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Carruthers, Bruce M, MD, CM, FRCPC; clinician: internal medicine with focus on ME
Independent, Vancouver, British Columbia, Canada
van de Sande, Marjorie I, BEd; educator
Independent, Calgary, Alberta, Canada
De Meirleir, Kenny L, MD, PhD; clinician and researcher: physiology & medicine
Professor: Physiology and Medicine, Vrije Universiteit Brussel, Belgium
Director: Himmunitas Foundation, Brussels, Belgium
Klimas, Nancy G, MD; clinician and researcher: microbiology, immunology, allergy
Professor of Medicine and Director: Institute for Neuro-Immune Medicine, Nova Southeastern University,
Ft. Lauderdale-Davie, Florida
Director: GWI and CFS/ME Research Center, Miami Veterans Affairs Medical Center, Miami, Florida, USA
Broderick, Gordon, PhD; researcher: systems biology, mathematical immunology, computational genomics –
ME, CFS, Gulf War Illness (GWI)
Associate Professor: Pulmonary Medicine, Faculty of Medicine & Dentistry, University of Alberta, Edmonton,
Alberta, Canada
Mitchell, Terry, MA, MD, FRCPath; clinician: internal medicine - pathophysiology and haematology
Retired clinical haematologist with 28 years of experience of ME and chronic fatigue syndrome, Suffolk, UK
Staines, Don, MBBS, MPH, FAFPHM, FAFOEM; public health medicine, occupational and environmental medicine,
researcher
Public Health Physician: Gold Coast Public Health Unit, Robina, Queensland
Associate professor: Faculty of Health Sciences and Medicine, Bond University, Robina, Queensland
Faculty of Medicine, Griffith University, Southport, Queensland, Australia
Powles, A C Peter, MBBS, FRACP, FRCPC, ABSM; clinician: internal medicine: sleep medicine, respirology
Professor Emeritus: Division of Respirology, Department of Medicine, McMaster University, Hamilton, Ontario
Sleep Disorders Consultant: St. Joseph's Healthcare Hamilton, Ontario, Canada
Diplomate: American Board of Sleep Medicine
Speight, Nigel, MA, MB, BChir, FRCP, FRCPCH, DCH; paediatrics
Retired clinical paediatrician with many years of experience of ME and chronic fatigue syndrome.
Durham, United Kingdom
Vallings, Rosamund, MNZM, MB, BS, MRCS, LRCP; clinician: primary care with focus on ME
Howick, New Zealand
Bateman, Lucinda, MS, MD; clinician: internal medicine with focus on ME & FM
Fatigue Consultation Clinic, Salt Lake City
Utah hospital affiliation: Salt Lake Regional Medical Center
Adjunct Instructor: Departments of Anesthesiology and Family and Preventive Medicine, University of Utah,
Salt Lake City, Utah, USA
Bell, David S, MD, FAAP; clinician and researcher: paediatrics
Retired clinical paediatrician with many years of experience of ME and CFS, Lyndonville, New York
Department of Pediatrics, State University of New York, (SUNY – Buffalo) New York, USA
Authors and their affiliations are continued on the back inside cover.
MYALGIC ENCEPHALOMYELITIS – Adult & Paediatric:
International Consensus Primer for Medical Practitioners
Authors - International Consensus Panel: Carruthers BM, van de Sande MI, De Meirleir KL,
Klimas NG, Broderick G, Mitchell T, Staines D, Powles ACP, Speight N, Vallings R, Bateman L,
Bell DS, Carlo-Stella N, Chia J, Darragh A, Gerken A, Jo D, Lewis D, Light AR, Light K, MarshallGradisnik S, McLaren-Howard J, Mena I, Miwa K, Murovska M, Steven S
Co-Editors: Carruthers B. M. & van de Sande M. I.
© Copyright 2012: Carruthers & van de Sande
This primer is a not-for-profit educational document.
In our efforts to enhance the understanding of ME and promote international consistency in optimal
clinical identification and treatment, this booklet may be downloaded, posted on websites, and
reprinted providing ALL of the following conditions are met:
1. This booklet must be posted, translated, or reprinted in its entirety, with no abbreviations,
additions, deletions, or changes in text and content including the inside and outside covers, in
any manner whatsoever.
2. The authorship information is retained and credited as the source.
3. No profit can be made by any individual, organization, company, university, or otherwise.
4. Translations must be reviewed by a medical doctor/expert for medical accuracy of translation.
5. A copy of any translation must be sent to Marj van de Sande at [email protected] Translations
will be shared with others.
The preparation of this work has been undertaken with great care to publish reliable data and current
information. Where published studies are lacking, recommendations are based on the consensus of the panel.
However, the authors are not responsible for any errors contained herein or for consequences that may ensue
from use of materials or information contained in this work. This work does not endorse any commercial
product.
The National Library of Canada Cataloguing-in-Publication Data:
Myalgic Encephalomyelitis – Adult & Paediatric: International Consensus Primer for Medical
Practitioners.
ISBN 978-0-9739335-3-6
Publishers: Carruthers & van de Sande
Correspondence to: Dr. Bruce M. Carruthers: [email protected]
4607 Blenheim Street, Vancouver, British Columbia V6L 3A3, Canada
Inquiries regarding reprinting the primer to:
Marj van de Sande: [email protected]
151 Arbour Ridge Circle NW, Calgary, Alberta T3G 3V9, Canada
Cover
Credits: brain - © Unlisted Images/Fotosearch.com; spinal cord – LifeART image copyright 2012 Wolters Kluwer
Health, Inc. - Lippincott Williams & Wilkins. All rights reserved; viruses - © Fotosearch.com
Funding
This Primer is free of sponsorship. All authors contributed their time and expertise on a voluntary basis and no
one received any payment or honorarium.
MYALGIC ENCEPHALOMYELITIS – Adult & Paediatric:
Development of the International Consensus Primer for Myalgic Encephalomyelitis (ME)
An International Consensus Panel, consisting of clinicians, research investigators, teaching faculty, and an independent
educator, represent diverse backgrounds, medical specialities and geographical regions. Collectively, the members of the
panel have:
• diagnosed and/or treated more than 50 000 patients who have ME;
• more than 500 years of clinical experience;
• approximately 500 years of teaching experience;
• authored hundreds of peer-reviewed publications, as well as written chapters and medical books; and
• several members have co-authored previous criteria.
Panel members contributed their extensive knowledge and experience to the development of the International Consensus
Criteria and this Primer. In addition, an International Symptom Scale will be developed to complement the criteria and
promote clearer identification of patients for research studies.
Primer Consensus: The authors, representing twelve countries, reached 100 % consensus through a Delphi-type process.
International Consensus Criteria (ICC)
Problem
The label ‘chronic fatigue syndrome’ (CFS), coined in the 1980s, has persisted due to lack of knowledge of its etiologic
agents and pathophysiology. Misperceptions have arisen because the name ‘CFS’ and its hybrids ME/CFS, CFS/ME and
CFS/CF have been used for widely diverse conditions. Patient sets can include those who are seriously ill with ME, many
bedridden and unable to care for themselves, to those who have general fatigue or, under the Reeves criteria, patients are
not required to have any physical symptoms. There is a poignant need to untangle the web of confusion caused by mixing
diverse and often overly inclusive patient populations in one heterogeneous, multi-rubric pot called ‘chronic fatigue
syndrome’. We believe this is the foremost cause of diluted and inconsistent research findings, which hinders progress,
fosters scepticism, and wastes limited research monies.
Solution
The rationale for the development of the ICC was to utilize current research knowledge to identify objective, measurable
and reproducible abnormalities that directly reflect the interactive, regulatory components of the underlying
pathophysiology of ME. Specifically, the ICC select patients who exhibit explicit multi-systemic neuropathology, and have
a pathological low threshold of physical and mental fatigability in response to exertion. Cardiopulmonary exercise testretest studies have confirmed many post-exertional abnormalities. Criterial symptoms are compulsory and identify
patients who have greater physical, cognitive and functional impairments. The ICC advance the successful strategy of the
Canadian Consensus Criteria (CCC) of grouping coordinated patterns of symptom clusters that identify areas of pathology.
The criteria are designed for both clinical and research settings.
1. Name: 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. Our panel strongly recommends that
only the name ‘myalgic encephalomyelitis’ be used to identify patients meeting the ICC because a distinctive disease
entity should have one name. Patients diagnosed using broader or other criteria for CFS or its hybrids (Oxford, Reeves,
London, Fukuda, CCC, etc.) should be reassessed with the ICC. Those who fulfill the criteria have ME; those who do not
would remain in the more encompassing CFS classification.
2. Remove patients who satisfy the ICC from the broader category of CFS. The purpose of diagnosis is to provide clarity.
The criterial symptoms, such as the distinctive abnormal responses to exertion can differentiate ME patients from
those who are depressed or have other fatiguing conditions. Not only is it common sense to extricate ME patients
from the assortment of conditions assembled under the CFS umbrella, it is compliant with the WHO classification rule
that a disease cannot be classified under more than one rubric. The panel is not dismissing the broad components of
fatiguing illnesses, but rather the ICC are a refinement of patient stratification. As other identifiable patient sets are
identified and supported by research, they would then be removed from the broad CFS/CF category.
(Continued on page iv)
ii
International Consensus Panel
International Consensus Primer for Medical Practitioners
TABLE OF CONTENTS
INTRODUCTION ..................................................................................................................................................... 1
Myalgic Encephalomyelitis ................................................................................................................................ 1
Classification ...................................................................................................................................................... 1
Epidemiology ..................................................................................................................................................... 1
Prevalence ..................................................................................................................................................... 1
Prognosis ........................................................................................................................................................ 1
Etiology............................................................................................................................................................... 1
Predisposing Factors ...................................................................................................................................... 1
Precipitating Events and Causal Factors.......................................................................................................... 2
ME Phases ..................................................................................................................................................... 2
PATHOPHYSIOLOGY .............................................................................................................................................. 2
Post-Exertional Neuroimmune Exhaustion ........................................................................................................ 2
Neurological Abnormalities ................................................................................................................................ 4
Immune Impairments ........................................................................................................................................ 5
Energy Production and Ion Transport Impairments ........................................................................................... 6
PERSONALIZED ASSESSMENT AND DIAGNOSIS ...................................................................................................... 6
International Consensus Criteria ........................................................................................................................ 6
Clinical Application Principles ............................................................................................................................ 9
Personalized Clinical Assessment and Diagnostic Worksheet for ME ............................................................... 10
PERSONALIZED MANAGEMENT AND TREATMENT .............................................................................................. 13
Goals ................................................................................................................................................................ 13
Guidelines ........................................................................................................................................................ 13
Medication Principles and Caveats .................................................................................................................. 13
Basic ‘Rs’ of Personalized Treatment ............................................................................................................... 13
Revise Life-Style: Self-Help Strategies .......................................................................................................... 14
Education and Personal Development ..................................................................................................... 14
Maximizing Sleep ..................................................................................................................................... 14
Nutrition, Diet and Hydration .................................................................................................................. 14
Energy Budget/Bank ................................................................................................................................ 15
Remove Pathogens, Toxins and Heavy Metals ............................................................................................. 16
Replenish Nutrients, Restore Homeostasis and Relieve symptoms .............................................................. 16
Neurological ............................................................................................................................................. 17
Immune and Gastro-Intestinal ................................................................................................................. 18
Energy Metabolism and Ion Transportation ............................................................................................. 18
Other Symptoms ...................................................................................................................................... 18
Reassessment – Regular Ongoing Follow-Up ................................................................................................ 19
Paediatric Treatment Considerations ............................................................................................................... 19
Considerations for the Child’s Education .................................................................................................... 19
Other Considerations ....................................................................................................................................... 19
Pregnancy and Raising a Child ..................................................................................................................... 19
Surgery ....................................................................................................................................................... 20
Immunization ............................................................................................................................................. 20
Blood Donations ......................................................................................................................................... 20
Medical Documentation .............................................................................................................................. 20
Exciting Research ............................................................................................................................................. 20
REFERENCES ......................................................................................................................................................... 21
APPENDICES
International Consensus Criteria – Short Form ................................................................................................ 25
Sleep and Pain Profile ..................................................................................................................................... 26
Letter to educators and agencies regarding young people with myalgic encephalomyelitis ........................... 27
Editors: Carruthers & van de Sande
iii
MYALGIC ENCEPHALOMYELITIS – Adult & Paediatric:
(Continued from page ii)
3. Research on ME: The logical way to advance science is to select a relatively homogeneous patient set that can be
studied to identify biopathological mechanisms, biomarkers and disease process specific to that patient set, as well as
comparing it to other patient sets. It is counterproductive to use inconsistent and overly inclusive criteria to glean
insight into the pathophysiology of ME if up to 90% of the research patient sets may not meet its criteria (Jason 2009).
Research on other fatiguing illnesses, such as cancer and multiple sclerosis (MS), is done on patients who have those
diseases. There is a current, urgent need for ME research using patients who actually have ME.
4. Research confirmation: When research is applied to patients satisfying the ICC, previous findings based on broader
criteria will be confirmed or refuted. Validation of ME being a differential diagnosis, as is multiple sclerosis (MS), or a
subgroup of chronic fatigue syndrome, will then be verified.
5. Focus on treatment efficacy: With enhanced understanding of biopathological mechanisms, biomarkers and other
components of pathophysiology specific to ME, more focus and research emphasis can target expanding and
augmenting treatment efficacy.
International Consensus Primer (ICP)
Problem
Overly inclusive criteria have created misperceptions, fostered cynicism and have had a major negative impact on how ME
is viewed by the medical community, patients, their families, as well as the general public. Some medical schools do not
include ME in their curriculum with the result that very significant scientific advances and appropriate diagnostic and
treatment protocols have not reached many busy medical practitioners. Some doctors may be unaware of the complexity
and serious nature of ME. Patients may go undiagnosed and untreated; they may be shunned or isolated.
Solution
The ICP was written to provide clinicians a one-stop, user-friendly reference for ME. It includes a concise summary of
current pathophysiological findings upon which the ICC are based. A comprehensive clinical assessment and diagnostic
worksheet enables clear and consistent diagnosis of adult and paediatric patients world-wide. The treatment and
management guidelines offer a blueprint for a personalized, holistic approach to patient care, and include nonpharmaceutical and pharmaceutical suggestions. Patient self-help strategies provide recommendations for energy
conservation, diet, and more. Educational considerations for children are included.
