Pediatric Neurology

This paper introduces the primary care physician to the unique and challenging aspects of initially diagnosing and managing a complex condition for which there are a plethora of symptoms, few physical findings, no known cause, and no specific treatments. While daunting, the rewards are many, and those who pursue an interest in ME/CFS find themselves at the forefront of medicine.



Myalgic is body pain.   Encephalomyelitis is inflammation of brain & spinal cord

Post-infectious and inflammatory encephalomyelitis are broadly represented by the syndrome acute disseminated encephalomyelitis (ADEM). ADEM forms one of several categories of primary inflammatory demyelinating disorders of the central nervous system. Others include multiple sclerosis (MS), acute transverse myelitis, and Devic’s disease. It should be remembered that these are syndromically defined diseases at present. There are no diagnostic tests presently available short of brain biopsy, but future advances may reveal diagnostic biological markers of disease and in so doing dramatically advance the pathophysiological and therapeutic understanding of these conditions. A wholesale change in classification and nomenclature may well follow. In the meantime clinicians must remain keenly appreciative of subtle shades of grey: ADEM, first MS relapse, or ultimately benign clinically isolated syndrome? The answers are relevant to prognosis and, more recently, selection of the correct therapeutic strategy.




The Importance of Accurate Diagnosis of ME and CFS in Children and Adolescents: A Commentary

Myalgic Encephalomyelitis and Chronic Fatigue Syndrome (ME and CFS) are chronic illnesses that causes a range of debilitating symptoms. While most research has focused on adults, the illness also presents in children and adolescents. Many physicians find it difficult to diagnose the illness. In this commentary paper, we discuss a range of salient themes that have emerged from our ongoing research into the prevalence of ME & CFS in children and adolescents. We discuss reasons why pediatric prevalence estimates vary widely in the literature, from almost 0% to as high as 3%. We argue that there is considerable misdiagnosis of pediatric cases and over-inflation of estimates of pediatric ME & CFS. Many children and teenagers with general fatigue and other medical complaints may meet loose diagnostic criteria for ME & CFS. We make recommendations for improving epidemiological research and identifying pediatric ME & CFS in clinical practice.




What Causes Brain Fog?

Brain fog is a term often used when our mind feel sluggish or foggy, for example when words just don’t come easily to us and we don’t feel as shard.  Or we lose our train of thought and can’t seem to have easy back and forth conversation with someone or even not remember what they did yesterday. Many of our patients often say it feels like a “hangover” after a night out.

The more medical term is neuroinflammation, which is inflammation of the brain and the nerves. There are many factors that can cause neuroinflammation. To new a few that we commonly see in our practice are chemical toxins, infections (biotoxins), poor gut health, food sensitivities/intolerance and stress.

Some people notice this brain fog and take action earlier, while others wait until their executive and cognitive functions get              much more impaired. At EnviroMed, we want to encourage people to take action earlier and explore their cause of                          brain fog in hopes to stop and reverse it.

Although brain fog is sometimes thought to be a condition itself, it is actually a symptom of another illnesses. It is characterized by episodes of “mental slowness, poor concentration and mental clarity” that can last anywhere between a few seconds to days

These episodes are often described as a type of cognitive dysfunction that involves:

  • Memory loss

  • Lack of mental clarity

  • Inability to concentrate

  • Increased irritability

  • Forgetting words in a sentence

  • Difficulty to read

  • Cramping

When you experience brain fog or these symptoms, your body is telling you something is causing your brain to be inflamed (also known as neuroinflammation).




A Systematic Review of Drug Therapies for CFS  or Myalgic Encephalomyelitis.


The pathogenesis of chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) is complex and remains poorly understood. Evidence regarding the use of drug therapies in CFS/ME is currently limited and conflicting. The aim of this systematic review was to examine the existing evidence on the efficacy of drug therapies and determine whether any can be recommended for patients with CFS/ME.



Chronic viral infections in Myalgic Encephalomyelitis

Journal of Translational Medicine201816:268   ///

©  The Author(s) 2018, Received: 2 August 2018,  Accepted: 24 September 2018,  Published: 1 October 2018


This review aims to compile all the studies done so far to investigate various viral agents that could be associated with ME/CFS. Furthermore, we suggest strategies to better design future studies on the role of viral infections in ME/CFS.


Understanding Myalgic Encephalomyelitis (M.E.) as per  Dr Byron Hyde, Canadian M.E. Expert


If a patient or a family member has tried to search the internet for an understanding of either Myalgic Encephalomyelitis (M.E.), they will have been overwhelmed by the multitude of technical descriptions and the numerous overlapping medical conditions. M.E. represent a complex, multi-system group of afflictions, adversely affecting the brain, heart, neuro-endocrine, immune and circulatory systems in our bodies and are two separate illnesses. At times, this has led to M.E. symptoms being confused with the symptoms for neurasthenia, multiple chemical sensitivities, fibromyalgia syndrome and chronic mononucleosis. 

Publications by Dr Hyde and his Nightingale Research Foundation.

2019  -  Symposium, and opening of the Institute for Scientific Freedom, 9 March 2019

Scientific freedom is under constant pressure. We will therefore open an Institute for Scientific Freedom on 9 March in Copenhagen in connection with an international scientific meeting, with experienced speakers from USA, Europe and Australia. Please register as early as possible.


Cochrane in moral downfall

Show trial against co-founder of the Cochrane Collaboration Peter C. Gøtzsche leading to his expulsion from Cochrane.




Law Project for Psychiatric Rights


Psych Rights has gotten as far as it can through the pro bono efforts of its founder James B. (Jim) Gottstein, Esq., and Mr. Gottstein is regrettably no longer financially able to devote himself to PsychRights on a volunteer basis. PsychRights is seeking substantial funding to further pursue its mission. See, Getting to the Next Level.


