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Research Overview
There are over 6,000 peer-reviewed papers in existence which evidence the biomedical nature of myalgic
encephalomyelitis.
Multi-systemic pathophysiological consequences include immune and neuroendocrine abnormalities;
brain dysfunction and neurocognitive defects; cardiovascular and autonomic disturbances; abnormalities
in energy production including mitochondrial dysfunction; and changes in the expression of certain
genes.
These abnormal findings have been identified in patients studied:
1. Immune System Findings
 A shift towards a Th2 dominant immune response, with a preponderance of humoral over cell-mediated
immunity
 Immune activation with increased numbers of activated T lymphocytes, including cytotoxic T cells and
elevated circulating cytokines
 Poor cellular function with low natural killer cell cytotoxicity
 Dysregulation of the antiviral defense pathway 205A synthetase/RNase L, with an increase in low molecular
weight 37kDa RNaseL
 The occasional finding of low levels of antinuclear antibodies, low levels of rheumatoid factor, thyroid
antibodies and Lyme disease antibodies
 Fatigue and flu-like symptoms may be linked to elevated levels of various cytokines, including interferons
and interleukins. The dysregulation of the RNase L pathway supports the hypothesis that viral infection
may play a role in the pathogenesis of the illness
2. Brain Abnormalities
 Global reductions in gray matter and punctuated areas of high signal intensity (white spots) in the white
matter
 Decreased brain perfusion and glucose metabolism
 More areas of the brain recruited for processing incoming information as compared to controls
 Slower cerebral activity in response to motor and visual imagery tasks than in controls
 Increased ventricular lactate
 Reduced slow wave sleep and prolonged sleep latency
 Unique proteins found in cerebrospinal fluid
3. Cognitive Impairment
 Documented deficits include impaired working memory, slowed processing speed, poor learning of new
information, decreased concentration and attention span, difficulty with word retrieval and increased
distractibility.
 Cognitive functioning may be disrupted by over sensitivity to noise and light, multiple stimuli and/or fast
paced activity and even routine social interaction.
 Intense cognitive activity in itself can bring about diminished cognitive functioning as well as other postexertional symptoms in a manner similar to that caused by physical exercise.
4. Autonomic/Cardiovascular Disturbances
 Autonomic dysfunction, if present, is manifested by an inability to maintain an upright posture or feeling
faint or weak upon standing (orthostatic intolerance). In such cases, tilt table testing may show neutrally
mediated hypotension (NMH) or postural orthostatic tachycardia syndrome (POTS).
 Some patients with ME may complain of heart palpitations and show persistent tachycardia at rest. Holter
monitoring may reveal benign cardiac rhythm disturbances and non-specific T wave changes such as
repetitive oscillating T-wave inversions and/or T-wave flattening. Suspected diastolic dysfunction has
been documented in some patients using echocardiography. This diastolic dysfunction (improper
ventricular filling) may be due to a lack of energy at the cellular level.
 Low blood volume has also been found in some patients.
5. Neuroendocrine Dysregulation
 Mild hypocortisolism and attenuated diurnal variation of cortisol
 Reduced function of the HPA axis, which can affect adrenal, gonad and thyroid function
 Blunted DHEA response to ACTH injection despite normal basal levels
 Low IGF1 (somatomedin) levels and an exaggerated growth hormone response to pyridostigmine
 Increased prolactin response to buspirone
 A disturbance of fluid metabolism as evidenced by low baseline levels of arginine vasopressin
 Relatively lower levels of aldosterone in patients compared to controls
 Raised levels of neuropeptide Y (released in the brain and sympathetic nervous system following stress)
possibly linked to the dysfunction of the HPA axis. Neuropeptide Y levels in plasma have been correlated
with symptom severity.
6. Mitochondrial/Energy Production Abnormalities
Evidence for mitochondrial abnormalities includes:
 Mitochondrial myopathy
 Impaired oxygen consumption during exercise
 Activation of anaerobic metabolic pathways in the early stages of exercise
 Raised brain ventricular lactate levels
 With respect to exercise, a study on two consecutive days showed and abnormal recovery response (decline
in V02 max) on day two, suggesting impaired metabolic function.