The ICP specifically targets primary care clinicians, as well as specialists in internal medicine. Other medical care
practitioners may find it helpful. Medical school faculties are encouraged to include this primer in their curriculum.
The International Consensus Primer represents the collective wisdom and experience of the members of the panel. They
share their insights into this complex disease gleaned through research and hundreds of thousands of hours of clinical
investigations.
The International Consensus Panel anticipates that the primer will bring forward movement in enhancing clarity and
consistency of diagnoses and treatment of ME internationally.
Acknowledgements
Patients: The panel would like to gratefully acknowledge the participation and support of the patients and their families,
both in the clinical setting and in the research described within, upon which these physicians’ guidelines are based.
Anne-Marie Kemp, BA, M Ed; David Kemp, BA, M Ed: proof-reading
This Primer will be updated when appropriate.
Authors and their affiliations are listed on the front and back inside covers.
iv
International Consensus Panel
International Consensus Primer for Medical Practitioners
An International Consensus Panel was formed to develop International Consensus Criteria (ICC)1 and a
physicians’ primer that includes the ICC, pathophysiology, and diagnostic and treatment protocols for myalgic
encephalomyelitis (ME) based on current knowledge and clinical experience.
Goal: to enhance the understanding of ME and promote clarity and consistency in optimal clinical identification
and treatment internationally
Target groups: primary care physicians, internists, pain and other health care practitioners, medical students
Epidemiology
Prevalence: ~ 0.4 – 1%2, 3
• affects all age groups, including children, all racial/ethnic groups, and all socioeconomic strata
• onset most commonly occurs between the ages of 30 and 50
ME: ● generally sporadic
• higher prevalence in females
Prognosis
● endemic
● widely dispersed epidemics
Etiology
Predisposing Factors: multifactorial and fairly individual
1. Genetic predisposition: increased susceptibility associated with
• Gene expression modifications: neurological, hematological, metabolic, sensory, immunological disease,
function/response, infection, inflammation, cardiovascular, cancer, cell death and endocrine5-12
• Clusters of combined gene data suggest distinct genomic subtypes and disease associations.12, 13
• Familial and twin studies indicate there is a higher degree of ME in relatives, to third generation. 14
Environmental factors may outweigh genetic predisposition.15 Several epidemics support an infectious cause.16
2. Pre-onset environmental events that may compromise the neurological and immune systems, and increase
susceptibility to infection: ● minor infecQons ● immunizaQon ● exposure to new infecQous agents,
especially when traveling or following recent infections ● contaminated water ● recycled air in flights
Editors: Carruthers & van de Sande
1
● E t i o l o g y
• Currently there is no known cure.
• Early intervention and appropriate treatment strategies may lessen severity of symptoms.
• Restoration to full pre-morbid health and function is rare.4
• Prognosis for an individual cannot be predicted with certainty.
Paediatric: Children can be very severely afflicted.
• Children with less severe symptoms are more likely to go into remission than adults.
● E p i d e m i o l o g y
Classification: Myalgic encephalomyelitis has been classified as a neurological
disease by the WHO since 1969. WHO stipulates that the same condition Myalgic encephalomyelitis:
neurological disease
cannot be classified to more than one rubric because, by definition, individual
WHO ICD G93.3
categories and subcategories must remain mutually exclusive. Thus, it is
essential that patients meeting the ICC for ME are removed from overly inclusive groups.
● C l a s s i f i c a t i o n
Myalgic Encephalomyelitis (ME): complex, acquired multi-systemic disease
Pathophysiology: Profound dysfunction/dysregulation of the neurological control system results in faulty
communication and interaction between the CNS and major body systems, notably the immune and
endocrine systems, dysfunction of cellular energy metabolism and ion transport, and cardiac impairments.
Cardinal symptom: a pathological low threshold of fatigability that is characterized by an inability to produce
sufficient energy on demand. There are measurable, objective, adverse responses to normal exertion,
resulting in exhaustion, extreme weakness, exacerbation of symptoms, and a prolonged recovery period.
Note: Myalgic encephalomyelitis (ME) is the name recommended for those meeting the ICC.
I N T R O D U C T I O N
MYALGIC ENCEPHALOMYELITIS - Adult & Paediatric:
International Consensus Primer for Medical Practitioners
P AP TAH TOHP O
H P
Y SH I YO SL IO OG LY O G Y
I N T R O D U C T I O N
●
C a u s a l
F a c t o r s
●
P h a s e s
MYALGIC ENCEPHALOMYELITIS – Adult & Paediatric:
● blood transfusions ● anaestheQcs ● toxic chemicals ● heavy metals ● severe physical trauma:
whiplash/spinal injury/surgery ● undue psychological stress17-23
Precipitating Events and Causal Factors: Most patients enjoyed healthy,
Onset Survey
+
1,000 patients
75.6%: infection alone or
infection + 1 or more factors:
environmental exposure,
physical trauma,
vaccinations,
other stressors
Vernon SD. CFIDS of America
active lifestyles prior to the onset of ME. Widely dispersed epidemics support an
infectious cause. Symptoms at onset are usually consistent with an infectious
process.
1. Infectious agents associated with ME
Viruses: ● Enterovirus24-26 ● Epstein Barr virus (EBV)27 ● Human herpes virus
(HHV 6 and 7)28, 29 ● Cytomegalovirus30 ● Parvovirus B1931
Bacteria: Chlamydophila pneumonia32 ● Mycoplasma33 ● Coxiella burnettii27
It is unclear whether these infectious agents initiated ME or are opportunistic and developed due to an
impaired immune system. No one virus has been universally implicated for all patients. A prospective study
reported that six months following acute infections of Epstein-Barr virus, Coxiella Burnetii, or Ross River
virus, 11% of the patients had CFS.34 This supports the presence of ME subtypes. Antibody testing for a
number of viruses revealed subtype-specific relationships for Epstein Barr virus and enterovirus, two of the
most common infectious triggers for ME.27
2. Possible etiological process: A growing body of evidence suggests that a primary cause of ME is neuropathic
viruses that may infect neurological and immune cells and damage the capillaries and micro-arteries in the
CNS bed causing diffuse brain injury. The initial infection may cause profound dysregulation of immune
system pathways that may become chronic or cause autoimmunity even when the level of the infectious
agent is reduced.35
ME Phases
1. Infectious Onset/Acute Phase < 6 months: Most patients have a distinct acute onset where flu-like or upper
respiratory symptoms or other signs of an infectious process are evident. The incubation period usually
runs a few days to a week. Instead of recovering, the patient’s condition worsens, and the symptoms that
identify the distinctive character of ME begin to appear as a cluster. Approximately 20% of patients have a
gradual onset that may follow events that compromise the immune system, making them vulnerable to new
or reactivation of persistent latent infections that can further overwhelm the immune system.26
2. Chronic Phase > 6 months: Generally, symptoms tend to be more stable in the chronic phase. Some
patients have some improvement in the chronic phase while others have a progressive decline in health.
PATHOPHYSIOLOGY
PENE: a pathological, low threshold of fatigability
• post-exertional exhaustion & symptom flare
- immediate or delayed, & not relieved by rest
• prolonged recovery period
Post- Exertional Neuroimmune Exhaustion (PENE pen‫׳‬-e)
Normal fatigue is proportional to the intensity and duration of activity, followed by a quick restoration of
energy. PENE is characterized 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 systems36, 37 This interacts with the immune and endocrine systems
affecting virtually all body systems, cellular metabolism and ion transport.38 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% in VO2 at AT on the second day evaluation.39 Both submaximal and self-paced exercise
resulted in PENE.40 These impairments and the loss of invigorating effects distinguish ME from depression.
2
International Consensus Panel
International Consensus Primer for Medical Practitioners
Fold increase in mRNA from baseline (+SEM)
C
4
1
CFS and CFS co-morbid with FM n=14
ASIC3
P2X4
P2X5
TRPV1
α-2A **
ADB1
ADB2
COMT
IL6
IL10
α-lym
TLR4
CD14
(Ad2A decrease patients)
baseline
30 min
8 hr
24 hr
48 hr
0.5
( ** P<.02 compared to controls for AUC)
D
ASIC3
P2X4
P2X5
TRPV1
α-2A
ADB1
ADB2
COMT
IL6
IL10
α-lym
TLR4
CD14
FM only n=18
2
1
baseline
30 min
8 hr
24 hr
48 hr
n.s. for all AUC compared to controls
yes
↑
↑
↑
↑
↑
↑
↑
↑
normal
normal
↓
↓
↑
↓
Channelopathy, oxidative
stress, nitric oxide toxicity
Exhaustion and ATP
normal
Pain threshold
↑
normal
Editors: Carruthers & van de Sande
42, 43
↑ elevated
42, 44, 45
↓ reduced maximum heart rate
↓ reduced peak oxygen uptake at maximum work load - approximately ½ of
42, 45 - 50
sedentary controls
42, 43
often cannot achieve it
42, 43, 51
sub-optimal level
46, 47, 52 - 54
↓ decreased cerebral blood flow
46 - 48, 52
↓ decreased cerebral oxygen
48
insufficient blood pressure increase on exertion
47
↓ decreased body temperature
47
↓ breathing irregularities: shallow breathing, shortness of breath
42
↓ decreased capacity to use oxygen
42
↓ reduced
45, 55
↓ are reached at a much lower oxygen consumption level
56
↑ increased abnormalities in gait
11, 57
↑ elevated sensory signaling interpreted by the brain as pain and fatigue
58
↑ unique post-exercise mRNA increases in metabolite-detecting receptors
↑ 70% of ME patients comorbid with FM: significantly elevated sensory,
41
adrenergic & immune system receptor expression
41
↓ 30% ME patients (with POTS): adrenergic receptors decreased, alpha 2A
58
↑ ME & MS patients show abnormal increases in adrenergic receptors.
↑ distinct inflammatory to anti-inflammatory imbalance
Immune activation: initial response to infection tends to be an exaggerated
pro-inflammatory cytokine response (e.g. interleuken 6 & 8), followed by a
35, 59, 60
blunted anti-inflammatory response.
61, 62
↑ elevated oxidative stress markers
50, 63
↑ increased with exerQon
64
↑ exhaustion reached more rapidly, accompanied by
64
↓ relatively reduced intracellular concentrations of ATP.
39, 65-67
↓decreased with exercise, suggesting abnormal pain processing
3
E x e r c i s e
Cytokine activity
Pro-inflammatory
Anti-inflammatory
normal
↑
↑
t o
Resting heart rate (HR)
HR at maximum workload
Maximum oxygen
consumption (VO2)
Age predicted heart rate
Cardiac output
Cerebral blood flow
Cerebral oxygen
Blood pressure
Body temperature
Respiration
Oxygen utilization
Oxygen delivery to muscles
Anaerobic threshold &
maximum exercise
Gait production
Sensory signaling to brain
Chronic pain & fatigue
receptors
ME Patients
R e s p o n s e
Response to Exercise Normal
●
Light AR, Bateman L, Jo D, et al. Gene expression alterations at
baseline and following moderate exercise in patients with Chronic
Fatigue Syndrome, and Fibromyalgia Syndrome. J Intern Med 2012;
271:64-81. Figure 3 - Reprinted with permission - John Wiley & Sons
P A T H O P H Y S I O L O G Y
Post-exertional mRNA receptor expression: Patients: ME & comorbid fibromyalgia (B) had significantly elevated sensory, adrenergic & immune system
receptor expression than controls (A) and FM only (D). Subgroup (C) had decreased Alpha 2A receptors & reported orthostatic intolerance (OI) symptoms.41
Response to Exercise
Normal
ME Patients
68
Acidosis in exercising
muscles
Post-exercise recovery
from acidosis
Sense of well-being
yes
Symptom exacerbation
no
Cognitive function
Recovery period
↑ alert
short
↑
↑ increased intracellular acidosis in exercising muscles
↓ Normal inverse correlation between maximum proton efflux and nadir
muscle pH following exercise is lost. Slow recovery time (~4-fold increase)
45, 69
from intramuscular acidosis following exercise and repeat exercise.
↓ loss of invigorating & antidepressant effects, physical and mental
70
exhaustion, flu-like symptoms, pain, and worsening of other symptoms
↑ Activation and worsening of symptoms can be immediate or delayed by
1, 46, 70
When exercise is repeated the next day, abnormalities
several days.
40
are more severe.
71
72
↓ cognitive functioning: prolonged reaction time, ↑perceived effort
prolonged recovery period: usually 24 hours, often 48 but can last days, weeks
39, 40, 42
or cause a relapse.
Neurological Abnormalities
Neurocognitive, sleep, autonomic and sensory disturbances, pain, headaches, and paresthesias are prominent
neurological signs and symptoms. Cognitive impairments including slow processing of information, poor
attention, word finding, and working memory are some of the most functionally disabling symptoms.1, 73, 74
P A T H O P H Y S I O L O G Y
●
P E N E
● N e u r o l o g i c a l
MYALGIC ENCEPHALOMYELITIS – Adult & Paediatric:
Structural and functional abnormalities within the brain and spinal cord are consistent with pathological
dysfunction of the regulatory centers and communication networks of the brain, CNS and ANS, and are essential
for effective ongoing self-organization.1, 75 Reduced brainstem gray matter volume is consistent with insult to the
midbrain at fatigue onset. Feedback control loops may suppress cerebral motor and cognitive activity, disrupt
CNS homeostasis, and reset elements of the ANS.76 These abnormalities play crucial roles in neurological and
neurocognitive symptoms.1, 5, 11, 57, 65 Greater source activity and more parts of the brain are utilized in cognitive
processing, which supports patients’ perception of greater effort.73, 77, 78 Reduced duration of uninterrupted
sleep may explain reported unrefreshed sleep, pain and overwhelming fatigue.79 These observed pathological
changes are consistent with neurological disorders but not psychiatric conditions.
