomes, some patients improve but many more follow a chronic trajectory. Lifelong disability is common.

The full range of symptoms and consequences of ME are too numerous to fully discuss here, however the most dangerous can be described as related to three factors. Infection of the brain, Metabolic changes and Immune dysfunction.

[Contains research]

Role of mitochondria in neurodegenerative diseases Cassarino DS, Bennett JP Jr. University of Virginia Health Sciences Center,  Brain Research Reviews, 1999, 29;1:1-25  PMID: 9974149
The significance of Mitochondria in Neurologic Disease, is the subject of this major review and reveals the devastating neurologic diseases that can result from mitochondrial dysfunctions. 

ABSTRACT. There is mounting evidence for mitochondrial involvement in neurodegenerative diseases including Alzheimer's, Parkinson's, and Lou Gehrig's Disease (ALS). Mitochondrial DNA mutations, whether inherited or acquired, lead to impaired electron transport chain (ETC) functioning. Impaired electron transport, in turn, leads to decreased ATP (energy) production, formation of damaging free-radicals, and altered calcium handling. These toxic consequences of ETC dysfunction lead to further mitochondrial damage including oxidation of mitochondrial DNA, proteins, and lipids, and opening of the mitochondrial permeability transition pore, an event linked to cell death. Although protective nuclear responses such as antioxidant enzymes may be induced to combat these pathological changes, such a vicious cycle of increasing oxidative damage may insidiously damage neurons over a period of years, eventually leading to neuronal cell death. This article's hypothesis, a synthesis of the mitochondrial mutations and oxidative stress hypotheses of neurodegeneration, is readily tested experimentally, and points out many potential therapeutic targets for preventing or ameliorating these diseases. 
(This article is taken/available from the TCJRME website)

Dr. Melvin Ramsay 'Epidemic neuromyasthenia' 1955-1978. A. Melvin Ramsay Postgrad Med J, 1978 Nov; 54(637)  PMID: 746017

ABSTRACT.  A record of fifty-three patients admitted to the Infectious Diseases Department of the Royal Free Hospital between April 1955 and September 1957 suffering from 'epidemic neuromyasthenia' establishes the fact that the condition was endemic in the general population before, during and after the outbreak among the staff of the hospital. A further outbreak occurred in North Finchley between 1964 and 1967 and sporadic new cases are still being encountered. The majority of these patients show evidence of involvement of the central and sympathetic nervous systems and the reticulo-endothelial system. Abnormal muscular fatigability [or paralytic muscle weakness] is the dominant clinical feature and it is suggested that mitochondrial damage may provide an explanation for this phenomenon. Enzyme tests carried out in seven cases show pathologically high levels of lactic dehydrogenase, and glutamic oxalo-acetic transaminase. A follow-up study suggests that there is one group of patients that recovers completely or nearly completely, a second that recovers but is subject to relapses and a third that shows little or no recovery, these patients remaining incapacitated. 
(This article is taken/available from the TCJRME website)

Metabolism and ME: Mitochondria and Myalgic Encephalomyelitis by The Committee for Justice and Recognition of Myalgic Encephalomyelitis

'Laboratory studies have confirmed an enormous array of metabolic abnormalities in the blood, breath, urine, stool, and from advanced in vivo assessments of ME patients. However, from the infectious disease specialist and world authority on Myalgic Encephalomyelitis, Dr. Melvin Ramsay, to the distinguished Drs; Behan, Richardson, Cheney, Martin, and Nicolson, the concern of mitochondrial damage as an essential area of pathogenesis has been an important consideration.'

The similarities of Poliomyelitis, Parkinson’s and Myalgic Encephalomyelitis, See this important article (Bruno, Creange, Frick);

See this article on Restoring Mitochondria 

Evidence of ME infection and Mitochondria damage in muscle biopsy Behan WM, More IA, Behan PO. Acta Neuropathol 1991;83(1):61-5.  PMID: 1792865

ABSTRACT. We have examined the muscle biopsies of 50 patients who had postviral fatigue syndrome (PFS) for from 1 to 17 years. We found mild to severe atrophy of type II fibres in 39 biopsies, with a mild to moderate excess of lipid. On ultrastructural examination, 35 of these specimens showed branching and fusion of mitochondrial cristae. Mitochondrial degeneration was obvious in 40 of the biopsies with swelling, vacuolation, myelin figures and secondary lysosomes. These abnormalities were in obvious contrast to control biopsies, where even mild changes were rarely detected. The findings described here provide the first evidence that PFS may be due to a mitochondrial disorder precipitated by a virus infection.

