A Hummingbirds' Guide to M.E.
Information on the neurological disease Myalgic Encephalomyelitis
M.E. (and ICD-CFS) Articles, Research and Books
Research topics: General Articles and Research Overviews, Immune System Research, Viral Research, Cardiac Research, Exercise Research, Muscle Research, Metabolic Research, Neurological and Cognitive Research, Genetic Research, Neuroendocrine Research, and Miscellaneous Research.
Article topics: The Definitions of M.E., On 'fatigue', CBT, GET and the unscientific 'behavioural' paradigm of M.E., On 'stress', M.E. Outbreaks, On the Name Myalgic Encephalomyelitis, M.E. and Other Illnesses, Children with M.E., The Severity of M.E., M.E. Fatalities, Activism Articles, Articles sorted by Author, Articles sorted by Country and Historical, Political and Medical Overviews.
Topic on this page: Enteroviral and Post Polio Syndrome Research, HHV6 Research, Stealth Virus Research, General Viral Research and Relevant Books - page 3 of 5
Enteroviral and Post-polio Research - continued
Post viral fatigue syndrome: persistence of enteroviral RNA in skeletal muscle and elevated creatine kinase. Archard LC, Bowles NE, Behan PO, Bell EJ, Doyle D. Journal of the Royal Society of Medicine 1988; 81: 326-9.
Abstract:
Enterovirus-specific probes have been prepared by reverse transcription of conserved sequences in purified Coxsackie B2 virus genomic RNA and molecular cloning techniques. These probes were used in quantitative slot blot hybridizations to test for the presence of enterovirus-specific RNA in skeletal muscle biopsy specimens from 96 patients who had suffered from the postviral fatigue syndrome myalgic encephalomyelitis for up to 20 years. Biopsy specimens from 20 patients were positive for the presence of virus-specific RNA with hybridization signals more than three standard deviations greater than the mean of the normal muscle controls. Biopsies from the remaining 76 patients were indistinguishable from the controls. These data show that enterovirus RNA is present in skeletal muscle of some patients with postviral fatigue syndrome up to 20 years after onset of disease and suggest that a persistent virus infection has an aetiological role.Enteroviruses and postviral fatigue syndrome. Behan PO, Behan WM, Gow JW, Cavanagh H, Gillespie S. Ciba Foundation Symposium 1993; 173: 146-54.
Abstract:
Postviral fatigue syndrome (PFS) occurs both in epidemics and sporadically. Many of the original epidemics were related to poliomyelitis outbreaks which either preceded or followed them. The core clinical symptoms are always the same: severe fatigue made worse by exercise, myalgia, night sweats, atypical depression and excessive sleep. The other common symptoms include dysequilibrium disorders and irritable bowel syndrome. We have detected enteroviral genome sequences in muscle biopsies from cases of PFS, using specific enteroviral oligonucleotide primers in the polymerase chain reaction (PCR). In addition, whole virus particles can be demonstrated in PCR-positive muscle, using solid-phase immuno-electron microscopy. An increase in the number and size of muscle mitochondria was found in 70% of PFS cases, suggesting an abnormality in metabolic function. Evidence of hypothalamic dysfunction was present, particularly involving 5-hydroxytryptamine metabolism. A putative model of PFS, based on persistent enteroviral infection in laboratory mice, revealed resolving inflammatory lesions in muscle with, however, a marked increase in the production of certain cytokines in the brain. This model may help to explain the pathogenesis of PFS.Persistence of enterovirus RNA in muscle biopsy samples suggests that some cases of chronic fatigue syndrome result from a previous, inflammatory viral myopathy. Bowles NE, Bayston TA, Zhang HY, Doyle D, Lane RJ, Cunningham L, Archard LC. The Journal of Medicine 1993; 24(2-3): 145-60.
Abstract:
Molecular hybridization using an enterovirus group specific probe detected virus RNA in muscle biopsy samples from 25 of 96 cases of inflammatory muscle disease and similarly from 41 of 158 cases of postviral fatigue syndrome (PFS). Enterovirus RNA was detected in only two of 152 samples of control muscle. The inflammatory myopathy group comprised patients with polymyositis (PM), juvenile dermatomyositis (JDM) or adult dermatomyositis (DM), and all showed the presence of an inflammatory infiltrate and fiber necrosis on histological examination of a muscle biopsy sample. In contrast, muscle samples from the PFS group were histologically normal except for non-specific changes such as occasional single fiber atrophy. By analogy with enteroviral myocarditis, which can progress to a post-inflammatory disease with persistence of virus in myocardium and disposes to the rapid development of dilated cardiomyopathy, we propose that PFS syndrome may be a sequela of a previous inflammatory viral myopathy.Detection of enterovirus-specific RNA in serum: the relationship to chronic fatigue. Clements GB, McGarry F, Nairn C, Galbraith DN. Journal of Medical Virology 1995; 45(2): 156-61.