3D Comparison VS Adult Norms II – Avg. activity sampling
By Dr. Ismael Mena 2010
↑InteracQve view – no cerebellum
Norm to min (Cortex Max, Cb Max)↓
↑LeU medial view
Extensive areas of hypoperfusion are characteristic of ME:
HMPAO c99m radiopharmaceutical for brain blood flow
assessment. Images of the patient are reconstructed and
compared against normal age matched data-base by
means of Oasis Segami USA Software. In color gray normal
perfusion equal to mean + 2 St Dev, colors blue, green and
black, 2-5 St dev. below the normal mean denoting
hypoperfusion. Left lateral view shows marked
hypoperfusion in the lateral aspects of the temporal lobe,
extending to the frontal and parietal lobes. Left medial
view shows extensive hypoperfusion in the limbic system
involving anterior, medial and posterior cingulates. There
is left temporal medial hypoperfusion that denotes
hypofunction in the projection of the hippocampus. Both
posterior cingulate and hippocampal hypofunction denote
cognitive impairment. (Ventricular system is in color
white.) Finally, there is hypoperfusion in the occipital lobe.
Ismael Mena, MD, nuclear medicine
Neurological Structural & Functional Abnormalities
80 - 84
Hypoperfusion
(Neuro-SPECT, arterial spinning labeling)
46, 85
↓ regional blood flow (rCBF), ↓ absolute cortical blood flow
83
↓ hypoperfusion in brainstem distinguishes ME from depression
↓ further reduction in cerebral blood flow after exercise
46
Greater involvement of the brain correlates with greater severity
4
International Consensus Panel
International Consensus Primer for Medical Practitioners
Immune Impairments
7, 9, 35, 100-104
Chronic Immune Activation:
35
↑ increased inflammatory cytokines • pro-inflammatory alleles • chemokines • T lymphocytes • CD26 expression
105
↑ indirect evidence of B cell activation (rituximab drug study - depleting B-cells with CD20 markers – 2/3 improved)
106
↑ bioactive transforming growth factor-beta (TGF-beta)
↑ rate of active HHV-6, HHV-7 and B19 infection/coinfection with the simultaneous increase in plasma
107
proinflammatory cytokine level and distinctive types of clinical symptoms may suggest subtypes of ME
98, 102, 108 – 115
Immune Functional Defects:
→
110
108
Th1 shift towards Th2 dominant immune response
• patient self-test for Th2 shift
102, 108
98
↑ decreased natural killer (NK) cell signalling , function, & cell cytotoxicity
• ↓ neutrophil respiratory bursts
Editors: Carruthers & van de Sande
5
I m m u n e
Immune Impairments
Neuropathic viruses can infect and damage the brain, ganglia and immune cells. The initial infection may cause
profound dysregulation of the immune system, which in turn may result in persistent infection or abnormal
immune response.35 Activated immune complexes, including elevated levels of various cytokines, cause
chronic inflammation against a background of immunosuppression, which makes the body more vulnerable to
opportunistic infectious agents and may play a role in post-exertional flares and flu-like symptoms.35, 39, 98, 99
•
Punctate lesions – white matter hyperintensities (MRI)
↑ Plaque or hyperintensities in the white matter & tracts is consistent with demyelination or inflammation & increase
86, 87
risk of cerebrovascular events
76
• brain stem injury and loss of homeostasis
Reduced brain matter – (MRI)
88
↓ Reduced regional gray and white matter volumes are consistent with impaired memory and visual processing.
54, 89
↓ global reduction of gray matter volume
76
↓ gray matter volume in midbrain & pulse pressure suggest impaired cerebrovascular auto-regulation
76
↓ white midbrain matter volume decreased with fatigue duration
↓ Hypometabolism – (PET)
36
46, 83
↓ metabolism of glucose in the brain, ↓ metabolism in brain stem differentiates ME from depression
Neurocognitive – (fMRI, qEEG & SPECT)
↑ Greater effort is required - elevated source current & more regions of the brain are utilized in cognitive activity &
73, 77, 78
fatiguing tasks: poor processing of auditory & spatial information, poor working memory.
↓ slower performance in visual imagery & motor tasks - ventral anterior cingulate cortex was active when controls made
54
an error but not in patients.
80, 81
↓ reduced blood flow in temporal lobes may contribute to memory and cognitive impairment & fatigue
Pain and Fatigue – mRNA assays
11, 57, 90
↑ Elevated sensory signaling perceived by the brain as pain and fatigue
Musculoskeletal – (surface EEG scalp)
90
CNS signals are altered when controlling voluntary muscle activities, especially when they are fatiguing.
90
91
↓ poor and slower motor performance & abnormal spatial and temporal symmetry of gait
Sleep – (EEG)
79
↑ prolonged sleep onset latency
92, 93
↓ disruption of REM sleep & reduced duration of uninterrupted sleep
79
↑ increased alpha intrusion into delta sleep
Cerebral spinal fluid - (spinal tap) increased opening pressure on lumbar puncture
94
Proteomes distinguish ME from post-treatment Lyme disease and controls.
95
94, 95
↑ increased lymphocytes and protein
• IL-10 increased with granulocyte-macrophage (GM), colony-stimulating factor (CSF) suppression 95
96
↑ elevated lactate is consistent with reduced cortical blood flow, mitochondrial dysfunction & oxidative stress
96
Lateral ventricular: 297% vs. anxiety disorder & 348% vs. controls
Spinal cord and ganglia - (autopsy)
97
↑neuroinflammation in the dorsal root ganglia, (modulators of peripheral sensory information traveling to the brain)
P A T H O P H Y S I OL O G Y ● N e u r o l o g i c a l
Neurological Structural & Functional Abnormalities
MYALGIC ENCEPHALOMYELITIS – Adult & Paediatric:
95
Energy Production and Ion Transport Impairments
Profound energy impairment suggests dysregulation of the mitochondria and cellular energy production,
channelopathy, and ion transport. There is an inverse relationship between diurnal variation in blood pressure
(BP) and fatigue. Impairments increase risk of cardiovascular events. Orthostatic intolerance (OI) suggests
impaired cerebral circulatory autoregulation.53 Low oxygen consumption, stroke volume, and reduced
circulation are associated with symptom severity and functional impairment.48, 53, 120, 121, 141
•
P r o d u c t i o n
111
E n e r g y
104
↓ decreased perforins and granzymes • abnormal growth factor profiles • macrophage abnormalities
112,113
antiviral riboneuclease L (RNase L) pathway dysregulation: ↑ 37kDa (cleaved) to 80 KDa (normal) ratio of RNase-L
116
• IL 8, 23, 6, with IL-1a, IL-2 and IFN-gamma associated with Th17 function may discriminate post-mononucleosis ME
26, 117-119
Gastro-intestinal Tract
26
• chronic enterovirus infection of the stomach
• intestinal dysbiosis: breakdown in balance between ‘protective’ and harmful’ bacteria with increased levels of D
117
Lactic acid producing bacteria
117
↑ hyperpermeable gut &/or bowel can induce low-grade systemic inflammation & alcohol intolerance
118
Sensitivities: ↑ new sensitivities to sensory input, food, medication, alcohol, or chemicals
P A T H O P H Y S I OL O G Y ● I m m u n e
P r o d u c t i o n
Energy Production & Ion Transport Impairments
I C C
Energy Production and Ion Transport Impairments
• mitochondria and cellular energy metabolism and ion transport dysregulation 38, 122 – 125
↓ mitochondrial dysfunction involves partial blocking of the translocator protein TL, and/or lack of substrate or essential
126
co-factors
64
↓ exhaustion is reached rapidly, at which point there is relatively reduced intracellular concentrations of ATP
50, 118, 119, 127, 128, 134
↑ oxidative stress
• channelopathy impairments129, 130
• NO/ONOO- cycle: biochemical positive feedback cycle may contribute to chronicity118, 119, 131
Cardiovascular and Autonomic Impairments
48
↓ insufficient increase in blood pressure (BP) on exertion
↓ low blood pressure and exaggerated diurnal variation may be due to abnormal blood pressure regulation, inverse
132
relationship with fatigue
118
↓ reduced blood flow and vasculopathy
133
↑ arterial elasticity dysfunction - hyper-elasticity/contractibility of arterial walls
133
↑ elevated response to acetylcholine
• ↑ increased arterial wave reflection134
135, 136
↓ ‘small heart’ with small left ventricular chamber
137-139
↓ cardiac and left ventricular dysfunction
↓ reduced heart rate variability during sleep suggests a pervasive state of nocturnal sympathetic hyper-vigilance and
140
may contribute to poor sleep quality
↓ low circulating erythrocyte volume (~ 70% of normal). Vascular abnormalities suggest there is insufficient circulating
53, 141
blood volume in the brain when in an upright position, and blood may pool in the extremities.
Abnormal Thermoregulatory Responses
• loss of thermostatic control 142
PERSONALIZED ASSESSMENT AND DIAGNOSIS
International Consensus Criteria
The ICC encompass symptoms that had the greatest ability to select ME patients in a study of more than 2,500
patients143 and are supported by other studies.141, 144 The ICC capture the unique characteristics of ME.
Operational notes following criterial categories clarify how symptoms may be expressed and interpreted.
Grouping symptoms by regions of pathogenesis provides focus. Making criterial symptoms compulsory
improves consistency and accuracy in patient selection.145 – 150
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International Consensus Panel
International Consensus Primer for Medical Practitioners
Adult and Paediatric ● Clinical and Research
C o n s e n s u s
C r i t e r i a
( I C C )
7
● I n t e r n a t i o a n a l
Editors: Carruthers & van de Sande
D I A G N O S I S
A. Post-Exertional Neuroimmune Exhaustion (PENE pen‫׳‬-e) Compulsory
This cardinal feature is a pathological inability to produce sufficient energy on demand with prominent symptoms
primarily in the neuroimmune regions. Characteristics are:
1. Marked, rapid physical and/or cognitive fatigability in response to exertion, which may be minimal such as
activities of daily living or simple mental tasks, can be debilitating and cause a relapse.
2. Post-exertional symptom exacerbation: e.g. acute flu-like symptoms, pain and worsening of other symptoms
3. Post-exertional exhaustion may occur immediately after activity or be delayed by hours or days.
4. Recovery period is prolonged, usually taking 24 hours or longer. A relapse can last days, weeks or longer.
5. Low threshold of physical and mental fatigability (lack of stamina) results in a substantial reduction in preillness activity level.
Operational Notes: For a diagnosis of ME, symptom severity must result in a significant reduction of a patient’s
premorbid activity level. Mild (meet criteria, significantly reduced activity level), Moderate (an approximate 50%
reduction in pre-illness activity level), severe (mostly housebound), or very severe (mostly bedridden and needs help with
basic functions). There may be marked fluctuation of symptom severity and hierarchy from day to day or hour to hour.
Consider activity, context and interactive effects. Recovery time: e.g. Regardless of a patient’s recovery time from
reading for ½ hour, it will take much longer to recover from grocery shopping for ½ hour and even longer if repeated the
next day – if able. Those who rest before an activity or have adjusted their activity level to their limited energy may have
shorter recovery periods than those who do not pace their activities adequately. Impact: e.g. An outstanding athlete
could have a 50% reduction in his/her pre-illness activity level and still be more active than a sedentary person.
B. Neurological Impairments At least One Symptom from three of the following four symptom categories
1. Neurocognitive Impairments
• Difficulty processing information: slowed thought, impaired concentration e.g. confusion, disorientation,
cognitive overload, difficulty with making decisions, slowed speech, acquired or exertional dyslexia
• Short-term memory loss: e.g. difficulty remembering what one wanted to say, what one was saying,
retrieving words, recalling information, poor working memory
2. Pain
• Headaches: e.g. chronic, generalized headaches often involve aching of the eyes, behind the eyes or back of
the head that may be associated with cervical muscle tension; migraine; tension headaches
• Significant pain can be experienced in muscles, muscle-tendon junctions, joints, abdomen or chest. It is noninflammatory in nature and often migrates. e.g. generalized hyperalgesia, widespread pain (may meet
fibromyalgia criteria), myofascial or radiating pain
3. Sleep Disturbance
• Disturbed sleep patterns: e.g. insomnia, prolonged sleep including naps, sleeping most of the day and being
awake most of the night, frequent awakenings, awaking much earlier than before illness onset, vivid
dreams/nightmares
• Unrefreshed sleep: e.g. awaken feeling exhausted regardless of duration of sleep, day-time sleepiness
4. Neurosensory, Perceptual and Motor Disturbances
• Neurosensory and perceptual: e.g. inability to focus vision, sensitivity to light, noise, vibration, odour, taste
and touch; impaired depth perception
• Motor: e.g. muscle weakness, twitching, poor coordination, feeling unsteady on feet, ataxia
&
Myalgic encephalomyelitis is an acquired neurological disease with complex global dysfunctions. Pathological dysregulation of the
nervous, immune and endocrine systems, with impaired cellular energy metabolism and ion transport are prominent features.
Although signs and symptoms are dynamically interactive and causally connected, the criteria are grouped by regions of
pathophysiology to provide general focus.
Compulsory Post-Exertional Neuroimmune Exhaustion – PEN’-Ẹ (A)
3
Neurological Impairments : at least 1 symptom from 3 symptom categories (B)
3
Immune/gastro-intestinal/genitourinary Impairments: at least 1 symptom from 3 symptom categories (C)
1
Energy metabolism/ion Transport Impairments: 1 symptom (D)
A S S E S S M E N T
Myalgic Encephalomyelitis: International Consensus Criteria (ICC)
( I C C )
MYALGIC ENCEPHALOMYELITIS – Adult & Paediatric:
D I A G N O S I S
●
I n t e r n a t i o n a l
C o n s e n s u s
C r i t e r i a
Notes: Neurocognitive impairments, reported or observed, become more pronounced with fatigue. Overload
phenomena may be evident when two tasks are performed simultaneously. Abnormal accommodation responses of the
pupils are common. Sleep disturbances are typically expressed by prolonged sleep, sometimes extreme, in the acute
phase and often evolve into marked sleep reversal in the chronic stage. Motor disturbances may not be evident in
moderate cases but abnormal tandem gait and positive Romberg test may be observed in severe cases.
C. Immune, Gastro-intestinal & Genitourinary Impairments
At least One Symptom from three of the following five symptom categories
1. Flu-like symptoms may be recurrent or chronic and typically activate or worsen with exertion. e.g. sore throat,
sinusitis, cervical and/or axillary lymph nodes may enlarge or be tender on palpitation
2. Susceptibility to viral infections with prolonged recovery periods
3. Gastro-intestinal tract: e.g. nausea, abdominal pain, bloating, irritable bowel syndrome (IBS)
4. Genitourinary: e.g. urinary urgency or frequency, nocturia
5. Sensitivities to food, medications, odors or chemicals
Notes: Sore throat, tender lymph nodes, and flu-like symptoms obviously are not specific to ME but their activation in
reaction to exertion is abnormal. The throat may feel sore, dry and scratchy. Faucial injection and crimson crescents
may be seen in the tonsillar fossae, which are an indication of immune activation.