(This article is taken/available from the TCJRME website)

From Neurology to Mitochondia Richardson J, Costa DC. J CFS 1998, 4(3)

Initial considerations suggested that in the SPECT scans, the fields of hypoperfusion which were shown to be significant demonstrated localised areas with diminished metabolic requirements. This could be related to diminished cell function which occurred as a result of mitochondrial dysfunction, possibly due to viral infection. This has been well demonstrated by Behan and coworkers.

It should be noted that mitochondria, as the name implies, are the "nuclear power house" of the cell, from "mitosis" to "apoptosis." During cell life, this mitochondrial "power" results in the generation of energy in the form of ion gradients and ATP synthesis. Mitochondria mediate energy generation through the oxidation of food material which has passed through the blood-brain-barrier (BBB). To this end, mitochondria also contain the enzymes for the Krebs and other fatty acid cycles, and thus govern the respiratory cell pathway of oxygen. Therefore, mitochondrial dysfunction results in a decrease in cell respiration. For instance, abnormal carnitine metabolism in ME/CFS patients is one of the energy metabolic dysfunctions in mitochondria. Carnitine itself is an amino acid used for the transport of fatty acids across the cell membrane to the matrix, a process which is catalysed by the co-enzyme carnitine palmitoxyl transferase. The resulting decrease in oxidation is no doubt the reason for the lack of perfusion requirements demonstrated in the SPECT scans.

Mitochondria contain DNA and RNA by means of which they replicate. This relates to the development of cells with the formation of deutoplasm and a large increase in protoplasm and mitochondria, which leads to the formation and future function of specialised cells. Other physiological aspects that may underlie the SPECT abnormalities seen in ME/CFS should be considered, such as the anatomical divisions of the brain with enormous variations in function. The latter variations are seen in both the neuroneural and neurohormonal control of the whole body. Consideration should be given to the BBB, as this possibly has some effect on the means of access to the higher centres of viruses or toxins as well as normal nourishment, with the areas above the BBB being possibly more protected than those beneath. However, viruses and other material, e.g., toxins and certain drugs which are fat soluble, may pass this BBB.

(This article is taken/available from the TCJRME website)

See also: Relationship Between SPECT Scans and Buspirone Tests in Patients with ME/CFS John Richardson, MB, BS,  Durval Campos Costa, MD, MSc, PhD Journal of Chronic Fatigue Syndrome, Vol. 4(3) 1998 

Damaged Mitochondria and Intracellular Inclusions in Brain Biopsy W. John Martin Exp Mol Path 2003, 74;(3):197  (from a victim of the recent Arizona ME outbreak)

ABSTRACT. Unusual pigmented intracellular inclusions are commonly seen in cultures obtained from patients infected with stealth viruses. Some of these structures may potentially provide a source of chemical energy for the infected cells to help compensate for the apparent damage to the cells' mitochondria. They have accordingly been termed alternative cellular energy pigments (ACE pigments). In keeping with this suggestion, the present paper illustrates the diversity of extraneous materials present in vacuolated, mitochondria-damaged cells seen in the brain biopsy of a child with a stealth-virus-associated encephalopathy. (article includes many micrographs of virus damaged mitochondria )

(This article is taken/available from the TCJRME website)

See, Electron microscopy study of damaged mitochondria

Cheney on the Mitochondrial Damage Except of interview with Paul Cheney, MD, PhD Carol Sieverling Reports DFW CFIDS - 2001

Dr Cheney confirmed: that in CFS there is so much injury to the mitochondria that CFS could be called a mitochondrial disease. A Mitochondrial Encephalomyopathy. 

The main problem in CFIDS is cellular metabolic dysfunction. The body's cells have been damaged and are not able to function normally. Every cell in the body is affected.

The center of gravity of this disease is a disturbance of cell function that is best described as a mitochondrial dysfunction or energy production dysfunction, with an associated intracellular acidosis.

Cheney describes some specialized brain scans “It means mitochondrial encephalopathy [brain cell dysfunction caused by mitochondrial dysfunction]. It means the brain isn't working because there isn't enough mitochondrial function to provide energy for it to work.”