Abstract: The serum of 88 chronic fatigue patients was screened for enteroviral specific sequences by polymerase chain reaction (PCR) assay. The PCR method used was "nested" PCR targetting the 5' nontranslated region of the enteroviral genome which yielded a final fragment length of 264 base pairs. Samples were obtained from patients during 1990-1991. In addition, buffy coat specimens and stool specimens were examined in some patients. Samples from two cohorts of comparison individuals were also obtained. The comparison groups were firstly, acutely ill individuals with symptoms consistent with a presumed enteroviral infection (matched by age, sex, and date of receipt of specimen) and secondly, healthy individuals (matched by age and date of receipt of specimen). Enteroviral specific sequences were detected in 36 of 88 serum samples from chronic fatigue patients, 22 of 82 acutely ill individuals, and 3 of 126 healthy individuals. The enteroviral PCR positivity did not correlate with any one particular feature of chronic fatigue nor did it reflect any history of illness at onset of fatigue, duration of fatigue, or age of patient. These results provide new evidence for the presence of enteroviral specific sequences in serum, buffy coat, and stool samples in many patients with chronic fatigue. This may reflect a persistent enterovirus infection in a proportion of chronic fatigue patients.
Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA. Cunningham L, Bowles NE, Lane RJ, Dubowitz V, Archard LC. Journal of General Virology 1990; 71 (6): 1399-402.
Abstract:
A subgenomic restriction fragment from cDNA prepared from Coxsackie B2 virus (CVB2) RNA was subcloned into a riboprobe vector allowing the production of enteroviral group-specific RNA probes complementary to either the positive (genomic) or negative (template) strand of enteroviral RNA. These riboprobes were used to follow productive infection of cultured cells by CVB2; as expected, positive strand RNA was synthesized in approximately 100-fold excess over negative strand. RNA was extracted from muscle biopsy samples from patients with chronic fatigue syndrome and probed for the presence of enteroviral RNA. In cases where enteroviral RNA was detected the amounts of positive and negative strands of enteroviral RNA were approximately equal, in contrast to the situation in lytic infection of cultured cells. This suggests that enterovirus persistence in muscle is due to a defect in control of viral RNA synthesis.Evidence for enteroviral persistence in humans. Galbraith DN, Nairn C, Clements GB. Journal of Genenal Virology 1997; 78(2): 307-12.
Abstract:
We have sought evidence of enteroviral persistence in humans. Eight individuals with chronic fatigue syndrome (CFS) were positive for enteroviral sequences, detected by PCR in two serum samples taken at least 5 months apart. The nucleotide sequence of the 5' non-translated region (bases 174-423) was determined for each amplicon. Four individuals had virtually identical nucleotide sequences ( > 97%) in both samples. The sequence pairs also each had a unique shared pattern indicating that the virus had persisted. In one individual (HO), it was clear that there had been infection with two different enteroviruses. In the remaining three individuals, the lack of unique shared features suggested that re-infection had occurred, rather than persistence. With the exception of HO, the sequences fell into a subgroup that is related to the Coxsackie B-like viruses.Phylogenetic analysis of short enteroviral sequences from patients with chronic fatigue syndrome. Galbraith DN, Nairn C, Clements GB. Journal of General Virology 1995; 76: 1701-1707.
Abstract:
This study used phylogenetic analysis based on a region of the 5' non-translated region (5'NTR) of a variety of enteroviral sequences to compare sequences associated with chronic fatigue syndrome (CFS) and those from enteroviruses causing acute infections. Direct sequencing of PCR products was used to obtain the nucleic acid sequences from CFS patients. The inferred phylogenetic tree identified three groupings, one correlating with the diagnosis of CFS. The analysis identified a close relationship between the chronic fatigue enteroviral sequences, and showed that 19/20 were distinct from previously described enteroviruses. These results suggest there is persistence of enterovirus infection in some CFS patients and indicate the presence of distinct novel enterovirus sequences.Enteroviral RNA sequences in muscle in patients with chronic fatigue syndrome. Gow RJ, Behan PO. British Medical Journal 1991; 302: 692-6.