D. Energy Metabolism/Ion Transportation Impairments: At least One Symptom
1. Cardiovascular: e.g. inability to tolerate an upright position - orthostatic intolerance (OI), neurally mediated
hypotension (NMH), postural orthostatic tachycardia syndrome (POTS), palpitations with or without cardiac
arrhythmias, light-headedness/dizziness
2. Respiratory: e.g. air hunger, laboured breathing, fatigue of chest wall muscles
3. Loss of thermostatic stability: e.g. subnormal body temperature, marked diurnal fluctuations; sweating episodes,
recurrent feelings of feverishness with or without low grade fever, cold extremities
4. Intolerance of extremes of temperature
Notes: Orthostatic intolerance (OI) may be delayed by several minutes. Patients who have OI may exhibit mottling of
extremities, extreme pallor or Raynaud’s Phenomenon. Moons of fingernails may recede in chronic phase.
Paediatric Considerations
Symptoms may progress more slowly in children than in teenagers or adults. In addition to post-exertional
neuroimmune exhaustion, the most prominent symptoms tend to be neurological: headaches, cognitive impairments,
and sleep disturbances.
• Headaches: Severe or chronic headaches are often debilitating. Migraine may be accompanied by a rapid drop in
temperature, shaking, vomiting, diarrhoea and severe weakness.
• Neurocognitive Impairments: Difficulty focusing eyes and reading are common. Children may become dyslexic,
which may only be evident when fatigued. Slow processing of information makes it difficult to follow auditory
instructions or take notes. All cognitive impairments worsen with physical or mental exertion. Young people will not
be able to maintain a full school program.
• Pain may seem erratic and migrate quickly. Joint hypermobility is common.
Note: Fluctuation and severity hierarchy of numerous prominent symptoms tend to vary rapidly and dramatically.
A S S E S S M E N T
&
Classification
____ Myalgic Encephalomyelitis
____ Atypical Myalgic Encephalomyelitis: meets criteria for PENE but has a limit of two less than required of the
remaining criterial symptoms. Pain or sleep disturbance may be absent in rare cases.
Notes: Patients who have met the full criteria for ME but treatment is effective in reducing their severity still have ME.
Exclusions: As in all diagnoses, exclusion of alternate explanatory diagnoses is achieved by the patient’s history, physical
examination, and laboratory/biomarker testing as indicated. It is possible to have more than one disease but it is important that each
one is identified and treated. Primary psychiatric disorders, somatoform disorder and substance abuse are excluded. Pediatric:
‘primary’ school phobia.
Co-morbid Entities: Fibromyalgia, Myofascial Pain Syndrome, Temporomandibular Joint Syndrome, Irritable Bowel Syndrome,
Interstitial Cystitis, Raynaud’s Phenomenon, Prolapsed Mitral Valve, Migraines, Allergies, Multiple Chemical Sensitivities, Hashimoto’s
Thyroiditis, Sicca Syndrome, Reactive Depression. Migraine and irritable bowel syndrome may precede ME but then become
associated with it. Fibromyalgia overlaps.
Carruthers BM, van de Sande MI, De Meirleir KL, Klimas DG, Broderick G, Mitchell T, Staines D, Powles ACP, Speight N, et al. Myalgic encephalomyelitis:
International Consensus Criteria. J Intern Med 2011; 270: 327-338. Reprinted with permission of John Wiley & Sons. Some notes are slightly modified.
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2011.02428.x/full http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2011.02428.x/pdf
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International Consensus Panel
International Consensus Primer for Medical Practitioners
4.
5.
Editors: Carruthers & van de Sande
9
P r i n c i p l e s
3.
A p p l i c a t i o n
2.
C l i n i c a l
1.
Each child (all young people) will have his/her own unique combination of the ME criterial symptoms. The
onset of ME in children often occurs around twelve years of age but it has been diagnosed in a child who
was two years old. More than one member of the family may have ME or other neurological diseases.
Interview: Have both parents present if possible because each may remember different symptoms or
interactive events that may help determine onset of illness and interactive symptom clusters. Children may
not report symptoms because they are unaware that they are not normal.
Assess impact: Children cannot be expected to judge their pre-illness function with current function.
Compare educational, social and sport activities, and hobbies before and after onset.
Neurological impairments: Pain, headaches, slowed processing of information, difficulty understanding and
remembering information, difficulty focusing eyes and following verbal instructions are prominent features
that make learning very challenging. There is often a marked deterioration in school performance.
Exhaustion, irritability and accommodation: Children may have brief periods of hyperactivity followed by
extreme weakness. They often have mood swings and may become irritable when exhausted. Children
may accommodate exhaustion by resting, which may be erroneously interpreted as laziness.
Secondary school phobia: Young patients spend most of their out-of-school hours resting; children with
primary school phobia are participating in activities and socializing. Patients may develop ‘secondary school
phobia’ due to academic difficulties caused by ME or bullying.
–
Paediatric considerations: See paediatric personalized treatment - page 19.
S ME EN NT T A &
A AS SS ES ES SS M
N DD IDAI G
AN
GO
N SO ISSI S
Clinical Application Principles
General Considerations: The Clinical Interview develops through observations and dialogue that follows the
flow of the illness and its impact as felt by the individual patient. Remain open-minded and be alert to:
1. Symptom cluster variability: Patients exhibit unique combinations of symptoms.
2. Symptom interaction and coherence: Symptoms that interact dynamically within a cluster and ‘travel
together’ likely share the same underlying causal system, e.g. be alert to symptoms that activate or worsen
with PENE. Flu-like symptoms and delayed exhaustion suggest activation of the immune system.
3. Separate primary symptoms from secondary symptoms and aggravators: Primary symptom clusters
formed by a disease process, e.g. undue cognitive fatigue following normal cognitive effort, must be
separated from the secondary effects of coping with a chronic disease, e.g. anxiety about finances. Many
objective indices can differentiate ME from primary depression, e.g. reactions to exercise, joint and muscle
pain, severe headaches, recurrent sore throats. Patients’ contextual observations will help determine which
symptoms are part of the primary illness structure and which are caused by the impact of environmental
aggravators and stress enhancers, e.g. fast paced environments, exposure to toxins.
4. Symptom severity & impact:
Mild: meet criteria and have a significant reduction in activity level;
Moderate: approximately 50% reduction in pre-illness activity level; Severe: mostly housebound;
Very severe: mostly bedbound and require assistance with daily functions.
Those who are very severely affected are too ill to attend regular medical appointments.
5. Symptom severity hierarchy: Periodically rank the severity of symptoms to ensure the treatment regimen is
focused on the more severe symptoms. Symptom severity and hierarchy frequently fluctuate.
6. Determine total illness burden: All aspects of the patient’s life – physical, occupational/educational, social,
emotional and personal activities of daily living (ADL) must be considered when assessing overall impact.
Talk with the patient to determine accumulative effects of symptom severity, interaction and total illness
burden. Some patients who prioritize activities may be able to do one important activity by severely
reducing activities in other areas of their life. Others are totally bedridden and need assistance.
7. Diagnosis: A tentative diagnosis is based on symptoms and evolves throughout the clinical assessment.
Laboratory and other investigations confirm or refute the tentative diagnosis.
8. Differential diagnosis: The collective pathophysiology of ME is quite distinctive. However, based on the
patient’s history, risks, and symptoms, it is important to rule out other infectious diseases that could
simulate the collective, complex pathophysiology of ME. New symptoms need to be investigated.
P E R S O N A L I Z E D
C L I N I C A L
A S S E S S M E N T
&
D I A G N O S I S
W O R K S H E E T
MYALGIC ENCEPHALOMYELITIS – Adult & Paediatric:
PERSONALIZED CLINICAL ASSESSMENT & DIAGNOSTIC WORKSHEET FOR ME
Name:
Date:
Clinical Interview
Patient History (specify items when possible)
1. Pre-onset environmental events: Infectious exposure or events □ minor infections, □ immunization, □ upper
respiratory infections, □ sinusitis, □ pneumonia, □ gastrointestinal illness after sinusitis or pneumonia, □ dental
infections, □ vaginal infection, cystitis, □ prostatitis, □ blood transfusion; exposure to: □ sick people, □ unfamiliar
infectious agents when travelling, particularly following vaccinations, □ contaminated water, □ poor quality recycled
air Non-infectious exposure or events: □ post-chemical toxins, □ heavy metals, □ moulds; □ severe physical trauma
e.g. whiplash/spinal injury/surgery, □ anaesthetics, □ undue stress, □ steroids (before or during acute respiratory
illness can turn immune response to Th2 and suppress T cell numbers) ____________________________________
Onset: date ________, □ sudden, □ gradual; □ infectious__________________, □ other______________________
Symptoms at onset (indicate interrelated clusters if possible) ____________________________________________
Severity of symptoms at onset _____________________________________________________________________
Duration of symptoms ____________________________________________________________________________
2. Medication history _______________________________________________________________________________
Immunizations & sensitivities ______________________________________________________________________
Other therapies __________________________________________________________________________________
3. Past history: pre-illness functioning ______________________________________ premorbid activity level _____%
4. Family history ___________________________________________________________________________________
Systems Review: Many symptoms involve more than one system. Be alert to the following & specify when possible:
Neurological: □ cognition: □ difficulty processing information, □ difficulty organizing tasks, □ difficulty remembering
sequences, □ information overload, □ short term memory loss ____________________________
□ pain: □ headaches, □ musculoskeletal pain, □ worsens with physical or cognitive exertion_______________
□ sleep disturbance: □ disturbed sleep pattern, □ unrefreshed sleep: quantity ____ hr., quality (1-10) ________
□ neurosensory & perceptual disturbance: □ sensory overload, □ motor disturbance ______________________
Immune: □ recurrent flu-like symptoms that activate/worsen with exertion, □ susceptible to repeated infections
GI: □ nausea, □ abdominal pain, □ bloating, □ IBS, □ food &/or alcohol sensitivities, □ chemical sensitivities (specify)
______________________________________________________________________________________
GU: □ urinary urgency, □ frequency, □ nocturia _______________________________________________________
Energy production/ion transport
Cardiovascular: □ orthostatic intolerance (OI) - inability to tolerate upright position, □ neutrally mediated
hypotension (NMH), □ postural orthostatic tachycardia syndrome POTS), □ palpitations with or without cardiac
arrhythmias, □ light headedness __________________________________________________________________
Respiratory: □ air hunger, □ laboured breathing, □ fatigue of chest wall muscles ___________________________
Endocrine & ANS: □ loss of thermostatic stability, □ intolerance of extremes of temperature_________________
Post-exertional neuroimmune exhaustion (PENE)
□ Marked, rapid physical or cognitive fatigability in response to exertion _________________________________
□ Symptoms that worsen with exertion _____________________________________________________________
□ Post-exertional exhaustion: □ immediate, □ delayed; □ prolonged recovery period ______________________
□ Exhaustion is not relieved by rest ________________________________________________________________
□ Substantial reduction in pre-illness activity level due to low threshold of physical and mental fatigability (lack of
stamina) ____________ Activity level: □100%, □90%, □80%, □70%, □60%, □50%, □40%, □30%, □20%, □10%
Symptom hierarchy, quality & severity __________________________________________________________________
Secondary symptoms & aggravators ____________________________________________________________________
Sleep quality: scale of 1-10 (excellent sleep 10): ____, onset____, duration ____, problems _______________________
Pain: scale of 1-10 (worst pain ever 10): _________, problems ______________________________________________
Energy/fatigue: scale of 1-10 (great energy 10): good day ________, bad day ________, today ___________________
10
International Consensus Panel
International Consensus Primer for Medical Practitioners
RT-PCR, serology, stomach biopsy
□ mycoplasma
DNA-PCR, serology
□ Borrelia burgdorferi DNA-PCR, serology, Western Blot
DNA PCR, serology
□ Parvovirus B19
DNA-PCR, IgG, IgM,
Immune system profiles: □ *↓NK cell function & ↑ cytotoxicity; □ B & T-cell function: □ IgG, □ IgG subclasses 1-4; □
IgA, □ IgM (shift from T1 to T2), □ cytokine/chemokine profile panel (94% accuracy): IL-8, IL-13, MIP-1β, MCP-1, IL4,
□ flow cytometry for ↑ lymphocyte activity, □ ↑ 37 kDa 2-5A RNase L immunoassay – defect/ratio & bioactivity, □
food sensitivity panel, □ chemical sensitivities, □ stool for WCB - D-lactic acid bacteria balance, ova & parasites, □
autoimmune profile, Intestinal dysbiosis: □ IgA & IgM for intestinal aerobic bacteria in serum, □↑ leukocyte
elastase activity in PBMCs, □ IgG food intolerance test, □ toxoplasmosis
Neurological & static testing: □ *SPECT scan with contrast - ↓ cortical/cerebellar region cerebral blood flow (rCBF) in
DNA-PCR, serology, antigenemia
the frontal, parietal, temporal and occipital & brain stem regions - more brain involvement indicates increased illness
severity, □ MRI of brain – (increased T2-weighted images in high white matter tracts & loss of GM volume) & rule
out MS, □ MRI of spine (dynamic disc bulges/herniation , stenosis), □ sleep study (↓ stage 4 sleep, sleep pattern &
rule out treatable sleep dysfunctions – upper airway resistance syndrome, sleep apnea, etc.)
PENE: A 2 consecutive day comprehensive 8-12 minute cardiopulmonary exercise stress test (measuring heart, lung, and
metabolic function) - only ME patients have significantly worse scores the second day & abnormal recovery from exertion.
* Exercise tolerance test with expired gas exchange - (2 consecutive days) – measure cardiovascular, pulmonary &
Editors: Carruthers & van de Sande
11
W O R K S H E E T
□ Enterovirus
□ EBV, □ CMV, □ HHV-6
□ Clamydia pneumonia
D I A G N O S T I C
panel of tests provides a more robust basis to identify symptom patterns, abnormalities and orient treatment.