The Law Project for Psychiatric Rights (PsychRights) is a non-profit, tax exempt 501(c)(3) public interest law firm whose mission is to mount a strategic litigation campaign against forced psychiatric drugging and electroshock in the United States akin to what Thurgood Marshall and the NAACP mounted in the 40's and 50's on behalf of African American civil rights. The public mental health system is creating a huge class of chronic mental patients through forcing them to take ineffective, yet extremely harmful drugs. Getting to the Next Level

Due to the pervasive psychiatric drugging of children and youth, PsychRights has made attacking this problem a priority. Children are virtually always forced to take these drugs because it is the adults in their lives who are making the decision. This is an unfolding national tragedy of immense proportions. As part of its mission, PsychRights is further dedicated to exposing the truth about these drugs and the courts being misled into ordering people to be drugged and subjected to other brain and body damaging interventions against their will



Neurological Symptoms

This website is about symptoms which are: • neurological (such as weakness, numbness or blackouts) • REAL (and not imagined) • and due to a PROBLEM with the FUNCTIONING of the nervous system, and NOT due to neurological disease. These symptoms have many names (including dissociative symptoms and conversion symptoms) but are often described as "functional symptoms" or "functional disorders" Symptoms like these are surprisingly common but can be difficult for patients and health professionals to understand. This website, written by a neurologist with a special interest in these problems, aims to give you a better understanding of these symptoms. It has no advertising and does not make any money for the author.



Vaccines & Neurological Damage

Imagine if the vaccine manufacturer admitted vaccines cause neurological damage.....
Most of these warnings are typically hidden in the very small print on some arbitrary page or in the vaccine packet insert which is almost never shown to doctors, medical staff, patients, or parents of infants and children.,-spinal-cord,-and-nerve-disorders/brain-infections/encephalitis?fbclid=IwAR1tS0XgYa6VdWCpa0PLblU3eSIASOFxnkjve0DSOxDp83it8nOeUlW4tHg





Encephalomyelitis or Encephalitis are an acquired brain injury

A traumatic brain injury interferes with the way the brain normally works. When nerve cells in the brain are damaged, they can no longer send information to each other in the normal way. This causes changes in the person's behavior and abilities. The injury may cause different problems, depending upon which parts of the brain were damaged most.

There are three general types of problems that can happen after TBI: physical, cognitive and emotional/ behavioral problems. It is impossible to tell early on which specific problems a person will have after a TBI. Problems typically improve as the person recovers, but this may take weeks or months. With some severe injuries changes can take many years.


Both Dr. Ramsay & Dr Hyde believe polio is in the center of ME.


Perhaps it is a problem with the actual polio vaccine. The serum used in the vaccine comes from the kidney of the Green Monkey.

I always found it ironic because I lived and worked in Barbados for over 20 years.


New petition set up for Cochrane members  November 2018.
"Most Cochrane members will have felt at best uneasy about the recent events in Cochrane. We also felt uncomfortable and wondered what caused our feelings. The biggest problem we felt was the lack of transparency. Who had been doing what? Who makes the decisions in Cochrane? What can I do as a member of a Cochrane Centre or a Review Group? Many questions were also triggered by the statement of the Governing Board that there will be ‘zero tolerance for bad behaviour’. We fear this will easily lead to ‘zero tolerance for different opinions’.

We are all members of Cochrane because we believe that evidence-based health care is an important asset for public health. Evidence that can be trusted is what we all want to create. We believe that the lack of transparency and trust which we experience at the moment is detrimental to Cochrane and we have to do something about it.

There are four major policy issues that we would like to improve.
Create a culture of open discussion
Refocus on the heart of Cochrane
Increase the involvement of Cochrane members
Find a better business model for Cochrane
Read the full text explaining these four points at: Please indicate in your comments if you are a Cochrane member and if you have additional concerns.
By signing this petition we all want to express our support of these four points as key areas of development in Cochrane.
This action was initiated by:

Jos Verbeek, Coordinating Editor, Cochrane Work
Gerd Antes, Director, Cochrane Germany
Matteo Bruschettini, Director, Cochrane Sweden
Jani Ruotsalainen, Managing Editor, Cochrane Work
Chris Del Mar, Coordinating Editor, Cochrane Acute Respiratory Infections
Mark Jones, Centre for Research in Evidence-Based Practice (CREBP), Bond University, Australia
Caroline Struthers, UK EQUATOR Centre, University of Oxford
Lotty Hooft, Director, Cochrane Netherlands
Tianjing Li, Co-ordinating Editor, (US Satellite) Eyes and Vision
Gerald Gartlehner, Director, Cochrane Austria
Nicole Skoetz, Senior Editor, Cochrane Cancer
Barbara Nußbaumer-Streit, Associate Director, Cochrane Austria
Nancy Santesso, Deputy Director, Cochrane Canada
Philipp Dahm, Coordinating Editor, Cochrane Urology
Malgorzata Bala, Director, Cochrane Poland




1. This memorandum relates to the work of NICE in one specific area, namely its Guideline on the management of adults and children with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis ("CFS/ME") currently in preparation, a draft of which was issued on 29 September 2006.

2. It is submitted by Malcolm Hooper, Professor Emeritus of Medicinal Chemistry at the University of Sunderland, in conjunction with Eileen Marshall and Margaret Williams—an established team whose aim is to expose and prevent the injustice perpetrated on patients with ME/CFS in the UK by those whose job is to help, not abuse, such patients. Both Eileen Marshall and Margaret Williams formerly held senior clinical posts in the NHS.

Read the whole report here:




This chapter discusses the neuroimmune system, and in particular the autonomic nervous system and its influence on immunity and inflammation. The innate immune system provides a global, nonspecific defense against pathogens. Major contributors to the innate immune system include epithelial cells, which prevent pathogen entry, phagocytes such as neutrophils and macrophages, the complement system, and pattern recognition receptors. In contrast to the innate immune system, the adaptive immune system provides highly specific responses to the invading pathogen. The predominant cells involved in adaptive immunity are B and T lymphocytes and antigen presenting cells (APCs), which provide a link between innate and adaptive immunity.