7. Gene Studies
In recent controlled study two subgroups of patients were identified with gene expression changes following
exercise. The larger subgroup showed increases in mRNA for sensory and adrenergic receptors and a cytokine.
The smaller subgroup contained most of the patients with orthostatic intolerance and showed a post-exercise
decrease in adrenergic α-2A receptor gene expression.
8. Associated Infectious Agents
Viruses:
 Enterovirus
 Epstein Barr virus (EBV)
 Human Herpes virus (HHV 6 AND 7)
 Cytomegalovirus
 Parvovirus B19
Bacteria:
 Chlamydophila pneumonia
 Mycoplasma
 Coxiella burnettii
9. Post-Exertional Neuroimmune Exhaustion
Post-Exertional Neuroimmune Exhaustion (PENE) is characterised by a pathological low threshold of physical
and mental fatigability, exhaustion, pain and an abnormal exacerbation of symptoms in response to exertion. It
is followed by a prolonged recovery period.
Fatigue and pain are part of the body’s global protection response and are indispensable bioalarms that alert
patients to modify their activities in order to prevent further damage.
The underlying pathophysiology of PENE involves a profound dysfunction of the regulatory control network
within and between the nervous systems. This interacts with the immune and endocrine systems affecting
virtually all body systems, cellular metabolisms and ion transport. The dysfunctional activity/rest control system
and loss of homeostasis result in impaired aerobic energy production and an inability to produce sufficient
energy on demand.
 A test-retest cardiopulmonary exercise study revealed a drop of 22% in peak VO2 and 27% VO2 at AT on
the second day evaluation. Both submaximal and self-paced exercise resulted in PENE.
 These impairments and the loss of invigorating effects distinguish ME from depression.
10. Implications for Diagnosis and Nomenclature
The purpose of diagnosis is to provide clarity. Criterial symptoms, such as the distinctive abnormal responses to
exertion, can differentiate ME patients from those who are depressed or have other fatiguing conditions.
Myalgic encephalomyelitis, a name that originated in the 1950s, is the most accurate and appropriate name
because it reflects the underlying multi-system pathophysiology of the disease. The International Consensus
Criteria (ICC) panel strongly recommends that only the name 'myalgic encephalomyelitis’ is used to identify
patients meeting the ICC.
NOTE: Collectively the members of the ICC panel had - diagnosed and/or treated more than 50,000 ME
patients; gained more than 500 years of clinical experience, and a similarly substantial amount of teaching
experience; authored hundreds of peer-reviewed publications, as well as chapters and medical books.
NOTE: Many of the abnormalities identified are not unique to this illness, and may not have been found in all of
the patients studied. However they can and do provide important clues to pathophysiology in this disorder.
References:
International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A Primer for Clinical
Practitioners 2012
 Source for items 1-7
 Can be downloaded from the website www.iacfsme.org
Myalgic Encephalomyelitis - Adult & Paediatric: International Consensus Primer for Medical Practitioners 2012
 Source for items 8-10
 The International Consensus Criteria (ICC) were published in the Journal of Internal Medicine, Vol 270,
Issue 4, pgs 327-338 Oct 2011. The Primer for Physicians was featured in the Quarterly in I34, Winter
2012.
POST SCRIPT: Further Immune System Findings
Professor I Lipkin, Director, Centre for Infection and Immunity, Columbia Univ USA has stated on record that
those with myalgic encephalomyelitis have a particular pattern of immunoreactivity, indicating a persistent
disease process. In Sept 2012 he revealed that he had uncovered a huge amount of immune activation in
‘ME/CFS patients’ with two-thirds to three-quarters of patients exhibiting polyclonal B-cell activation.
This may help explain why B-cell depletion therapy has shown such remarkable results in people with severe
M.E.
Grateful Thanks to Lesley Scott and Carol Flack for assistance in putting together this article