Routine laboratory investigation: □ CBC, □ ESR, □ CA, □ P, □ RBC Mg, □ vitamin D3, □ B12 & folate, □ ferritin, □ zinc,
□ FBS, □ PC, □ Hb A1C, □ serum electrolytes, □ TSH, □ protein electrophoresis screen, □ CRP, □ creatinine, □ ECG
(U+ T wave notching), □ CPK and liver function, □ rheumatoid factor, □ antinuclear antibodies, □ urinalysis,
□ essential fatty acids, □ CoEnzyme Q10, □ immunoglobulins, □ diurnal cortisol levels, □ TTG, □ serotonin
Additional laboratory investigation: (as indicated by symptoms, history, clinical evaluation, lab findings, risk factors)
□ 24 hour urine free cortisol, □ DHEA sulphate, □ ACTH, □ chest x-ray, □ hormones including free testosterone □
panoramic x-ray of dental roots, □ amino acid profile, □ abdominal ultra sound, □ lactose/fructose breath test
Further testing with specificity to ME, if and as indicated. Some tests are in the research stage but can identify
abnormalities and focus treatment. Viral tests should be interpreted by a physician experienced in these infections.
Pathogen
Tests
Pathogen
Tests
&
Laboratory/Investigative Protocol: Diagnose by criteria. Confirm by laboratory and other investigations. A broad
A S S E S S M E N T
temp. _______; pH: _______;
BP/pulse: 1. lying down: BP _______/_______, Pulse ________;
2. immediately after standing: BP _____/_____, Pulse ______; 3. after standing 3 min.: BP _____/_____, Pulse _____ ;
4. after standing 5 min.: _______/_______, Pulse ________ (Caution: Someone should stand beside the patient.)
Neurological
CNS: reflex examination: (neck flexion & extension may accentuate abnormalities from cervical myelopathic changes)
Neurocognitive: □ slowed thought, □ impaired concentration, □ difficulty remembering questions;
□ cognitive fatigue: during assessment, serial 7 subtraction (subtracting by 7 from 100)_______________________
□ cognitive interference: (e.g. serial 7 subtraction done simultaneously with tandem walk) ____________________
Pain/musculoskeletal: □ hyperalgesia, □ widespread, □ myofascial or radiating, □ muscle-tendon junctions,
□ taut muscles; joints: □ inflammation, □ hypermobility, □ restricted movement; positive tender points ____/18;
□ meets fibromyalgia criteria; muscle tone: □ paretic, □ spastic; muscle strength ___________________________
Neurosensory, perceptual and motor disturbance: □ abnormal accommodation responses of the pupils, □ suborbital
hyperpigmentation; tandem walk: □ forward, □ backwards; □ Romberg test; □ reflex examination _____________
Immune: Tender lymphadenopathy: □ cervical, □ axillary, □ inguinal regions (more prominent in acute phase),
□ flares with exertion; □ crimson crescents in the tonsillar fossa: □ demarcated along margins of both anterior and
pharyngeal pillars, □ if patient has no tonsils, they assume a posterior position in the oropharynx; □ splenomegaly
GI: □ increased bowel sounds, □ abdominal bloating, □ abdominal tenderness: epigastrium (stomach), right lower
quadrant (terminal ileum) and left lower quadrant (sigmoid colon) – most patients have tenderness in 2-3/3 areas
Cardiovascular & respiratory: □ arrhythmias: □ BP as above; □ mottling of extremities, □ extreme pallor,
□ Raynaud’s phenomenon, □ receded moons of finger nails (chronic phase) _________________________________
C L I N I C A L
Physical Examination: Standard examination with attention to:
W O R K S H E E T
MYALGIC ENCEPHALOMYELITIS – Adult & Paediatric:
metabolic responses at rest & during exercise: □ peak oxygen consumption VO2 or VO2 at anaerobic threshold (AT) decline of 8% or greater on test 2 indicates metabolic dysfunction, □ post-exercise blood analysis - increase in
sensory, adrenergic and immune genes - increase in metabolite receptors unique to ME
Energy metabolism/ion transport: □ ATP profile – identifies insufficient energy due to cellular respiration dysfunction
□ further ATP related parameters, superoxide dismutase and cell-free DNA Respiratory: □ pulmonary function test
Cardiovascular: □ Tilt table test to confirm OI (70 -80% tilt, measure HR continuously, BP periodically – 30 min or
presyncope); □ Cardiac output decreases - left ventricular dysfunction in the heart; □ 24-Hour Monitor for
suspected arrhythmia, NMH/POTS, myocarditis (Note: Repetitively oscillating T-wave inversions &/or T-wave flats, typical of
D I A G N O S T I C
ME International Consensus Criteria
_____
Post-exertional neuroimmune exhaustion (PENE)
Compulsory 1. Marked, rapid physical or cognitive fatigability in response to exertion
2. Post-exertional symptom exacerbation
3. Post-exertional exhaustion: immediate or delayed
4. Recovery period is prolonged
5. Low threshold of physical and mental fatigability (lack of stamina) results in a substantial reduction in
pre-illness activity level.
_____ 3
Neurological impairments: 1 or more symptom from 3 symptom categories
___ 1. Neurocognitive impairments
___ 2. Pain
___ 3. Sleep Disturbance
___ 4. Neurosensory, perceptual and motor disturbances
_____ 3
Immune, gastro-intestinal & genitourinary impairments: 1 or more symptoms from 3 categories
___ 1. Flu-like symptoms: recurrent, chronic, worsen with exertion
___ 2. Susceptibility to viral infections – prolonged recovery periods
___ 3. Gastro-intestinal tract disturbances
___ 4. Genitourinary disturbances
___ 5. Sensitivities
_____ 1
Energy production/transportation impairments: At least one symptom
___ 1. Cardiovascular
___ 2. Respiratory
___ 3. Loss of thermostatic stability
___ 4. Intolerance of extremes of temperature
C L I N I C A L
A S S E S S M E N T
Differential Diagnosis: When indicated on an individual basis, rule out other diseases that could plausibly simulate the
widespread, complex, symptom pathophysiology defining ME. E.g.: Infectious disorders: TB, AIDS, Lyme, chronic
hepatitis, endocrine gland infections; Neurological: MS, myasthenia gravis, B12; Autoimmune disorders:
polymyositis & polymyalgia rheumatica, rheumatoid arthritis; Endocrine: Addison’s, hypo & hyper thyroidism,
Cushing’s Syndrome; cancers; anemias: iron deficiency, B12 [megaloblastic]; diabetes mellitus; poisons
&
ME, may be subsumed under non-specific T-wave changes.)
Exclusions: Primary psychiatric disorders, somatoform disorder, substance abuse & paediatric ‘primary’ school phobia.
Comorbid Entities: Myofascial Pain Syndrome, TMJ, interstitial cystitis, Raynaud’s phenomenon, prolapsed mitral valve,
Irritable Bladder Syndrome, prolapsed mitral valve, Hashimoto’s thyroiditis, Sicca Syndrome, secondary depression,
allergies, MCS, etc. FMS is an overlap condition. IBS & migraine may precede ME and then become associated with it.
Diagnosis
Onset
Severity
Subgroups
_____ ME; ____ Atypical ME: meets criteria for PENE but has a limit of two less than required of the
remaining criterial symptoms. ____other __________________________________________________
□ sudden, □ gradual; □ infectious ____________________, □ other____________________________
□ mild: meets criteria, significantly reduced activity level; □ moderate: ~ 50% reduction in activity level; □
severe: mostly housebound; □ very severe: mostly bedbound, needs assistance with personal care
Prominent cluster: □ neurological; □ immune; □ metabolism/cardiorespiratory; □ eclectic (balanced)
Worksheet may be copied and used for patient diagnosis, educational and individual purposes. © International Consensus Panel
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International Consensus Primer for Medical Practitioners
Goals
1. To support the well-being of the patient by providing a definite diagnosis, respecting his/her illness
experiences, assuring that the disease is real, and providing realistic hope and continuing care
2. To empower the patient by collaborating with the patient on the management of ME and assuring s/he will
maintain autonomy regarding the complexity and pacing of activities and management
3. To optimize functionality without aggravating symptoms
Replenish, Restore & Relieve
• replenish nutrients, etc.
• restore homeostasis
• relieve symptoms
Reassessment
Editors: Carruthers & van de Sande
13
G u i d e l i n e s
Remove
• pathogens
• toxins
• heavy metals
&
Revise
• life-style
● G o a l s
Basic ‘Rs’ of Personalized Management & Treatment
T R E A T M E N T
Medication Principles and Caveats
1. Identify pathological components of symptoms and target treatment at cause.
2. Most patients are extremely sensitive to medication. Start low – Go slow! Dosage levels are not given
because it is recommended that dosage be reduced, at least initially. Start at ¼ - ½ of the recommended
dose. Medications may need to be adjusted or changed periodically to avoid building up tolerance to a
medication. Avoid the use of TCAs, Pregabalin, and Quetiapine for overweight patients.
3. Patients need to understand the reason they are taking a particular medication. Warn of side-effects!
4. No pharmaceutical is universally effective. In order to determine effectiveness and side effects, add or
change one medication at a time. Balance benefits against adverse effects.
5. Keep regime as simple, safe, effective and inexpensive as possible.
&
Guidelines
1. The pathophysiology of ME and laboratory findings must be reflected in all treatment/management
programs. Adverse reaction to exertion accompanied by a prolonged recovery period must be respected and
accommodated. All health-care personnel must be knowledgeable about ME.
2. Prioritize greatest symptom concerns and dysfunctions in order to determine the best treatment strategies.
3. Begin treatment promptly based on present clinical parameters and laboratory test findings.
4. Identify and treat comorbid conditions & aggravators.
5. The treating physician is responsible for overseeing the patient’s care. Coordinate referrals and treatment
efforts. Bedridden patients may require appointments via phone, home care services and assistance devices.
6. A comprehensive, holistic approach is vital. Laboratory findings are enormously helpful but it is important
to understand the difference between treating the patient and treating laboratory test results.
7. Personalized treatment plan: Involve the patient in setting realistic goals and developing a personalized
program based on his/her top priority health issues. The plan should be flexible, reflect the pathophysiology
and be conducive to healing. Consider all aspects of the patient’s life. Begin at a level that will ensure patient
success, assist in recognizing early warning signs, conserving energy, and planning alternate strategies for
low-energy days. Therapeutic alliance is an integral part of the patient’s self-management support.
M A N A G E M E N T
PERSONALIZED MANAGEMENT & TREATMENT
M A N A G E M E N T :
R E V I S E
L I F E - S T Y L E :
P a t i e n t
S e l f - H e l p
S t r a t e g i e s
( S H S )
MYALGIC ENCEPHALOMYELITIS – Adult & Paediatric:
Revise Life-Style: Patient Self-Help Strategies (SHS)
SHS assist patients in being proactive in conserving their energy, minimizing symptom flare-ups, and
maximizing functionality. SHS are what patients can do to support and optimize their body’s ability to heal.
The health care provider and patient should work as a collaborative team. It is important that patients learn
how to problem-solve and manage their day to day self-care, if able. SHS empower patients.
Education and Personal Development: Knowledge is power.
1. Meet with the patient’s partner/family as soon as possible after the diagnosis to discuss ME, what to
expect, assist in developing SHS, and provide realistic hope. Provide written educational information.
2. Notes: It is helpful if the patient brings someone to appointments to take notes that can be reviewed later.
3. Encourage patients to trust their feelings and experiences.
4. Recognize and avoid stressors and aggravators. Develop energy and environmental modifications.
Maximizing Sleep
Sleep disturbance is typically expressed by prolonged sleep, sometimes extreme in the acute phase, and often
evolves into marked sleep reversal in the chronic phase. Patients should:
1. Reduce stimulants such as coffee, alcohol, and decongestants. Create a quiet environment.
2. Pace day-time activities and incorporate rest periods. Over-exertion can increase insomnia.
3. Listen to the body and rest or sleep when needed. Sleep dysfunction and an inability to produce sufficient
energy on demand makes it essential that low energy reserves are not depleted.
4. Establish a regular bedtime as much as possible. However sleeping when needed takes priority. In the
chronic phase, incorporating short naps into the day may assist in being able to establish a regular bedtime.
5. Quiet activities or listening to a relaxation DVD before bedtime are helpful. Those who are severely ill or in
the acute phase may sleep much of the time but sleep is non-restorative.
6. Have a warm bath prior to bed and keep the body warm at night.
7. Keep the bedroom dark and quiet: use black-out curtains, turn the face of clocks away from the bed, use
eye masks and/or ear plugs if necessary.
8. Postural support: make sure the mattress and pillow give proper postural support.
9. Keep the bedroom as a ‘worry free sanctuary’ reserved for sleep and sex.
10. If sleep is impossible, get up and go to another room and do calming meditations or relaxing activities.
Nutrition, Diet and Hydration
The biochemistry and nutritional needs of each patient are unique. Standards for vitamin intake are based on
estimated amount required to prevent overt deficiency symptoms. Vitamin, mineral, digestive enzyme, and food
sensitivity profiles are helpful in assuring that patients receive the nutrient intake required to facilitate healing.
1. Keep well hydrated: approximately 30 ml. of water/kg. of body weight daily (½ oz./lb./day)
2. Eat a balanced, highly nutritious diet at regular times. Eating 3 small meals and 2-3 snacks daily, rather
than three bigger meals is less stressful on the digestive system, and helps stabilize blood sugar levels and
avoid hypoglycemia. Most fresh vegetables, fruits and herbs are high in antioxidants and nutrients.
3. No diet fits all. Generally, patients do better on a diet that is higher in low fat protein, vegetables and fruit.
Eat a small portion of protein at each meal. Eat a variety of nutritional foods.
4. Sensitivities/intolerance to gluten, milk & dairy, and eggs are common. Do elimination trials as indicated.
5. Reduce refined foods: e.g. white sugar & flour. Reduce polished rice intake to avoid vitamin B1 deficiency.
6. Avoid processed foods: glutamate additives, artificial sweeteners. Limit sugar and alcohol.
7. Eat organic food as much as possible. Prioritize: greens, berries, apples, soft skin fruit. Soaking non-organic
produce in water with 1 tablespoon of both lemon juice and sea salt for 20 minutes helps remove toxins.