Diffuse Brain Injury Observed on Brain SPECT:

If the patient’s illness is not measurable using a dedicated brain SPECT scan such as a Picker 3000 or equivalent, then the patient does not have M.E. For legal purposes these changes may be confirmed by PET brain scans with appropriate software and / or QEEG.

These changes can be roughly characterized as to severity and probable chronicity using the following two scales: A: Extent of injury and B: degree of injury of CNS vascular function.

Extent of Injury:
Type 1:
One side of the cortex is involved. Those patients labeled as 1A have the best chance of recovery.

Type 2:
Both sides of the cortex are involved. These patients have the least chance of spontaneous recovery.

Type 3
Both sides of the cortex, and either one or all of the following: posterior chamber organs, (the pons and cerebellum), limbic system, the sub- cortical and brainstem structures are involved. Type 3B are the most severely affected patients and the most likely to be progressive or demonstrate little or no improvement with time.

Degree of injury
Type A:
Anatomical integrity is largely maintained in the
Brain SPECT scan.
Type B:
Anatomical integrity is not visible in the CNS SPECT scan.
Type 3B are some of the most severely and chronically injured patients.



Definitions & aetiology of Myalgic Encephalomyelitis:

 How the Canadian Consensus Clinical definition of Myalgic Encephalomyelitis works

If such clarity and adequacy are not achieved, several types of smudging may result. In other words, if the generalisations from the medical model are too generic, they have no chance of adequately meeting the patients' experience of illness and much relevant data may be overlooked or misinterpreted. Thus, the move from a more specific clinical concept such as myalgic encephalomyelitis or fibromyalgia to a more generic concept such as chronic fatigue syndrome or chronic pain syndrome entails missing a lot of the information that makes the syndrome a name match, and an experience. The syndrome as an experience is a coherent entity whose parts run together as a process—as the word syndrome indicates etymologically—and whose causal interactions are sensed directly in the mode of causal efficacy.8 This entity arises against a background that is treated as a non‐entity for the purposes of the observation. Thus, the attempt to organise clinical activity around a non‐entity, such as in somatisation disorder and Munchausen syndrome where diagnosis depends on the absence of an entity, may interfere with proper clinical activity by importing a misplaced forensic attitude towards a patient's experience of illness, discounting or distorting its relevance. The move towards ignoring the distinctions between primary and secondary which designate sensed causal directions in a clinical entity, whether applied to depression, anxiety, infection or fibromyalgia, add to the confusion and impede the elucidation of a properly dynamic clinical entity. The widespread use of the holistic biopsychosocial model of disease without any distinction between a clinical entity and its background encourages the “drowning” of clinical entities by risk factors, which can proliferate endlessly in a nominalist fury without orientation as to their state of relevance or lack thereof with respect to a real entity.



Via Jerrold Spinehirne - Aug/Sept 2018

Similar "discoveries" were made after the CDC expanded the definition of CFS in 2005 using the Reeves "empirical" method of diagnosis.

For example, this 2006 study "Early Adverse Experience and Risk for Chronic Fatigue Syndrome" by the CDC and researchers at Emory University in Atlanta, where the CDC is located, produced this result:

"Our results suggest that childhood trauma is an important risk factor for CFS. This risk was in part associated with altered emotional state. Studies scrutinizing the psychological and neurobiological mechanisms that translate childhood adversity into CFS risk may provide direct targets for the early prevention of CFS."

Now researchers, also at Emory University, by using the nonspecific new criteria for SEID (CDC-defined ME/CFS) have "uncovered" a link between SEID and excessive daytime sleepiness disorder (hypersomnolence).

This shows the confusion and unreliable results connected with using overly inclusive, nonspecific criteria in research. Unfortunately, this is likely to be only the beginning of such dubious studies based on the new CDC/IOM SEID criteria. History repeats itself.



Damning criticism of the flawed #PACEtrial by psychologist Prof Brian Hughes

Rampant methodological crisis' - describes how psychologists invent their own study methods, change them part way if the data don't fit their preconceptions, misuse stats etc.
“The controversies surrounding the PACE trial can be seen as emblematic of the real-world

problems caused by psychology’s many crises.”




Background to, consideration of, and quotations from the Manuals for the Medical Research Council’s PACE

Trial of behavioural interventions for Chronic Fatigue Syndrome / Myalgic Encephalomyelitis, together with evidence

that such inte rventi ons are unlikely to be effective and may even be contraindicated.


​​​​​​​What is Myalgic Encephalomyelitis?

Unfortunately, the majority of physicians in the UK, Europe and North America, not to mention the rest of the world, have a poor and sometimes distorted idea of what Myalgic Encephalomyelitis represents. One of the several fallacies is that M.E. is just another name for Chronic Fatigue Syndrome (CFS). It is not and never has been. M.E. is a biphasic epidemic and sporadic enteroviral infectious disease. Up to 1955 and the introduction of Jonas Salk’s polio immunization M.E. tended to occur in the same location and at the same time as polio epidemics. In epidemic form, both Polio and M.E. tend to peak in the north temperate hemisphere during the period of July to November, with a last small blip around Christmas when families tend to get together.

CFS is a syndrome based upon a series of symptoms that are common to hundreds of different, often serious diseases and diagnostic of none. CFS can also represent multiple different pathologies or diseases in the same person. At times, CFS may be related to undiagnosed genetic illnesses. Many physicians assume patients with multiple symptoms and no easily observable pathologies are actually hysterical, anxiety neurosis or depressive patients. They employ the term CFS in place of making the unwelcome diagnosis of hysteria or psychiatric disease. The term CFS should not be utilized, as in the minds of most physicians it is a disparaging term, and in the minds of many physicians, a term belittling to the patient.