Abstract:
OBJECTIVE-To determine the presence of enteroviral sequences in muscle of patients with the postviral fatigue syndrome. DESIGN-Detection of sequences with the polymerase chain reaction in a well defined group of patients with the syndrome and controls over the same period. SETTING-Institute of Neurological Sciences, Glasgow. SUBJECTS-60 consecutive patients admitted to the institute with the postviral fatigue syndrome who had undergone extensive investigation to exclude other conditions. 41 controls from the same catchment area without evidence of fatigue, all undergoing routine surgery. MAIN OUTCOME MEASURES-Routine investigations, serological screen for antibodies to a range of viruses, and presence of enteroviral RNA sequences in muscle biopsy specimens. RESULTS-15 (25%) patients and 10 (24.4%) controls had important serological findings. 12 patients had neutralising antibody titres of greater than or equal to 256 to coxsackieviruses B1-5 (six positive for enteroviral RNA sequences, six negative); three were positive for Epstein-Barr virus specific IgM (two positive, one negative). Six controls had similar neutralising antibody titres to coxsackieviruses (all negative); one was positive for Epstein-Barr virus specific IgM (negative); and three had titres of complement fixing antibody greater than or equal to 256 to cytomegalovirus (all negative). Overall, significantly more patients than controls had enteroviral RNA sequences in muscle (32/60, 53% v 6/41, 15%; odds ratio 6.7, 95% confidence interval 2.4 to 18.2). This was not correlated with duration of disease, patient and age, or to raised titres of antibodies to coxsackieviruses B1-5. CONCLUSIONS-Persistent enteroviral infection of muscle may occur in some patients with postviral fatigue syndrome and may have an aetiological role.Are echoviruses still orphans? Hill WM. British Journal of Biomedicine Science 1996; 53(3): 221-6.
Abstract:
A review of some of the outbreaks of disease caused by echoviruses demonstrates their ability to cause significant morbidity and mortality world-wide. There are now 30 recognised echovirus serotypes; several of the original serotypes have been re-classified. More recently, echovirus 22 has been shown to have significant molecular differences from other types and unusual epidemiological features. Echovirus types 7, 11, 19 and 30 have been associated with significant outbreaks in neonatal units and echovirus types 9, 16 and 25 are more frequently associated with exanthem. Echovirus type 3, although relatively uncommon in the UK, was associated with large outbreaks in China. Since the decline in poliomyelitis, the increase in reports of non-polio enteroviruses has revealed a corresponding increase in associated cases of myalgic encephalomyelitis and post-viral fatigue syndrome.Disturbance of hypothalamic function and evidence for persistent enteroviral infection in patients with chronic fatigue syndrome. Richardson J. Journal of Chronic Fatigue Syndrome 1995; 1(2): 59-66.
Abstract:
It has been suggested that one of the major effects of persistent virus infections in the production of disorders such as the chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is on the hypothalamus (1). Buspirone, which is one of the anxiolytic drugs of the azapyrone group, causes a release of prolactin by stimulation of serotonin 5-hydroxytryptamine (5-HT) receptors. The buspirone-prolactin response was studied in a subgroup of patients with CFS/ME and evidence of persistent enteroviral infection, as shown by the repeated detection of the group-specific protein of enteroviruses, VP1, in the blood. Family controls who were asymptomatic were studied at the same time. In addition to the response to buspirone, diurnal variations in cortisol and prolactin levels were studied. It was found that the patients with CFS/ME had much greater rises in prolactin levels one hour after buspirone compared to controls. Cortisol levels were elevated in the patients, but the rise was not significantly different between the two groups. There was a significant association between the pattern of sleep disturbance, which we speak of as the OWL syndrome, and the ratio of pre- and post-buspirone prolactin levels. This study shows that there is a hypothalamic disturbance in the patients who also had evidence of enteroviral infection as part of the disorder of CFS/ME. It represents a quantifiable biochemical alteration to be found in this group of patients.Chronic enterovirus infection in patients with postviral fatigue syndrome. Yousef G, Bell E, Mann G, et al. Lancet 1988; 1: 146-50.