8. Take multi-enzyme tablet with meals as indicated or if IBS is present.
9. Take nutritional supplements as indicated. A multi-vitamin and a multi-mineral supplement will ensure
minimal RDA intake. Consider vitamin B complex, D3, fish Omega 3 essential fatty acids and Co-enzyme Q10.
10. Replenishing electrolytes may be helpful.
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International Consensus Primer for Medical Practitioners
Energy Budget/Bank (EBB)
Energy Savings
Investment
Description
First priority is to conserve energy for the essential activities of daily living.
Conserve some energy for unexpected events that require additional energy.
Budget some time to share with others, whether by phone, email or in person. Talking
and listening can be exhausting so these periods should be kept very short, with rest
periods before and after. Prioritizing is essential.
Ideally, work towards saving a little energy every day in order to get stronger and invest
in their future health.
Problem: Typically patients consistently overestimate what they can do and are not aware that they have
B u d g e t / B a n k
( E B B )
15
E n e r g y
Editors: Carruthers & van de Sande
–
Patients must always be in control of the pacing and duration of any activity. Encourage patients to:
1. Pay attention to body signals & become alert to subtle clues of overexertion: It is essential that patients
learn is to recognize early warning signs that they have exceeded energy boundaries.
SHS: Wear a heart rate monitor set approximately 5% below the anaerobic threshold. Stop when the
beeper rings. Lie down and rest. Try to determine what activity, duration of activity or aggravator set off
the beeper and detect subtle differences in how they feel - e.g. feet are cold, feel more confused, etc.
Other tools: • activity logs • charts • devices, such as wearing a step counter, or an Actigraph monitor can
assist the patient in becoming attuned to subtle cues of over-exertion • Take temperature before and
after activity: a drop in temperature indicates the patient has done too much.
A daily activity log should include duration and quality of sleep, functional level (scale of 0 – 10), activity,
time and duration of activity, change in symptoms or severity, change in temperature, aggravators, etc.
2. Prioritize, prioritize, prioritize! The more limited the energy, the more important it is to prioritize which
items are essential. Patients need to know their energy limits and the specific pacing required to do an
activity in order to make knowledgeable decisions when choosing which activities are best for them.
3. Stay active within their limitations and rest frequently: Alternating short activity and rest periods enables
patients to do more in the long run. Always rest before and after an activity. Find an enjoyable activity.
4. Set personal boundaries and activity limits. Learn to say “No” without guilt. Save energy for ADLs, etc.
5. Adjust body position: (standing vs. sitting vs. lying down) Use joint protection devices as indicated.
6. Optimize functionality: Depending on severity, some but not all patients in the chronic phase are able to
incorporate some brief activities into their day to assist in maintaining and improving function. Monitor
functional level (1-10) initially and on an ongoing basis. Start low – go slow. Use a heart rate monitor set a
little below the anaerobic threshold to give activity biofeedback. Breathing exercises promote relaxation
and strengthen respiratory muscles. Active stretching with breathing improves range of motion/flexibility.
These can be done either seated or supine. If and when able, add slight resistance (elastic bands), then take
brief walks or swim. Use good body mechanics and ergonomics. Do not exceed energy boundaries – obey
the heart rate monitor. Notes: Aerobic metabolism may be impaired. Do not exercise in pollution.
S H S
EBB Self-Help Strategies: education, functionality, and activities
P a t i e n t
overexerted themselves until after they are in a ‘crash mode’.
Objective: Optimize daily functionality and activity endurance without aggravating symptoms.
Pathological components: PENE: post-exertional physical and mental exhaustion, pain, immune activation and
symptoms flare • decreased cerebral oxygen • impaired aerobic energy metabolism • reduced anaerobic
threshold heart rate, VO2 peak and peak work • drop in ability to produce energy after repeated exercise • OI
• abnormalities in heart function • prolonged recovery period • inability to recover from acidosis
Both submaximal & self-paced physiological limited exercise can result in PENE.
L I F E - S T Y L E :
EBB Accounts
ADL
Emergency
Sharing
R E V I S E
Pacing is not a cure but it is essential as it enables patients to make the best use of their limited energy. Similar
to a household budget, the more limited the patient’s energy, the more important it is to prioritize energy
needs and budget its use. Ideally patients should work towards having four energy accounts.
MYALGIC ENCEPHALOMYELITIS – Adult & Paediatric:
Remove Pathogens, Toxins and Heavy Metals
Replenish Nutrients, Restore Homeostasis, and Relieve Symptoms
R E P L E N I S H
REMOVE PATHOGENS & TOXINS
Develop alternate strategies for days when energy is low.
Simplify routines & conserve energy e.g. cook enough for 2+ meals. Have a special place for items e.g. keys.
Make environmental modifications, avoid multisensory overload, and use functional assistant devices.
Avoid owing any energy account at the end of the day, if possible.
N U T R I E N T S
7.
8.
9.
10.
1. Microorganisms: Persistent infections worsen symptoms and increase disability. Antivirals and antibiotics
should be used with caution. Identify infectious agent (pg. 11) and refer patients to an infectious disease
specialist. The following brief description is provided for your information.
Non-pharmaceutical: • prebiotics • probiotics • vitamins C • B12 • L-glutathion • antioxidants
Pharmaceutical: Antivirals - lymphotropic viruses and other viruses: • Valacyclovir (for confirmed herpes
viruses) • Ganciclovir • Valganciclovir (Ganciclovir prodrug) • Cidofovir • CMX001 • Foscarnet • Acyclovir
Immune boosters • oxymatrine (for enteroviral infections)• Omega 3 essential fatty acids (EFA)
Antibiotics: 21 consecutive days or alternate 8-10 days of antibiotics followed by 3 weeks of prebiotics and
probiotics until under control. Older antibiotics are recommended in order to avoid developing
resistance to newer antibiotics that may be needed in acute medical situations. Bacteria, mycoplasma
& Chlamydophila pneumoniae: • Doxycycline • Clarithromycin • Ciprofloxacin • Azithromycin.
Intestinal dysbiosis: • Erythromycin or • Clarithromycin or • Xifaxan with probiotics • VSL-3 • Mutaflor to recover from each treatment & restore gut bacteria. Treatment suppresses overgrowth.
Anaerobic dental bacteria produce very toxic wastes. Photo disinfection utilizes a cold, low-power
diode laser to inactivate many bacteria and toxins and reduces gum pockets.
Antifungals: such as candida change sugars to aldehydes. Treat with anti-fungals.
2. Toxins: Remove toxins from chemicals (e.g. PCP, DU, organophosphates), and from microorganisms that
can build up within and around cells. The toxins can cause a Th1/Th2 shift and inhibit cellular respiration.
• drink non-chlorinated water • omega 3 essential fatty acids • bentonite
3. Heavy metals: disrupt the immune system. The structure of one of the RNase L fragments is almost identical
to a protein involved in the removal of heavy metals and toxic chemicals. When this protein is blocked, the
cells become highly sensitive to mercury. Remove heavy metals • consider chelation (not confirmed)
Replenish probiotics, hydration, nutrients, vitamins, minerals/electrolytes, enzymes, antioxidants.
Restore cellular oxygenation, acid/alkaline balance (pH), sleep, intestinal flora balance, hormonal balance
1. Cellular oxygenation: When cellular oxygenation drops, respiratory enzymes decrease and the cells cannot
produce adequate energy aerobically, mitochondria become damaged and restrict transport of cellular
oxygen. Insufficient Omega 3 essential fatty acids levels may restrict oxygen exchange through the cell walls.
Non-pharmaceutical: • Omega 3 essential fatty acids – fish oils, flax seed oil • methyl sulfonyl methane (MSM)
2. Hydration: Approximately 30 ml of water per kilogram of patient’s weight daily (½ ounce/pound/day).
3. Acid/alkaline balance: In order to maintain blood pH of 7.4, the body uses stored alkalizing minerals as
buffers to neutralize elevated acidic load. Excess acidic substances and toxins are deposited in the cells,
which decreases their oxygen levels and increases susceptibility to disease.151 Check pH regularly.
Non-pharmaceutical: • eat fresh fruit and vegetables • replenish minerals and vitamins • remove toxins
• alkaline water • betaine hydrochloride with meals • pH balancers • sodium bicarbonate – 1 teaspoon of
baking soda dissolved in a glass of water - at least one hour after meals, 2 times a day.
4. Vitamins & Minerals: Vitamins are generally cofactors that aid enzymes in utilizing nutrients. Standard
recommended intake is based on amount needed to prevent overt deficiency. A vitamin/mineral profile is
helpful to ensure patients are getting optimal nutrients for healing. Deficiencies in vitamins C, D3, B12,
other B complex vitamins, magnesium, potassium, sodium, zinc, L-tryptophan, L-carnitine, coenzyme Q10,
and essential fatty acids have been reported.152
Vitamins: Vitamin D3: calcium metabolism, healthy bones & helps regulate heartbeat; • B complex:
metabolism, RNA & DNA synthesis, cell oxidation, antibody production & nerve health; • C: antioxidant,
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International Consensus Primer for Medical Practitioners
Neurological
2. Pain
Possible pathological types/components: • altered sensory information and pain processing in the brain
that is perceived as pain • peripheral neuropathies • decreased pain threshold • dysregulation of sodium
channels & ion transport • magnesium deficiency • inflammatory conditions • muscle pain generated by
movement: paretic (decrease in muscle bulk/tone), spastic – (increase in muscle bulk/tone) • structural
pain: failure of supportive structures; • differential pain diagram and descriptive words help determine
type of pain: • aching • stabbing • shooting • pins & needles; (visual analogue scale: estimate severity)
Treat localized pain because it can intensify general pain.
Non-pharmaceutical: avoid pain exacerbators • pacing • local heat or cold • gentle stretching; manipulative
body therapy: • massage • physiotherapy • chiropractic • myofascial release techniques; relaxation
techniques: • biofeedback • ultrasound • meditation; • TENS (Transcutaneous Electrical Nerve Stimulation)
• acupuncture • magnesium sulfate (for muscle spasm) • hydrotherapy • Synaptic® Electronic Activation
Pharmaceutical: topical ointments; anti-inflammatory/degenerate/neuropathies: • NSAIDs • ibuprofen
• naproxen; COX-2 inhibitors: • Celecoxib; anticonvulsants: Gabapentin • Pregabalin; TCA – low dose for
short time • Amitriptyline • Nortriptyline • Doxepin; muscle relaxants: • Baclofen • Cyclobenzaprine;
migraines • Sumatriptan Succinate; narcotic/opiates: only if severe – requires rationale & documentation
3. Cognition and Fatigue: not relieved by rest
Possible pathological types/components • neuropathy: sensory information is interpreted by the brain as
fatigue • cognitive fatigue: more parts of the brain are utilized during auditory processing • brain
hypotension • arousal fatigue: poor sleep quality & quantity • metabolic fatigue: cells are unable to
transform substrates of energy into useful function • oxygenation fatigue: insufficient oxygen is delivered
to the brain & tissue • OI: inability to maintain upright position • muscle fatigue: generated by movement
• structural fatigue: failure of weight bearing supportive structures; • hypoadrenalism • hypothyroidism
• food intolerance • nutrient malabsorption • insulin imbalance • stress • medication • MCS
Non-pharmaceutical: • energy budget/bank (EBB) pg. 15 • pacing • sleep management • simple, quiet
environment • simplifying tasks • adaptive devices • relaxation techniques • restorative postures • some
patients think better in a semi-reclined position • speech therapy may help problems with word finding,
processing information, & memory • read within one’s ability & then learn new information/skills – as able
B12/Cyanocobalamin or Methylcobalamin: anecdotal studies suggest some patients with normal blood
counts improve in energy level, cognition, weakness and mood with mega B12 injections.
Editors: Carruthers & van de Sande
17
N e u r o l o g i c a l
1. Sleep Disturbance: consider sleep quantity and restorative quality
Possible pathological symptoms/components: • reduced stages 3 and 4 sleep, which is when the body is
restored • feeling tired but wired • prolonged sleep onset • restless sleep • coma-like sleep • awakening
early • can’t go back to sleep • unrefreshed sleep • morning stiffness & mental ‘fog’.
Identify and treat associated sleep dysfunctions: • upper airway resistance syndrome • sleep apnea
• restless leg syndrome • periodic limb movement • leg cramps
Non-pharmaceutical: • sleep hygiene • relaxation • cervical pillow • calcium & magnesium salts • melatonin
Pharmaceutical: sleep onset: sedative/hypnotics • Zopiclone • Zolpidem • Zaleplon • Eszopiclone;
sleep sustainers: • Trazodone • tricyclic antidepressants (TCA) – Doxepin, Amitriptyline, (short term low
dose – side effects can be severe) • L-tryptophan; muscle relaxant: • Baclofen
T R E A T M E N T :
healthy adrenals, collagen, capillary tissue, fights infection; • A & E: antioxidants, red cell health, protein
synthesis. Vitamins A, D & E are fat soluble and can cause toxicity if taken in excess.
Minerals: Calcium: healthy bones & teeth, heart rhythm regulation; • magnesium: calcium & vit. C
metabolism, nervous & muscular systems; potassium: nerves, muscle tone, heart action, enzymes reaction;
zinc: normal tissue function, protein & carbohydrate metabolism; manganese: activates enzymes; sodium:
helps regulate acid-base balance, muscle contraction. Trace minerals: involved in many body processes.
MYALGIC ENCEPHALOMYELITIS – Adult & Paediatric:
Immune and Gastro-Intestinal
Intestinal dysbiosis: leaky gut syndrome, nausea, indigestion, reflux, bloating, vomiting, abdominal pain
Possible pathological components: • bacterial imbalance – elevated levels of D Lactic acid-producing
bacteria in the gastrointestinal tract • chronic enteroviral infection of the stomach • slow gastric emptying
Non-pharmaceutical: test for food sensitivities • food elimination trials to determine food intolerance
• adjust diet (See nutrition/diet pg.14) Common food sensitivities: gluten, lactose, fructose, milk, eggs
Pharmaceutical: Confirm infection. Refer to specialist. See pg. 16, Remove pathogens - #1
T R E A T M E N T :
N e u r o l o g i c a l
-
P E N E
•
I m m u n e
• E n e r g y
M e t a b o l i s m
Pharmaceutical: CNS stimulants for fatigue • Methylphenidate (for concentration) • Modafanil
• Armodafinil • Moclobemide. Most drugs have short-term effects and may not improve endurance.
a. PENE is the pronounced summation effects and after–effects of numerous interactive dysfunctions.