Understanding M.E. is relatively simple. However, understanding M.E. was much simpler sixty years ago. Prior to 1954, if the patient fell ill with M.E. their illness would have been called: Missed Polio.

Sepsis Leaves Long Legacy on Brain and Body

Surviving sepsis doesn't mean troubles are over for older adults, who face substantial cognitive impairment and functional disability afterward, according to results from a longitudinal population-based study.

An episode of sepsis boosted the odds of acquiring moderate to severe cognitive impairment 3.3-fold, whereas other types of hospitalizations had no effect, Theodore J. Iwashyna, MD, PhD, of the University of Michigan, in Ann Arbor, and colleagues found.

It also added 1.5 new functional limitations on average for older adults with no more than moderate disability prior, they reported in the Oct. 27 issue of the Journal of the American Medical Association.  (USA) (Canada)

Understanding long term effects of Sepsis

Cardiology Handout Support - Issues Specific to Myalgic Encephalomyelitis as per the ICC 2011

Can be printed from PDF  to take to Dr


Epstein-Barr virus protein can “switch on” risk genes for autoimmune diseases

Infection with Epstein-Barr virus (EBV), the cause of infectious mononucleosis, has been associated with subsequent development of systemic lupus erythematosus and other chronic autoimmune illnesses, but the mechanisms behind this association have been unclear. Now, a novel computational method shows that a viral protein found in EBV-infected human cells may activate genes associated with increased risk for autoimmunity. Scientists supported by the National Institute of Allergy and Infectious Diseases report their findings today in Nature Genetics.

“Many cases of autoimmune illness are difficult to treat and can result in debilitating symptoms. Studies like this are allowing us to untangle environmental and genetic factors that may cause the body’s immune system to attack its own tissues,” said NIAID Director Anthony S. Fauci, M.D.  “A better understanding of the complex causes of autoimmunity promises to lead to better treatment and prevention options.”

EBV infection is nearly ubiquitous in the human population worldwide. Most people acquire EBV in early childhood, experience no symptoms or only a brief, mild cold-like illness, and remain infected throughout their lives while remaining asymptomatic. When infection first occurs in adolescence or young adulthood, EBV can lead to a syndrome of infectious mononucleosis characterized by prolonged fever, sore throat, swollen lymph nodes and fatigue.  This syndrome, also known as “mono” or the “kissing disease,” generally resolves with rest and only rarely causes serious complications.



Understanding Traumatic Brain Injury

Make no mistake about it.  Inflammation of the brain is a brain injury.

A traumatic brain injury interferes with the way the brain normally works. When nerve cells in the brain are damaged, they can no longer send information to each other in the normal way. This causes changes in the person's behavior and abilities. The injury may cause different problems, depending upon which parts of the brain were damaged most.

There are three general types of problems that can happen after TBI: physical, cognitive and emotional/ behavioral problems. It is impossible to tell early on which specific problems a person will have after a TBI. Problems typically improve as the person recovers, but this may take weeks or months. With some severe injuries changes can take many years.


Viral Diseases of the Central Nervous System

Virus-induced diseases of the central nervous system (CNS) represent a significant burden to human health worldwide. The complexity of these diseases is influenced by the sheer number of different neurotropic viruses, the diverse routes of CNS entry, viral tropism, and the immune system. Using a combination of human pathological data and experimental animal models, we have begun to uncover many of the mechanisms that viruses use to enter the CNS and cause disease. This review highlights a selection of neurotropic viruses that infect the CNS and explores the means by which they induce neurological diseases such as meningitis, encephalitis, and myelitis.


The central nervous system (CNS) is protected by a highly complex barrier system, yet a wide variety of viruses still manage to gain access and induce disease. In fact, the number CNS viral infections each year is greater than all bacterial, fungal, and protozoa infections combined [1]. Following CNS infection, inflammation can arise in distinct anatomical regions such as the meninges (meningitis), brain (encephalitis), and spinal cord (myelitis), or simultaneously in multiple regions (meningoencephalitis, encephalomyelitis). For many neurotropic viruses, viral cytopathology plays a major role in CNS dysfunction. However, experimental animal models have revealed that the antiviral immune response can also under certain conditions be an active contributor to disease. This brief review will break down CNS viral pathogenesis into distinct anatomical regions and discuss selected viruses that drive pathology involved in each.


Great strides have been made to identify viruses that infect the CNS and mechanisms they use to cause disease. However, many viruses that drive CNS disease remain unidentified and thus it is imperative to survey cohorts of patients with neurological diseases suspected to have an infectious etiology [135]. While human pathology studies have been instrumental in identifying CNS regions affected by neurotropic viruses, the development of experimental animal models are often critical for the discovery of immunological and virological mechanisms that lead to CNS diseases. For example, in vitro and in vivomodels have helped uncover the role of apoptosis and specific viral proteins in the pathogenesis of enterovirus, alphavirus, and flavirus infection of neurons.

M.E. and ME

ME sufferer Emma Donohoe investigates how young people cope with the debilitating illness, of which symptoms can include devastating fatigue, digestion issues and brain fog. It comes as current treatments for the condition are being reviewed, after years of controversy. Emma meets the mother of a 21 year old who died after suffering for years from ME and says her daughter’s condition is so stigmatised and misunderstood she was embarrassed to tell people what she was suffering from. We discover it’s an illness which many doctors don’t understand and people still talk about “yuppy flu” - thinking sufferers are being lazy or too depressed to get out of bed.