(This article is taken/available from the TCJRME website)

Cheney comments on Pathophysiology, see;

Medical Reports on the Muscles in ME compiled by Cesar Quintero

Preliminary determination of a molecular basis of chronic fatigue syndrome.  McGregor NR, Dunstan RH, Zerbes M, Butt HL, Roberts TK, Klineberg IJ Collaborative Pain Research Unit, University of Sydney, Westmead Hospital, NSW, Australia.Biochem Mol Med 1996 Apr;57(2):73-80 PMID: 8733884, UI: 96316008

Chronic fatigue syndrome (CFS/ME) is a debilitating fatigue illness that has an unknown etiology. We studied 20 chronic fatigue syndrome (CFS) patients, who complied with the Oxford and American CDC definitions, and 45 non-CFS subjects. Participants completed questionnaires, were clinically examined, and had first morning urine specimens collected, which were screened by gas chromatography-mass spectrometry for changes in metabolite excretion. Multivariate analysis of the urinary metabolite profiles differed significantly in the CFS patients compared to the non-CFS patients (P < 0.004).  The CFS patients had increases in aminohydroxy-N-methylpyrrolidine (P < 0.00003, referred to as chronic fatigue symptom urinary marker 1, or CFSUM1), tyrosine (P < 0.02), beta-alanine (P < 0.02), aconitic acid (P < 0.05), and succinic acid (P < 0.05) and reductions in an unidentified urinary metabolite, CFSUM2 (P < 0.0007), alanine (P < 0.005), and glutamic acid (P < 0.02). CFSUM1, beta-alanine, and CFSUM2 were found by discriminant function analysis to be the first, second, and third most important metabolites, respectively for discriminating between CFS and non-CFS subjects.  The abundances of CFSUM1 and beta-alanine were positively correlated with symptom incidence (P < 0.01 and P < 0.001, respectively), symptom severity, core CFS symptoms, and SCL-90-R somatization (P < 0.00001), suggesting a molecular basis for CFS.

Preliminary determination of the association between symptom expression and urinary metabolites in subjects with chronic fatigue syndrome. McGregor NR,  Dunstan RH,  Zerbes M,  Butt HL,  Roberts TK,  Klineberg IJ Collaborative Pain Research Unit, University of Sydney, Australia. Biochem Mol Med 1996 Jun;58(1):85-92 Publication Types: Clinical trial   PMID: 8809350, UI: 96405210

Chronic fatigue syndrome (CFS) patients have a urinary metabolite labeled CFSUM1 with increased incidence (P < 0.004) and relative abundance (P < 0.00003). The relative abundances of urinary CFSUM1 and beta-alanine were associated with alterations in metabolite excretion and symptom incidence. In 20 CFS patients and 45 non-CFS subjects, symptom/metabolite associations were investigated by assessing symptom sensitivity and specificity, and symptom indices of total symptom incidence, CFS core symptoms, cognitive, neurological, musculoskeletal, gastrointestinal, infection-related and genitourinary symptom indices, as well as a visual analogue pain scale of average pain intensity. Thirty-three symptoms had significant (P < 0.005) sensitivity and specificity in the CFS patients compared to that in the non-CFS controls. Severe fatigue was the only symptom with 100% sensitivity and specificity and CFSUM1 excretion was the primary metabolite for expression of this symptom. All nine symptom indices had elevated responses in the CFS patients (all P < 0.0000001). Multiple regression analyses indicated that all the symptom indices had significant correlations (R) with changes in the urinary excretion of metabolites (P < 0.0001). CFSUM1 and beta-alanine were the first and second metabolites correlated with the CFS core symptom index and CFSUM1 was primarily associated with infection-related and musculoskeletal indices whereas beta-alanine was primarily associated with gastrointestinal and genitourinary indices. The strong associations of CFSUM1 and beta-alanine with CFS symptom expression provide a molecular basis for developing an objective test for CFS.

Biochemical Abnormalities in Chronic Fatigue Syndrome Phillip Clifton Bligh 2, Suzanne Niblett 1, Leigh Hoskin 2, R Hugh Dunstan 1, Greg Fulcher 2, Neil McGregor 1,4, Julie Dunsmore 3, Timothy K Roberts 1, Henry L Butt 1, Katrina King 1, Iven Klineberg 4       

Chronic fatigue syndrome is defined as a disorder in which the subject has unexplained prolonged fatigue, often worse after minimal exercise, frequently associated with impaired sleeping, painful muscles, intermittently swollen lymph glands and impaired cognitive function. The pathogenesis has eluded explanation. The bioanalytical research group of the University of Newcastle has developed methodology for examining excretion of amino acids and organic acids into the urine. In collaboration with the Department of Endocrinology at the Royal North Shore Hospital, the overnight urine excretion rate of a number of amino acids and organic acids was measured in 100 patients with chronic fatigue syndrome, and in 83 age- and sex-matched normal controls.

The excretion rate of the metabolites was measured in units/minute. The most striking differences between patients with chronic fatigue syndrome and controls was a reduction in urine asparagine (p<0.0001) and a reduction in urine succinic acid (p<0.0003) in patients with chronic fatigue syndrome.