Abstract:
76 patients with the postviral fatigue syndrome (PVFS) and 30 matched controls were investigated. Virus isolation was attempted from concentrated faecal samples by direct culture and after acid dissociation of virus from antibody. Positive cultures of enteroviruses were obtained from 17 (22%) patients and 2 (7%) controls. An enterovirus-group-specific monoclonal antibody, 5-D8/1, directed against the VP1 polypeptide, was used to detect enteroviral antigen in the circulation, either free or complexed with antibody. VP1 antigen was detected in the serum of 44 (51%) of a further group of 87 PVFS patients. The number of patients positive for VP1 antigen was greater (42/44) when IgM complexes were detectable than when they were no (2/23). 1 year later, the 17 patients of the first group of 76 with positive cultures were again studied. The same virus was again isolated from 5 (29%), 13 (76%) had detectable IgM responses to enteroviruses, and 9 (53%) were positive from VP1 antigen in the serum. These results show that chronic infection with enteroviruses occurs in many PVFS patients and that detection of enterovirus antigen in the serum is a sensitive and satisfactory method for investigating infection in these patients.CFS May Be Result of Childhood Non-paralytic Polio Infection A layperson-accessible introductory article on this subject by Dr. Richard Bruno appears on-line at www.polionet.org/pen&ink/PI33-Sum00.htm#Childhood in "Pen and Ink," an E-zine of the Polio Experience Network.
Some excerpts and notes:
"A childhood poliovirus infection may cause chronic fatigue in baby-boomers concludes a paper published in the January, 11, 2000, issue of the American Journal of Physical Medicine and Rehabilitation "Paralytic Versus 'Non-Paralytic' Polio: A Distinction without a Difference," by Dr. Richard L. Bruno, director of The Post-Polio Institute at New Jersey's Englewood Hospital and Medical Center and chairperson of the International Post-Polio Task Force." Dr. Bruno notes that L. Jason's recent CFS prevalence study, published in the October 11, 1999 issue of Archives of Internal Medicine (available on-line at: www.archinte.ama-assn.org/issues/v159n18/full/ioi90161.html), found that baby-boomers have a higher incidence of CFS:
"Potentially half of those diagnosed today with CFS may in fact have had Summer Grippe or undiagnosed non-paralytic polio as children in the years before the polio vaccine became available," said Dr. Bruno. "They may also have brain activating system damage that causes chronic fatigue [syndrome]."
*O* The Late Effects Of M.E. - Can they be distinguished from the Post-Polio Syndrome? by Dr Elizabeth Dowsett
"The number likely to be affected by the post-polio syndrome has been calculated as between 200-270/100,000 currently[7], but no account has been taken of survivors from non-paralytic polio which could easily double that figure. Possible costing for ME support has been based on 3 times the cost of maintenance for multiple sclerosis on the supposition that ME is 3 times as common[4]. The only costs that we can be sure of are those derived from the failure of appropriate management, and of inappropriate assessments which waste vast sums of money and medical time while allowing patients to deteriorate unnecessarily.[16]
Research workers must be encouraged and appropriately funded to work in this field. However they should first be directed to papers published before 1988, the time at which all specialised experience about poliomyelitis and associated infections seem to have vanished mysteriously![11,12,13]"
*O* A Rose By Any Other Name by Dr Elizabeth Dowsett
Both the earliest definition (HOLMES et al, 1988) and its revision (FUKUDA, 1994) elevated tonsillitis, glandular enlargement and fatigue to unreal importance while overlooking the characteristic encephalitic features of the genuine illness. These mistakes also inflated the possibility of a psychiatric diagnosis, leading to the incorporation of such a heterogeneous population of psychiatric and non-psychiatric causes later on, that research groups of different persuasions were unable to compare results or evaluate treatment.
The tools we can use today to study the brain offer possibilities which were unimaginable 50 years ago2. These include Molecular Biology: for example PCR – a microbiological technique capable of amplifying and identifying minute fragments of viral genes, hidden away in internal organs (such as brain, heart or muscle 3) while a test for rapid diagnosis (within five hours) is currently available. These tests indicate that viruses from the polio group, or related to it, are involved both in the late effects of ME and the Post Polio Syndrome 4. Brain Imaging: the use of CT, MRI, SPECT and PET scans clearly indicates that metabolic dysfunction in the brain stem and the spinal nerve radiations which transverse it, are initially associated with viral (inflammatory) damage and are the major cause of the cardinal symptoms of ME – central fatigue, stress induced weakness, autonomic nervous dysfunction and the breakdown of homoeostasis over hormonal and other vital functions5.