August 2018 - Submitted by Alex Young

PEM, PENE, ICC, CCC, SEID and ME ... a review of distortions in the discussion 


There are inaccuracies being propagated about ME, ME/CFS and SEID definitions. I support the ICC as a research definition. I think its probably the best clinical definition as well, with the best definitions in order -

  1. International Consensus Criteria

  2. Canadian Consensus Criteria

  3. Systemic Exertion Intolerance Disease


Is PEM defined as a feeling of general discomfort or uneasiness

The ICC uses PENE, or Post Exertional Neuroimmne Exhaustion-

"Postexertional 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 as follows:

  • 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.

  • Postexertional symptom exacerbation:e.g.acute flu-like symptoms, pain and worsening of other symptoms.

  • Postexertional exhaustion may occur immediately after activity or be delayed by hours or days.

  • Recovery period is prolonged, usually taking 24 h or longer. A relapse can last days, weeks or longer.

  • Low threshold of physical and mental fatigability (lack of stamina) results in a substantial reduction in pre-illness activity level."


The ICC can be thought of as a modernised and updated CCC definition.

The CCC defines PEM as - (broken up for easier reading as this is one paragraph)


Post-Exertional Malaise and/or Fatigue -

  • The malaise that follows exertion is difficult to describe but is often reported to be similar to the generalized pain, discomfort and fatigue associated with the acute phase of influenza. 


  • Delayed malaise and fatigue may be associated with signs of immune activation: sore throat, lymph glandular tenderness and/or swelling, general malaise, increased pain or cognitive fog. Fatigue immediately following activity may also be associated with these signs of immune activation.

  • Patients who develop ME/CFS often lose the natural antidepressant effect of exercise, feeling worse after exercise rather than better. Patients may have a drop in body temperature with exercise.

  • Thus fatigue is correlated with other symptoms, often in a sequence that is unique to each patient. After relatively normal physical or intellectual exertion, a patient may take an inordinate amount of time to regain her/his pre-exertion level of function and competence. For example, a patient who has bought a few groceries may be too exhausted to unpack them until the next day.

  • The reactive fatigue of post-exertional malaise or lack of endurance usually lasts 24 hours or more and is often associated with impairment of cognitive functions. There is often delayed reactivity following exertion, with the onset the next day, or even later.

  • However, duration of symptoms also varies with the context. For example, patients who have already modified their activities to better coincide with the activity level they can Carruthers et al. 15 handle without becoming overly fatigued will be expected to have a shorter recovery period than those who do not pace themselves adequately."

As you can see there is minimal difference between PEM and PENE. PENE is however a bit more succinct.


The ICC later goes on to expand on the malaise term - (again broken up for ease of reading)


Postexertional neuroimmune exhaustion (PENE pen'-e)

‘Malaise’– a vague feeling of discomfort or fatigue [41] – is an inaccurate and inadequate word for the pathological low-threshold fatigability and postexertional symptom flare.

  • Pain and fatigue are crucial bioalarm signals that instruct patients to modify what they are doing in order to protect the body and prevent further damage.

  • Postexertional neuroimmune exhaustion is part of the body’s global protection response and is associated with dysfunction in the regulatory balance within and between the nervous, immune and endocrine systems, and cellular metabolism and ion transport [42-46]. The normal activity/rest cycle, which involves performing an activity, becoming fatigued and taking a rest whereby energy is restored, becomes dysfunctional.

  • Numerous papers document abnormal biological responses to exertion, such as loss of the invigorating effects of exercise [20], decreased pain threshold [47-49], decreased cerebral oxygen and blood volume/flow [50-53], decreased maximum heart rate [54], impaired oxygen delivery to muscles [55], elevated levels of nitric oxide metabolites [56] and worsening of other symptoms [57].

Patients reach the anaerobic threshold and maximal exercise at a much lower oxygen consumption level [58]. Reported prolonged effects of exertion include elevated sensory signalling to the brain [59] that is interpreted as pain and fatigue [29], elevated cytokine activity [60], delay in symptom activation [61] and a recovery period of at least 48 h [57]. 
When an exercise test was given on two consecutive days, some patients experienced up to a 50% drop in their ability to produce energy on the second evaluation [62]. Both submaximal and self-paced physiologically limited exercise resulted in postexertional malaise [48]."

Its easy to see the ICC takes advantage of the many advances in the science since the CCC, and this is very useful, but it does not substantially alter the definition.

Systemic Exertion Intolerance Disease defines PEM in the clinicians guide as -

"Post-exertional malaise (PEM) PEM is worsening of a patient’s symptoms and function after exposure to physical or cognitive stressors that were normally tolerated before disease onset. Subjective reports of PEM and prolonged recovery are supported by objective evidence in the scientific literature, including failure to normally reproduce exercise test results (2-day cardiopulmonary exercise test) and impaired cognitive function after exertion. There is sufficient evidence that PEM is a primary feature that helps distinguish ME/CFS (SEID) from other conditions."

This is the succinct version. The IOM report discusses earlier definitions as well as giving their own. The full report says -

"PEM is an exacerbation of some or all of an individual’s ME/CFS symptoms that occurs after physical or cognitive exertion and leads to a reduction in functional ability (Carruthers et al., 2003).

As described by patients and supported by research, PEM is more than fatigue following a stressor. Patients may describe it as a post-exertional “crash,” “exhaustion,” “flare-up,” “collapse,” “debility,” or “setback.”2 PEM exacerbates a patient’s baseline symptoms and, in addition to fatigue and functional impairment (Peterson et al., 1994), may result in flu-like symptoms (e.g., sore throat, tender lymph nodes, feverishness) (VanNess et al., 2010); pain (e.g., headaches, generalized muscle/joint aches) (Meeus et al., 2014; Van Oosterwijck et al., 2010); cognitive dysfunction (e.g., difficulty with comprehension, impaired short-term memory, prolonged processing time) (LaManca et al., 1998; Ocon et al., 2012; VanNess et al., 2010); nausea/ gastrointestinal discomfort; weakness/instability; lightheadedness/vertigo; sensory changes (e.g., tingling skin, increased sensitivity to noise) (VanNess et al., 2010); depression/anxiety; sleep disturbances (e.g., trouble falling or staying asleep, hypersomnia, unrefreshing sleep) (Davenport et al., 2011a); and difficulty recovering capacity after physical exertion (Davenport et al., 2011a,b).