Effects: physical and mental exhaustion, weakness, symptom flare and a prolonged recovery.
Possible pathological components: • neuroimmune exhaustion • decreased cerebral oxygen & blood
volume flow, cardiac output & pain threshold • impaired aerobic metabolism & oxygen delivery to
muscles • elevated sensory signalling to the brain perceived as fatigue and pain • immune activation
Treatment: Pacing is the best prevention. (pg. 15) A heart rate monitor can assist in keeping cardiovascular
responses below the anaerobic threshold. Treat sleep, pain, fatigue & cognitive problems.
b. Overload Phenomena: hypersensitive to many kinds of sensory input
It can cause a “crash” – a temporary period of immobilizing physical and/or cognitive exhaustion.
Possible pathological components: • hypersensitivity to and overload of sensory stimuli • more than
one source of information • mixed modalities of input – auditory & visual, physical & cognitive
• physical or mental exertion • fast paced or confusing environments • extremes of temperature
Non- pharmaceutical: Treat sleep, pain, fatigue and cognitive problems.
Pharmaceutical: Sensory overload crash sometimes responds to gentle, low dose benzodiazepines:
• Lorazepam • Alprazolam
Energy Metabolism and Ion Transportation
1. Orthostatic intolerance (OI): sympathetic response to decreased venous return. Confirm with tilt table test.
Possible pathological components: • cerebral hypoperfusion • dehydration • decreased cardiac output •
reduced circulating red cell count • reduced plasma volume • reduced ability of the blood to carry oxygen
to the brain • decreased venous return • neck problems • medication • low ADH • CNS disorder
Non-pharmaceutical: • supine or semi-supine posture • proprioceptive neck disturbances– avoid extension
or quick rotation • support stockings • get up slowly while holding on to something • eat small meals •
keep well hydrated • elevate legs • lying down at the first sign of dizziness usually relieves symptoms
caused by POTS and NMH • electrolytes • volume expansion: • quality sea salt with adequate water intake
Pharmaceutical: volume expansion: sodium chloride – IV normal saline, if salt helps initially then wanes
consider Fludrocortisone (monitor potassium) • can add a beta blocker to increase ventricular filling and
reduce postural tachycardia or palpitations e.g. • Atenolol • Pindolol; peripheral alpha agonist • midodrine
2. Urinary difficulties: urinary urgency, frequency, nocturia Rule out infection and refer patient to urologist.
3. Neuroendocrine: Hypothalamic-Pituitary-Adrenal (HPA) Axis: • Galangtamine • Melatonin
Other Symptoms
1. Altered mood: Patients may become anxious or develop secondary depression due to coping with a poorly
understood, chronic disease, and greatly reduced functionality. Let patients know that research is
advancing. Evaluate suicide risk. Refer those with severe depression for supportive counseling.
Non-pharmaceutical: Support patients through the grieving process from loss of health, lifestyle,
occupation, income, etc. • bright light therapy • massage • uplifting music or activities • support groups
Pharmaceutical: SNRIs: • Venlafaxine • Duloxetine; MAOIs: • moclobemide (improves fatigue); • buprolon
2. Gynecological: Female patients have a higher than normal incidence of peri-menstrual symptoms, which
can last two weeks, and more severe peri-menopausal and post-menopausal symptoms. 153
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Pharmaceutical: peri-menstrual: low-dose progesterone may be helpful (only use on a 3-6 monthly cycle risk of thromboembolism); peri-menopausal/post-menopausal: hormone replacement therapy (HRT) may
help some and reduce risk of osteoporosis (only use short-term - risk of breast, uterus & ovarian cancer)
Reassessment – Regular Ongoing Follow-Up
1. Monitor and reassess symptom severity, evaluate improvements and concerns, and problem solve.
2. Revise prioritized items and adjust treatment strategies and action plan as indicated.
3. Follow-up tests can be limited to a small number of key parameters but the importance of the corelations between test findings and clinical progress cannot be overemphasized.
4. Determine total illness burden by talking with the patient to determine the severity of symptoms, the
dynamics of interaction within their cluster of symptoms, their accumulative effects, and the overall
impact to patients’ lives over longer periods of time. All aspects of patients’ lives must be considered –
physical, occupational/educational, social, personal and emotional.
5. Investigate new symptoms appropriately because ME patients can develop other medical problems. Do
not assume that all new symptoms are part of the ME complex.
6. Charts, etc. Activity logs and scales are helpful. International Symptom Scale (being developed) will
help position a patient within the group, orient the treatment program and monitor its effectiveness.
7. Coordinate care and extended care referrals: specialists, peer support groups, group appointments, etc.
R E A S S E S S M E N T
Paediatric Treatment Considerations
Prompt treatment can lessen the impact of ME in some cases. Monitor the child’s health on an ongoing basis.
Management is similar to adults. Great caution is required in prescribing any medications - use low dosage.
Involvement of family members is essential. They monitor the child’s health and are the primary care givers.
Additional support: Provide information about relevant agencies, support groups, and other resources.
P A E D I A T R I C
Considerations for the Child’s Education: The clinician may be required to make serious decisions regarding
the child’s education. Consider options in conjunction with the parents, child, and liaise with the school when
appropriate. (Child refers to all young people of school age.) *See letter to educators, pgs. 27-28
The GP and specialist should work in partnership but it is usually the GP, in consultation with the family, who
stewards the child’s educational management to assure that ongoing medical care is not undermined. The
GP is more accessible to the family and can have a positive influence on the child’s education and well-being.
Marked cognitive impairments in concentration and slowed processing of information make learning very
challenging and exhausting. The speed of the teacher’s speech may be a barrier to learning. Difficulty in
processing information compounded by impaired ability to retain the information after making so much
effort often results in feelings of failure. This causes anxiety and can lead to depression or school phobia.
Minimal physical and mental effort often results in relapse that may be delayed. The child has lost
approximately 50 % or more of their pre-illness activity level due to pathophysiological exhaustion, etc. The
Advice Line Records (UK) indicate that education is frequently the main source of relapse.154
Determine whether the patient is well enough and has the ability to benefit from education at this time.
Unfortunately, the education to which all children are entitled may worsen their medical condition.
Generally it is better to stop education until the child is stronger and his/her health has stabilized and then
tutor at home. Children diagnosed with ME cannot maintain a full educational program.
Educational accommodations must be selected on an individual basis, according to the patient’s health
status, capabilities, and special educational needs, in order to provide the best opportunity for recovery.
Other Considerations
Pregnancy and raising a child requires very careful consideration for ME patients. Important issues include the
patient’s health, creating a healthy environment for the fetus, whether or not the patient has sufficient
energy to nurture the child into adulthood, and opportunities for long-term assistance in the child’s care.
Risks: ME is not inherited but research suggests a person can inherit a genetic susceptibility to ME.
Medications: Are they a risk to the fetus? • Can they be gradually stopped prior to pregnancy? • Avoid DHEA.
Editors: Carruthers & van de Sande
19
O T H E R
C O N S I D E R A T I O N S
MYALGIC ENCEPHALOMYELITIS – Adult & Paediatric:
Pregnancy: frequent, small meals of optimum nutrition are essential • keep well hydrated • draining on iron
and calcium • folic acid is advised • iodine supplement may be indicated • avoid stress • need extra rest
• some patients feel better during pregnancy with the increased production of hormones
Lactation: Breast milk is best but babies can thrive on formula. When nursing, some medications must be
avoided. If breast feeding, milk can be expressed so the partner can bottle feed if the patient needs to rest.
Nurturing baby & child: The responsibility and joy must be shared by both partners. Accept all help offered.
Pregnancy and raising a child are physically and emotionally draining, but also joyful and rewarding. The
decision to have a child should be made jointly by the patient and partner. That decision must be respected.
Surgery: Prior to surgery, alert the surgeon to important factors of ME: hypersensitivity to pharmaceuticals
including anesthetics, low circulating blood volume, OI, NMH, low intracellular magnesium and potassium
levels, rapid fatigability and elevated pain and fatigue levels. Ensure patients are well hydrated prior to
surgery. Patients take longer to recover and may need extra time in the hospital.
Immunization: Live vaccine immunization is generally not recommended because of the weakened immune
system plus risk of worsening symptoms and triggering relapses. Decisions regarding vaccinations must
remain with the treating physician and patient. If immunization is chosen, it is recommended that injections
are administered by the treating physician. Some clinicians have found it helpful to divide the dose into two
to four mini doses, with each dose given a full month apart to ensure there are no delayed reactions.
Blood and Tissue Donations: The Red Cross and most countries stipulate that donors should be healthy.
Therefore, ME patients should not donate blood or tissue. In addition, genetic blood testing and other tests
suggest that some patients carry infectious agents in their blood. This is a potentially serious health issue.
Medical Documentation: Clinicians often are required to provide medical documentation regarding the
severity of symptoms and level of functionality. Requirements vary from country to country and between
policies. Check the wording of the policy. Generally, the following items need to be documented:
Medical history should include assessment by a clinician conversant on the ICC criteria, abnormal laboratory
findings, objective physiology findings, severity of symptoms, duration of illness, responses to treatments,
functionality and total illness burden.
Biomarkers & tests: Cardiopulmonary exercise test-retest, recorded by use of an electrocardiogram (ECG)
can confirm many symptoms: PENE, decreased cerebral oxygen, prolonged recovery period, loss of capacity
to recover from acidosis. There is significant peak oxygen consumption VO2 or VO2 at AT - decline of 8% or
greater on test 2 indicates metabolic dysfunction. Brain scans support cognitive impairments. Refer to
pathophysiology and laboratory assessment for further objective impairment markers.
Scales, patient diaries and questionnaires completed on first visit and then periodically are helpful.
Functional limitations: Consider physical, cognitive and emotional functional limitations, effects of
unpredictability and fluctuation of symptom dynamics, lack of endurance, neurocognitive impairments,
chronicity, and the cumulative effects of cognitive and physical fatigue. Describe how functional limitations
affect ability to do ADL, instrumental ADL (e.g. housework), rehabilitative programs and work activities.
Prognosis is a clinical estimate. It is not possible to predict prognosis for an individual with certainty.
Generally, the greater the severity of symptoms at onset, the poorer is the prognosis.
Provide medical opinion as to whether or not the patient is ready to return to work.
Exciting Research: More comprehensive approaches and new developments in research technology are
advancing the understanding of clinical correlates. It is anticipated that research using patient sets selected by
the ICC will elicit or confirm biopathological mechanisms and biomarkers that are specific to ME. The members
of the International Consensus Panel wish to acknowledge the more than 50,000 patients they have diagnosed
and/or treated and from whom they have gleaned much of the insight offered in this primer. The authors hope
that clinicians will find this primer to be a helpful, user-friendly resource and that it will enhance clarity and
consistency of diagnosis and efficacy of treatment world-wide.
20
International Consensus Panel
International Consensus Primer for Medical Practitioners
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marker for chronic fatigue syndrome. Am J Med 2000; 108: 99-105. [PMID: 11126321]
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Editors: Carruthers & van de Sande
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24
International Consensus Panel
International Consensus Primer for Medical Practitioners
Appendix 1: Myalgic Encephalomyelitis: INTERNATIONAL CONSENSUS CRITERIA (ICC) Short Form
Adult and Pediatric ● Clinical and Research
Compulsory
Post-Exertional Neuroimmune Exhaustion (A)
3
Neurological : 1 symptom from 3 symptom categories (B)
3
Immune/gastro-intestinal/genitourinary : 1 symptom from 3 symptom categories (C)
1
Energy metabolism/ion transportion : 1 symptom (D)
___ A. Post-Exertional Neuroimmune Exhaustion (PENE pen‫׳‬-e) Compulsory
Characteristics are:
1. Marked, rapid physical and/or cognitive fatigability in response to exertion, which may be minimal such
as activities of daily living or simple mental tasks, can be debilitating and cause a relapse.
2. Post-exertional symptom exacerbation: Post-exertional exhaustion may occur immediately after activity
or be delayed by hours or days.
3. Prolonged recovery period, usually 24 hours or longer. A relapse can last days, weeks or longer.
4. Low threshold of physical and mental fatigability (lack of stamina) results in a substantial (approximately
50%) reduction in pre-illness activity level.
___ B. Neurological Impairments: At least One Symptom from three of the following four symptom categories
___ 1. Neurocognitive Impairments
• Difficulty processing information: slowed thought, impaired concentration: slowed speech
• Short-term memory loss: poor working memory, difficulty remembering what one wants to say, etc.
___ 2. Pain
• Headaches: chronic, generalized headaches associated with cervical muscle tension, migraines
• Significant pain in muscles, muscle-tendon junctions, joints, abdomen or chest: hyperalgesia
___ 3. Sleep Disturbance
• Disturbed sleep patterns: hypersomnia, sleep reversal, frequent awakenings, vivid dreams
• Unrefreshed sleep: awaken feeling unrefreshed regardless of duration of sleep, day-time sleepiness
___ 4. Neurosensory, Perceptual and Motor Disturbances
• Neurosensory hypersensitivity, inability to focus vision; impaired depth perception
• Motor: muscle weakness, poor coordination, feeling unsteady on feet, ataxia
___ C. Immune, Gastro-intestinal & Genitourinary Impairments
At least One Symptom from three of the following five symptom categories
___ 1. Flu-like symptoms may be recurrent or chronic and typically activate or worsen with exertion.
___ 2. Susceptibility to viral infections with prolonged recovery periods
___ 3. Gastro-intestinal tract symptoms: nausea, bloating, irritable bowel syndrome
___ 4. Genitourinary: urinary urgency or frequency, nocturia
___ 5. Sensitivities to food medications odors or chemicals: food, chemicals, odours, medications, alcohol
___ D. Energy Production/Ion Transportation Impairments: At least One Symptom
___ 1. Cardiovascular: orthostatic intolerance, palpitations with or without cardiac arrhythmias, dizziness
___ 2. Respiratory: air hunger, laboured breathing, or fatigue of chest wall muscles
___ 3. Loss of thermostatic stability: marked diurnal fluctuations, sweating episodes, cold extremities
___ 4. Intolerance of extremes of temperature
Classification: ____ Myalgic Encephalomyelitis
____ Atypical Myalgic Encephalomyelitis: meets criteria for PENE but has two or less than required of
the remaining criterial symptoms. Pain or sleep disturbance may be absent in rare cases.