National ME / FM Action Network's 1st Annual Symposium on Parallels Between Post-Polio Sequelae, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. June 15, 2002
Dr. Dowsett believes that the polio vaccine made room for other polio-like viruses (from the family of viruses called enteroviruses) to take over. According to Dr. Dowsett's research and other work, these other viruses may even hit some parts of the brain harder than in polio, judging by the brain fatigue and research on the ME/CFS brain. So, even if people with ME/CFS don't have paralysis and get as physically weak as people who had polio, they may be even more impaired in other ways. This has VERY IMPORTANT implications for assessment of disability and for treatment.
Important Treatment Information Dr. Bruno says pacing, NOT cognitive behavioural therapy and NOT graded exercise, is the cornerstone of treatment for people with PPS and ME/CFS. The key message is that people with ME/CFS and PPS have demonstrated brain stem dysfunction. This explains a multitude of symptoms because the brain stem controls so many physical and mental processes. Dr. Dowsett supports this view As the Canadian Newsletter `Quest` reports, both Dr Dowsett`s and Dr Bruno`s presentations are amazing, Dr Dowsett tells of her work throughout the years on ME/CFS linking it up with the Post Polio Sequelae. Dr Bruno, himself a paraplegic after Polio, is admirable in his determination to get over to people the effects of PPS, ME/CFS. and what can be done to allow people to help themselves improve their quality of life.
Pleconaril - A New Drug For Enteroviral Infections by Dr Elizabeth Dowsett
If the American multicentre placebo controlled randomised trial of PLECONARIL in neonatal disease is successful, what a chance we have to treat, stop and prevent enteroviral illness now! Please talk to your MP as soon as possible about why similar studies are not being carried out within the UK despite large amounts of money being provided!!
Polioencephalitis and the brain fatigue generator model of post-viral fatigue syndromes. Bruno RL, Frick NM, Creange S, Zimmerman JR, Lewis T. Journal of Chronic Fatigue Syndrome 1996; 2(2/3): 5-27.
Abstract: Fatigue is the most commonly reported and most debilitating Post-Polio Squelae (PPS), affecting millions of polio survivors world-wide. Post-polio fatigue is associated with: (1) subjective reports of difficulty with attention, cognition, word-finding and maintaining wakefulness; (2) clinically significant deficits on neuropsychological tests of information processing speed and attention; (3) gray and white matter hyperintensities in the reticular activating system on magnetic resonance imaging of the brain; (4) neuroendocrine evidence of impaired activation of the HPA axis. Many of these findings are identical to those documented following a variety of viral encephalitides, including acute poliovirus infection, lethargic encephalitis, Iceland Disease, myalgic encephalomyelitis, and, most recently, Chronic Fatigue Syndrome. The clinical, historic, neuropsychologic, neuroanatomic and physiologic parallels between poliovirus infection, post-polio fatigue and post-viral fatigue syndromes (PVFS) will be explored in an attempt to describe the pathophysiology of PVFS. The disinhibition of a putatitve Brain Fatigue Generator will be implicated as a cause of the subjective symptoms and objective signs that accompany PVFS. The results of a pilot placebo-controlled study of a dopamine 2 receptor agonist to treat post-polio fatigue will also be described.
Chronic fatigue, fainting and autonomic dysfunction: further similarities between post-polio fatigue and chronic fatigue syndrome? Bruno RL. Journal of Chronic Fatigue Syndrome 1997; 3(3): 109-116.
Abstract: To test the hypothesis that fatigue and fainting occur together, 1,047 polio survivors and 419 non-disabled control subjects were asked about the frequency and cause of fainting and asked to rate their typical daily fatigue severity. Fatigue severity was significantly higher in polio survivors as compared to controls, and in both polio survivors and controls who had fainted, as compared to those who had not. Daily fatigue severity also increased in both groups as the number of lifetime faints increased. Fatigue was significantly higher in controls who fainted one time and three times as compared to controls who had never fainted. Daily fatigue severity was significantly higher in polio survivors who had fainted three, four and five times as compared to those who had never fainted. These findings suggest a physiological relationship between fatigue and fainting, possibly attributable to the close proximity of cardiovascular regulation and brain activation centers within the brain stem. Fatigue and hypotension in patients with chronic fatigue syndrome and in polio survivors with late-onset fatigue may result from damage to brain stem and hypothalamic neurons.