In some cases, patients experience new symptoms as part of the PEM response."

The report then goes on to expand this for another EIGHT pages. Its a much more comprehensive review.


PEM and SEID versus ICC and CCC

The arguments commonly raised against the IOM definition of PEM and SEID have little scientific validity. I nearly always agree with those raising these in the scientific literature, especially Jason, but in this case I do not.

Definitions used in research need to be as tight as possible, so for research you need lots of exclusion criteria. Its mandatory. For clinical use you want the opposite, broad definitions that allow doctors to diagnose the condition and decide for themselves about exclusion criteria. 

SEID is NOT a research criteria, its clinical.

The exclusion criteria of CCC or ICC, if treated dogmatically, are actually a point against these criteria. However I think most doctors should be aware that exclusions mostly form a good basis in ruling out other conditions and should not be applied dogmatically to clinical diagnoses.

Could SEID lead to excessive diagnosis of patients with depression and other conditions? Yes. Of course. However this is only if the diagnostic criteria are not properly applied.

Post exertional issues are unique to ME so far as we can tell. MS is now ruled out as having them, though MS and many diseases do often show exercise intolerance, but this is not the same thing.

So a proper use of SEID diagnostic criteria only applies to a diagnostic entity with post exertional symptom exacerbation.

However lets look at PENE and PEM from the CCC. If you do not diagnose depression, or consider depression as following ME rather than causing it, then the CCC and ICC have the same flaw as SEID does. They will contain lots of depressed people. IF you do diagnose depression then you might exclude a diagnosis of ME, and yet the depression might be due to ME or a co-morbidity. This may mean, if exclusion criteria are applied dogmatically, many ME patients might be diagnosed with depression (or any of the other exclusion criteria) and yet have undiagnosed an untreated ME. This is undesirable in an ME clinical definition. Its entirely desirable in a research definition.

The real issue is this - there is no commonly used diagnostic test for PEM or PENE. Doctors can use the two day CPET protocol on less severe patients, but how many actually do it? So doctors may frequently get this wrong, and it does not matter if they are using CCC, ICC or SEID. We really need more PEM or PENE diagnostic biomarkers, not just the two day CPET protocol, even though it does mark a major advance in our understanding.

Now if someone is to broadly use SEID in research, especially for biomarker discovery and clinical trials, and do not apply strict exclusion criteria as are commonly added in such trials, then we have every reason to criticise those studies.


Evidence Based Risk

My problem with SEID mostly stems from the methodology used to develop the definition. Evidence based methods allow you to sift through and review evidence, and it works well to create operational guidelines for diseases in which there is abundant and adequate research. In ME and even CFS there is not abundant and adequate research. Its massively under funded, under resourced, and full of pet theories that failed, findings that were not independently replicated, and so on. Its NOT an area in which evidence based methods can be considered reliable. I was saying this even before the IOM review started.

Do support the ICC, for the right reasons.

We SHOULD support the ICC in my view. We should not, however, do so for simplistic and incorrect reasons. The ICC is the most up to date RESEARCH definition, and that is the most important definition. Its use should be required in research till it becomes superseded, preferably by diagnostic biomarker definitions.

We should also support the IOM report, not for SEID, but as the only large evidence based review in existence. It was premature, the evidence base is poor, but we need it politically. Its not an adequate scientific review, simply because the evidence base was not adequate. Given the current advances I suspect a new evidence based review in a few years will be much more valuable. If SEID were redefined based upon an even better evidence base then it should be considered again.

July 2018
Estimates of the number of people in the US meeting the criteria for ME, CFS, and IOM SEID (CDC "ME/CFS")
July 24th, 2018

In an effort to clear up confusion about the difference between the IOM (SEID) and the International Consensus Criteria, MEadvocacy.orghas created a comparison chart.

Hoping this helps clarify that the ICC does a much better job of defining the distinct neuro immune disease myalgic encephalomyelitis.
July 1990
Myalgic encephalomyelitis--a persistent enteroviral infection?
E. G. DowsettA. M. RamsayR. A. McCartney, and E. J. Bell
Myalgic encephalomyelitis is a common disability but frequently misinterpreted. Amongst 6,000 patients referred for general microbiological diagnosis between 1975 and 1987, 420 cases were recognized. Coxsackie B neutralization tests, in 205 of these, demonstrated significant titres in 103/205 (50%), while of 124 additionally investigated for enteroviral IgM, 38/124 (31%) were positive. This illness is distinguished from a variety of other post-viral states by an unique clinical and epidemiological pattern characteristic of enteroviral infection. Prompt recognition and advice to avoid over-exertion is mandatory. Routine diagnosis, specific therapy and prevention, await further technical advances.

This has been making the rounds.  It’s not a new discovery but it has been ignored by those who want you to believe viruses are not involved. 

For ME Patients, Viral Immunities Come at a Devastating, Lifelong Cost

New research shows a connection between a common human herpes virus-6 exposure that leaves a DNA copy of the virus behind and many of the symptoms of a disabling disease called myalgic encephalomyelitis/chronic fatigue syndrome.




Has the U.S. government responded to the disease with the appropriate funding and research

since Osler's Web was published?


Sepsis-associated acute brain inflammation,

if unresolved, may cause chronic neuroinflammation and resultant neurodegenerative diseases.

However, little is known how the transition from acute to chronic neuroinflammation, which is critical for the following progressive neurodegeneration, occurs in sepsis.  The goal of this study was to investigate potential immune factors

regulating the transition process using a widely used endotoxemia LPS mouse model. This model shows

distinct acute and chronic phases of neuroinflammation and recapitulates many cardinal features of

Parkinson’s disease, thus, providing a unique opportunity for studying phase transition of neuroinflammation.