Differential Diagnosis: When indicated on an individual basis, rule out other diseases that could plausibly simulate the widespread,
complex, symptom pathophysiology defining ME. E.g.: Infectious disorders: TB, AIDS, Lyme, chronic hepatitis, endocrine gland
infections; Neurological: MS, myasthenia gravis, B12; Autoimmune disorders: polymyositis & polymyalgia rheumatica, rheumatoid
arthritis; Endocrine: Addison’s, hypo & hyper thyroidism, Cushing’s Syndrome; cancers; anemias: iron deficiency,
B12/megaloblastic; diabetes mellitus; poisons
Exclusions: Primary psychiatric disorders, somatoform disorder, substance abuse and paediatric ‘primary’ school phobia.
Comorbid Entities: Myofascial Pain Syndrome, TMJ, interstitial cystitis, Raynaud’s phenomenon, prolapsed mitral valve, Irritable
Bladder Syndrome, prolapsed mitral valve, Hashimoto’s thyroiditis, Sicca Syndrome, secondary depression, allergies, MCS, etc. FMS
is considered an overlap syndrome. IBS and migraine may precede ME and then become associated with it.
Editors: Carruthers & van de Sande
25
MYALGIC ENCEPHALOMYELITIS – Adult & Paediatric:
Appendix 2: Sleep and Pain Profile
Name:
Date Energy
% a.m.
Sun
Mon
Tues
Wed
Thur
Fri
Sat
Sun
Mon
Tues
Wed
Thur
Fri
Sat
Date:
Pain
HR
BP
Activities/Factors
0-10
a.m.
to
Energy
Pain
Day ↑↓ Day↑↓
Body
temp.
Min. to
fall asleep
Time
Slept
Awake
Depth Refresh# of min. 1-5
ed 0-10
Pain Visual Analog Scale (PAIN VAS): Indicate the amount of pain you have had in the last 48 hours by marking a ‘/’ through the line.
0
1
2
3
4
5
6
7
8
No Pain
Body Pain
Diagrams:
9
10
Excruciating Pain
Aching: ===== , Burning Pain: xxxxx, Stabbing Pain: //////, Pins & Needles: ooooo, Joint Pain: •••••
Other Pain: ppppp Describe:
Pain on Day 1
Visual Energy & Pain Chart
Blue line: Energy Red line: Pain
Sun.
Mon. Tues. Wed. Thur. Fri.
Sat.
Sun.
100%
Pain on Day 14
Mon.
Tues.
Wed.
Thur.
Fri.
Sat.
90%
80%
70%
60%
50%
40%
30%
20%
10%
26
International Consensus Panel
International Consensus Primer for Medical Practitioners
Letter to educators & agencies regarding young people with myalgic encephalomyelitis (ME)
My = muscle
Educators may be perplexed by the many symptoms and degree of disability in students who have
algic = pain
ME. A long-term study of absence of students in 1,098 schools indicated that 51% of students
Encephalo = brain
absent had ME [Dowsett E, Colby J. JCFS 1997]. In a long-term follow-up study, the average loss of
mye= spinal cord
school was 1.8 years per child [Speight N]. It is hoped that this letter will enhance your
itis = inflammation
understanding of ME and its educational implications. Educators have an opportunity to support
these young people, accommodate their educational needs, and make a positive difference in their delicate lives.
ME affects all age groups, including young children, all ethnic/racial groups, and all socioeconomic strata. Currently there
is no curative treatment. Prognosis for an individual cannot be predicted with certainty.
ME: WHO ICD G93.3
neurological disease
Myalgic encephalomyelitis (ME) is a severe, complex neurological disease that affects all body
systems. The initial infection may damage the brain and cause profound dysregulation of the nervous and immune
systems, impair cellular energy production, and cardiovascular function. ME is more debilitating than most diseases.
Symptom severity and hierarchy of symptoms in children can fluctuate rapidly and may appear to be erratic.
They can’t produce
Hallmark feature: The body is unable to produce sufficient energy on demand, like a furnace
the energy they need.
that has its pilot light on but it cannot be turned up to address the need for additional heat.
Simple activities are
• Neuroimmune exhaustion: Physical or mental exertion, which can be minimal such as
exhausting.
activities of daily living, causes rapid exhaustion and worsening of symptoms.
• Post-exertional exhaustion and flare of other symptoms can be immediate or delayed by hours or days.
• Recovery period is long, taking 24 hours to several days. A relapse can last days, weeks or much longer.
• The lack of physical and mental stamina results in a substantial reduction in pre-illness energy and activity levels.
Cognitive and central nervous system impairments: Children may have
• Difficulty processing information: slowed thought and speech, poor concentration, confusion, disorientation, difficulty
making decisions, difficulty absorbing information, dyslexia that may only be evident when fatigued, difficulty
sequencing words and numbers, cannot multi-task
• Short-term memory loss: difficulty remembering what one wanted to say, what one was saying, retrieving words,
recalling information, poor working memory
Messages between the brain
• Headaches: severe and chronic headaches are often debilitating; migraine can be
and the other body systems
accompanied by rapid drop in temperature, shaking, severe weakness, vomiting
are miscommunicated and
• Pain: muscles, joints, chest, abdomen, etc. Pain can be widespread, and quickly
are misinterpreted.
fluctuate and migrate.
• Sleep disturbances: In the acute stage, patients typically have prolonged sleep, sometimes extreme, and cannot stay
awake. This often evolves into sleep reversal – insomnia and sleeping much of the day. When patients “crash”
(immobilizing exhaustion), they revert to being unable to stay awake. No matter how long they sleep, they awaken
feeling very tired physically and mentally.
• Motor impairments: muscle weakness, twitching, “pins and needles”, poor balance, poor coordination and fine motor
skills, may appear clumsy, joint hypermobility
• Sensory/perception disturbances: inability to focus vision, hypersensitivity to light, sound, vibration, odour (including
perfume & paint), taste, some foods, chemicals, medications; poor depth perception
Other prominent symptoms
ME is like having the flu every day. Symptoms
• Immune: flu-like symptoms frequently reoccur or activate with exertion
worsen with mental or physical exertion.
• Digestive/gastro-intestinal disturbances, urinary urgency or frequency
• Cardiovascular: inability to tolerate an upright position, light-headedness/dizziness, periods of heart racing
• Body temperature: fluctuates, cold hands and feet, periods of feeling feverish without fever, shivery
• Temperature: cannot tolerate extremes in temperature
Secondary symptoms
• Mood: When young people are trying to cope with this complex, poorly understood disease that can be very
debilitating, they often have mood swings and become anxious or depressed. Temporary hyperactivity is followed by
overwhelming exhaustion. They may become irritable or appear lazy when exhausted.
• Secondary school phobia may develop due to bullying and academic difficulties. Children with ME spend most of their
out-of-school time resting, whereas those with primary school phobia are socializing and participating in activities.
The physician may stop the child’s education until the child is stronger and his/her health has stabilized.
Editors: Carruthers & van de Sande
27
MYALGIC ENCEPHALOMYELITIS – Adult & Paediatric:
Educational considerations and recommendations: Ensure the child receives the education to which s/he is entitled. The
pathophysiology of ME must be respected and reflected in all educational programs.
It is helpful for teachers to meet with the parents and student as soon as the student has been diagnosed with ME and at
the beginning of each year if attending school. Liaise with the child’s physician when appropriate.
Educational accommodations should be selected on an individual basis according to the patient’s health status,
capabilities, special educational needs, and in order to provide the best opportunity for recovery.
1. Modes of education to be considered include home education, tutoring, on-line and virtual learning, correspondence
courses, part-time school attendance, or combinations of various modes.
2. Location of learning environment for education: “What environment provides the best opportunity for this child to
learn and become educated?” In the past there has been too much emphasis on returning the child to school as
quickly as possible. This strategy has failed because the fast paced school environment is too demanding, even on a
part-time basis, and in many cases it has caused the child’s fragile health to spiral downward.
• Energy Efficient Education: Home educating is becoming the method of choice as it makes the most efficient use of
the child’s limited energy in a quiet environment without distractions, and is more conducive to recovery. It is easier
to prioritize and streamline course work in the home setting. Not only does it accommodate pacing and rest periods
as needed, but the mode in which information is given can be adjusted to the individual child. This ensures the child
understands the information at each step and eliminates much of the stress. Ideally a teacher or tutor should be part
of the program. On-line virtual tutoring, with the use of Skype or similar program, can be beneficial.
• School environment: • usually very busy • fast-paced • multi-sources of input • several things may be going on
simultaneously • requires social interaction • sensory overload - bright lights, noise, odours, etc. The physical,
mental, sensory and emotional overload can cause exhaustion, symptom flare, anxiety, depression and relapse.
• Attending school part-time: Is the child strong enough? Does school exacerbate symptoms?
• Combination of part-time school and home tutoring may be considered in mild cases.
• Social contact is secondary to the child’s health and education. Visiting school for social contact may be beneficial
when the child becomes strong enough.
3. Curriculum must be modified, course-work streamlined, and submissions minimalized.
• Prioritize the essentials and focus on concepts.
• Begin a program at a level that will ensure success. Short intervals on a daily basis are better than longer intervals
that can cause exhaustion. After resting during the summer, children typically overestimate what they can do.
• Exams: Focus on exams that are necessary for qualifications. Patients may need to write exams at home under the
supervision of an invigilator. Marked cognitive impairments should entitle a minimum of a 25% increase in the
allotted test time to reflect the work quality of which the patient is capable.
With patience, understanding and support, educators can help these children acquire the education they desire.
Sincerely,
International Consensus Panel for Myalgic Encephalomyelitis (physicians, researchers & an educator representing 12 countries)
References & helpful resources
• TEACH-ME: online in both English & French: http://www.mefmaction.com/index.php?option=com_content&view=article&id=288&Itemid=356
• Tymes Trust: most comprehensive information regarding education of young people with ME http://www.tymestrust.org
• Carruthers BM, van de Sande MI, De Meirleir KL, et al. Myalgic encephalomyelitis: International Consensus Criteria. J Intern Med 2011;270(4):327-38.
28
(Physician’s confirmation of
diagnosis is required.)
Endorsed by:
ME International Consensus
Panel
___________________________
principal/head teacher’s signature
teacher’s signature
________________________
has permission to use
disabled facilities and
obtain other assistance.
________________________
student’s name
photo
School Pass
Access to Education
Myalgic
Encephalomyelitis
International
Access to Education School Pass: Simple accommodations that have been prearranged and agreed upon by the teacher and student,
such as taking a rest, eating a snack to regain strength, wearing sunglasses due to light hypersensitivity, not standing in a cue, or being
excused to the bathroom can be made without discussion or disruption of the class by showing the school pass.
International Consensus Panel
Authors and their affiliations continued from front inside cover.
Carlo-Stella, Nicoletta, MD, PhD; clinician and researcher: immunology, immunogenetics of ME
Azienda Ospedaliera della Provinca di Pavia, Pavia
Primary care private practice with focus on ME, Pavia, Italy
Chia John, MD; clinician and researcher: internal medicine - infectious diseases, immunopathogenesis
Clinical assistant professor: Harbor-UCLA Medical Center, University of California, Los Angeles, CA
Director: EV Med Research, Lomita, California, USA
Darragh, Austin, MA, MD, FFSEM (RCPI, RCSI), FRSH, FI Biol I (Hon); clinician and researcher: endocrinology
University of Limerick, Limerick, Ireland
Gerken, Anne, MB, BS, D ObstRCOG, FRCPath: clinical microbiologist
Retired consultant microbiologist with many years of experience working with ME, Suffolk, United Kingdom
Jo, Daehyun, MD, PhD; clinician and researcher: pain and anesthesiology
Director: Pain Clinic, Konyang University Hospital, Daejeon
Professor: Department of Anesthesiology and Pain Medicine, Konyang University, Daejeon, Korea
Lewis, Don, MD; clinician: primary care with focus on ME
Donvale Specialist Medical Centre, Donvale, Victoria, Australia
Light, Alan R, PhD; researcher: physiology, neuroscience, medical neurobiology and neuroanatomy, mechanisms
of pain & fatigue
Professor: Anesthesiology and Neurobiology and Anatomy; Molecular and Cellular Neuroscience, University of
Utah School of Medicine, Salt Lake City, Utah, USA.
Light, Kathleen C, PhD; researcher: behavioral medicine – physiological dysregulation in chronic pain and fatigue
disorders, behavioral factors in cardiovascular disease, health benefits of family support, minority and
women’s health issues
Professor: Anesthesiology and Psychology, University of Utah School of Medicine, Salt Lake City, Utah, USA.
Marshall-Gradisnik, Sonya, PhD; researcher: immunology - natural killer cells, vasoactive neuropeptide
dysfunction and receptor expression, T cell regulatory dysfunction
Professor: School of Medical Sciences, Griffith Health Institute, Griffith University, Southport, Australia
McLaren-Howard, John, DSc, FACN; clinical biochemistry, biochemistry of nutrition, biochemical features of ME,
mitochondrial dysfunction, vascular disease & intestinal dysbiosis
Fellow: American College of Nutrition
Director: Acumen Medical Limited, Tiverton, Devon, United Kingdom
Mena, Ismael, MD; nuclear medicine
Director: Imagenologia Funcional Cerebral, Department of Medicina Nuclear, Clinica las Condes, Santiago, Chile
Professor Emeritus: Radiological Sciences, UCLA School of Medicine, California, USA
Doctor Honoris Causa: University, d'Auvergne, France
Miwa, Kunihisa, MD, PhD; clinician and researcher: internal medicine: cardiology, cardiovascular physiology
Director: Miwa Naika Clinic, Toyama, Japan
Murovska, Modra, MD, PhD; researcher: virology, medical microbiology, molecular biology
Director: A. Kirchenstein Institute of Microbiology and Virology, Riga Stradins University, Riga, Latvia
Associate Professor: Riga Stradins University, Riga, Latvia
Stevens, Staci, MA; exercise physiology
Director: Workwell Foundation, Ripon, California, USA
Conflict of interest statement
Dr. McLaren-Howard has declared a vested interest in Acumen Medical Ltd., UK.
All other members declare that they have no competing interests.
Consensus Coordinator: Marj van de Sande

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