The excretion of urinary asparagine and succinic acid was highly correlated (p<0.00001). Urinary tyrosine (p<0.04) and urinary 3-methyl histidine (p<0.03) were significantly increased in patients with chronic fatigue syndrome. The urinary excretion of tyrosine, a protein catabolism marker, was associated with symptoms of fatigue, muscle pain, lymph node pain and cognitive disturbance.

The overnight excretion of succinic acid was correlated with the fasting plasma glucose (p<0.002). It is not known at present whether urine excretion rates of succinic acid and asparagine are correlated with serum concentrations of these metabolites or whether renal tubular function independently influences the urine excretion rates, and if so, whether renal tubular function is itself altered in chronic fatigue syndrome.

It is possible that urine asparagine excretion rates are low because of reduced entry of asparagine into the circulation, and thence into the urine. If the rate of entry of asparagine into the circulation is reduced, this could come about because of more rapid metabolism of asparagine in cells or because total body stores of asparagine are depleted. Further work is necessary to define these issues.

EVIDENCE FOR GLUTATHIONE DEFICIENCY IN CHRONIC FATIGUE SYNDROME Paul R Cheney MD, PhD conference presentation at London, April 1999

'Chronic Fatigue Syndrome has recently been linked to activation of a novel, low molecular weight (37 Kda) Rnase L (1). Such activity would be expected to significantly impair key enzyme systems important to human function. Recent studies have also suggested that xenobiotic toxicity plays a substantial role in the symptoms of chronic fatigue syndrome (2). Urinary xenobiotics which are likely of gut microbial origin, correlate with the severity of and types of symptoms associated with chronic fatigue syndrome. We will present evidence of impairment of glutathione synthesis and function in chronic fatigue syndrome. Dysfunction in this key detoxification system would be expected to cause portal circulation toxicity as well as other xenobiotic toxicity now reported for chronic fatigue syndrome.'

1. Suhadolnik, JR; Peterson, DL; O'Brien, K; Cheney PR et al. "Biochemical Evidences for a Novel Low Molecular Weight 2-SA-Dependent RnaseL in Chronic Fatigue Syndrome" Journal of lnterferon and Cytokine Research, 17:377-385 (1997)
2. McGregor, NR; Dunstan, RN et al. "Preliminary Determination of a Molecular Basis to Chronic Fatigue Syndrome" Biochemical and Molecular Medicine, 57:73-80 (1996)

Elevated apoptotic cell population in patients with chronic fatigue syndrome: the pivotal role of protein kinase RNA Vojdani A;  Ghoneum M;  Choppa PC;  Magtoto L;  Lapp CW Immunosciences Laboratory Inc., Beverly Hills, California, USA.J Intern Med  1997  Dec;242(6):465-78   (ISSN: 0954-6820) Unique NLM Identifier: 98100060

OBJECTIVES:  A prominent feature of chronic fatigue syndrome (CFS) is a disordered immune system.  Recent evidence indicates that induction of apoptosis might be mediated in a dysregulated immune system by the upregulation of growth inhibitory cytokines.  Therefore, the purpose of this study was to evaluate the apoptotic cell population, interferon-alpha (IFN-alpha) and the IFN-induced protein kinase RNA (PKR) gene transcripts in peripheral blood lymphocytes (PBL) of CFS individuals, as compared to healthy controls.   SUBJECTS AND METHODS: PBL were isolated from CFS (n = 29) and healthy control individuals (n = 15) and subjected to quantitative analysis of apoptotic cell population and cell cycle progression by flow cytometry.  Quantitative competitive polymerase chain reaction (Q/C PCR) and Western blot analysis were used to assess the levels of PKR mRNA and protein in control and CFS individuals.  In addition, circulating IFN-alpha was measured by ELISA assay.   RESULTS: Increased apoptotic cell population was observed in CFS individuals, as compared to healthy controls (26.6 +/- 12.9% and 9.9 +/- 4.2%, respectively).  The increased apoptotic subpopulation in CFS individuals was accompanied by an abnormal cell arrest in the S phase and the G2/M boundary of the cell cycle as compared to the control group (8.6 +/- 1.2 to 22.8 +/- 2.4 and 3.6 +/- 0.82 to 24.3 +/- 3.4, respectively).  In addition, CFS individuals exhibited enhanced PKR mRNA and protein levels (mean basal level 3538 +/- 1050 and 2.7 +/- 0.26, respectively) as compared to healthy controls (mean basal level 562 +/- 162 and 0.89 +/- 0.18, respectively).  In 50% of the CFS samples (n = 29) treated with 2-aminopurine (2-AP) (a potent inhibitor of PKR) the apoptotic population was reduced by more then 50%.   CONCLUSIONS: PKR-mediated apoptosis in CFS individuals may contribute to the pathogenesis and the fatigue symptomatology associated with CFS.