Education Thread; Encephalomyelitis, Encephalitis are both “acquired brain injuries”.

Meningitis and Encephalitis Fact Sheet

What is meningitis? What is encephalitis?
What causes meningitis and encephalitis?
Who is at risk for encephalitis and meningitis?
How are these disorders transmitted?
What are the signs and symptoms?
How are meningitis and encephalitis diagnosed?
How are these infections treated?
Can meningitis and encephalitis be prevented?
What is the prognosis for these infections?
What research is being done?
Where can I get more information?



Slides from ME  event 15th Feb 2020  EventsTeachings

Dr Dietrich Klinghardt MD, Ph.D What is ME? What are the leading theories? Diagnostic tools? – View PDF Successful treatment strategies, latest discoveries, methods and cases. Plus ‘Towards an ME treatment protocol’ Dr. Klinghardt, together with his life partner Daniela Deiosso, is the Founder of the Klinghardt Institute (UK), the American Association of Neural Therapy.




 "Competences to be Demonstrated by IAPT Therapists after training on ME/CFS" This table gives a good idea

of the sort of approach being taken towards ME/CFS.   Check out the image here:



News and views in myalgic encephalomyelitis/chronic fatigue syndrome ME

Though affecting many thousands of patients, myalgic encephalomyelitis should be considered an orphan disease, since the cause remains elusive and no treatment is available that can provide complete cure. There is reasonable insight into the pathogenesis of signs and symptoms, and treatments specifically directed to immunological, inflammatory and metabolic processes offer relief to an increasing number of patients.


Mortality in Patients with Myalgic Encephalomyelitis and Chronic Fatigue Syndrome

Stephanie L. McManimenAndrew R. DevendorfAbigail A. BrownBillie C. MooreJames H. Moore, and Leonard A. Jason (Oct 2016)

The results suggest there is an increase in risk for earlier mortality in patients with ME and CFS. Due to the small sample size and over-representation of severely ill patients, the findings should be replicated to determine if the directional differences for suicide and cancer mortality are significantly different from the overall U.S. population.



AHummingbirdsGuide  You Tube Video's Jodi Bassett founder of the Hummingbird Foundation for M.E.


PGD2 deficiency exacerbates food antigen-induced mast cell hyperplasia - Tatsuro Nakamura,

"Here we investigate the role of PGD2 in food allergy. Oral administration of ovalbumin induces allergic responses in sensitized wild-type (WT) mice. Systemic gene deficiency of haematopoietic PGD synthase (H-PGDS−/−) exacerbates all of the manifestations accompanying severe mast cell hyperplasia in the intestine.

Thus, PGD2 deficiency results in food antigen-induced mast cell hyperplasia."



Myalgic Encephalomyelitis is not a Psychiatric Disorder but all the nonsense of changing names and creating

broad based criteria has opened the door for opportunists trying to build their careers and

charismatic snake oil salesmen. Don't be fooled.   psychiatric disorder is a mental illness

diagnosed by a mental health professional that greatly disturbs your thinking, moods, and/or behavior and

seriously increases your risk of disability, pain, death, or loss of freedom.

In addition, your symptoms must be more severe than expected response to an upsetting event, such as

normal grief after the loss of a loved one.



Many important points raised in this response to criticisms of the ICC in 2011 are just as relevant and valid today:  
Response to ‘A controversial consensus’;  By the International Consensus Panel
"The 2011 ICC for ME continues the direction of refinement undertaken in the Canadian Consensus Criteria and incorporates more recent knowledge and understanding.  More specifically, the rationale of the ICC document advances the successful strategy of the Canadian Consensus Criteria of not viewing symptoms isolated in a nominal list, but rather as coordinated patterns of symptoms that directly reflect the regulatory interactions of the underlying systems involved.  If the same symptoms consistently flare in response to exertion, they are more likely to share a common cause.  For example, if a patient consistently experiences flu‐like symptoms, sore throat and tender lymph nodes in response to exertion, it suggests that immune activation is a component of their underlying pathophysiology, which then can be studied scientifically.

Many thanks to Ya Seen for finding this:


Reprinted from American Journal of Medicine, Vol. 26, Issue 4, Pages 569–595, Copyright (1959), with permission from

Excerpta Medica. The Clinical Syndrome Variously Called

Benign Myalgic Encephalomyelitis, Iceland Disease and Epidemic Neuromyasthenia E.D. Acheson, D.M., M.R.C.P.

Department of Medicine, State University of New York, College of Medicine of New York, and Department of Medical Services, Maimonides Hospital, Brooklyn, New York “Disease is very old and nothing about it has changed.

It is we who change as we learn to recognise what was formerly imperceptible.” J.M.




Michael VanElzakker says that Jen Brea's case is only one person, and that there were many variable things with her, and that the causes of her symptoms are not definitive.  Surgery for this rare condition is dangerous.  ancy Klimas says that this popular attention to the subject of CCI is a phenomenon that has been repeated several times in the history of Myalgic Encephalomyelitis, with other conditions such as Chiari malformation and others.  The two say that these things are not ME.



An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized

Lymphocytes from ME Patients



What is tick-borne encephalitis? Tick-borne encephalitis (TBE) is a type of viral encephalitis caused by a virus that is spread by ticks. Ticks are small parasites that survive by sucking blood from animals – including humans. Ticks are the main carriers of the virus. The virus is also found in small rodents and some larger animals such as deer, sheep and goats. There are three different types of TBE virus: the European (Western), the Siberian and the Far-Eastern (spring-and-summer encephalitis) types. The European type is mainly found in central, eastern and northern Europe. People get TBE mostly in spring, summer and early autumn.



Estimates of the Prevalence and Number of Fibromyalgia Syndrome Patients and Their Alpha1 Antitrypsin Phenotypic

Distribution in Ten Countries

During the last few years, clinical, epidemiological, and pathological evidence has suggested that inherited alpha-1 antitrypsin [AAT] deficiency might play a role in the development of the fibromyalgia syndrome [FMS], probably because of the loss of AAT anti-inflammatory efficacy. The objective of this study was to estimate the prevalence and number of FMS patients, and their AAT phenotypic distribution worldwide. Methods: A critical review selecting reliable studies on the subject. Results: Studies on AAT gene frequencies and FMS prevalence were retrieved for ten countries worldwide, namely Canada, the United States of America [USA], Denmark, Finland, Germany, Italy, the Netherlands, Spain, Sweden, and Pakistan. The severe deficiency Z allele was found in all these countries, with very high frequencies in Denmark and Sweden [23 and 27 per 1,000, respectively], high frequencies in Italy and Spain [16 and 17], intermediate frequencies in Germany, the Netherlands, Canada, and the USA [10 to 14], and a low frequency in Pakistan [nine per 1,000]. The calculated prevalence of AAT deficiency and the number of FMS patients with AAT deficiency were 1/10 and 25,408 in Canada, 1/11 and 478,681 in the US, 1/9 and 3,124 in Denmark, 1/ 36 and 726 in Finland, 1/16 and 48,523 in Germany, 1/13 and 84,876 in Italy, 1/15 and 9,639 in the Netherlands, 1/4 and 114,359 in Spain, 1/11 and 9,065 in Sweden, and 1/25 and 85,965 in Pakistan. Our calculations predict that AAT deficiency would remain undetected in around nine percent of FMS patients, with about eight percent of them carrying moderate deficiency phenotypes [MS, SS, and MZ], and less than one percent with severe deficiency phenotypes [SZ and ZZ]. Conclusions: Therefore, AAT phenotype characterization should be recommended in FMS patients and the possible efficacy of AAT replacement therapy in severe deficiency FMS patients should warrant further studies




From the paper:  "Significance"

It appears highly likely that the vascular cuffing phenomenon arising from enteroviral infection in poliomyelitis and it’s associate ME in the early part of the last century remains alive and well in the world today with the latter enjoying the benefits of being overlooked or conflated with the nonsensical CFS definitions and their offspring by the general medical profession.

Despite this, essential data describing the basic nature of ME have been increasingly well developed by the dedicated and insightful work of a small handful of experienced physicians and researchers.

Contrary to erroneous assumptions that ME cannot be measured, or is defined solely by subjective fatigue, the evidence herein shows that reliable empirical measurement is possible right now with the use of appropriate functional brain imaging technology. This includes SPECT and now qEEG in combination with sLORETA software. Both modalities strongly support the historical record of symptomology going back to 1934 as told by the neurons and blood cells themselves."


Medical Abuse In ME Sufferers (MAIMES)

  • This is a campaign to get MPs to sign slips that will be used to demand a Public Inquiry into the abuse of ME sufferers over the last few decades. This campaign is called MAIMES. [the slip calls for a Public Inquiry]

  • The first goal is to sign up as many MPs as possible to the aims of MAIMEs. Once we have sufficient MPs on side we will approach the Secretary of Health to demand a Public Inquiry

  • We first need “adopters” who are preferably physically able (see comments below) to attend their MPs’ surgery and also who feel that they can explain the issues as detailed below in as convincing a manner as possible! Please - we don't want anyone to feel pressurised in any way to do this. Our goal is to make people better not worsen their condition by attempting something they are not capable of. This is why we also suggest family, friends or carers getting involved where this may be possible - see below also.




This article is reproduced with the kind permission of Katharina Voss.

Katharina is author of the German textbook Myalgische Enzephalomyelitis vs. Chronic Fatigue Syndrom:

Fakten Hintergründe Forschung (tredition 2017) and also writes the blog "ME versus CFS"

The article reproduced below is entitled

"My Therapy Regime for Antiretroviral Treatment of Myalgic Encephalomyelitis".

Katharina has written this article to describe the successful antiretroviral therapy

that she has employed for her ME afflicted daughter.

You can download the article in pdf format here:

Antiretroviral Treatment of Myalgic Encephalomyelitis



Myalgic Encephalomyelitis and Chronic Fatigue Syndrome: A Comprehensive Review

At the moment, there are no specific pharmacological therapies to treat the disease, but several studies’ aims and therapeutic approaches have been described in order to benefit patients’ prognosis, symptomatology relief, and the recovery of pre-existing function.


The term “myalgic encephalomyelitis” (muscle pain, “myalgic”, with “encephalomyelitis” inflammation of the brain and spinal cord) was first included by the World Health Organization (WHO) in their International Classification of Diseases in 1969. It isironic that Donald Acheson, who subsequently became the Chief Medical Officer first coined the name in 1956.8

In 1978 the Royal Society of Medicine accepted ME as a nosological organic entity. The current version of the International Classification of Diseases—ICD‐10, lists myalgic encephalomyelitis under G.93.3—neurological conditions. It cannot be emphasised too strongly that this recognition emerged from meticulous clinical observation and examination.

The contrasting view of myalgic encephalomyelitis as mass hysteria originated with the work of Beard and McEvedy in 197010. It is a matter of record, since both authors are now dead, that Byron Hyde visited McEvedy to discuss his thesis and to meet people involved in the Royal Free outbreak. McEvedy stated that he did not examine any patients and undertook only the most cursory examination of medical records. This was a source of great distress to Melvin Ramsay who carried out the first meticulous study of the Royal Free outbreak. The outcome of McEvedy's work has been described by one of the ME/CFS charities as “the psychiatric fallacy”.

None of the participants in creating the 1988 CFS case definition and name ever expressed any concern that it might TRIVIALISE the illness. We were insensitive to that possibility and WE WERE WRONG.




 In 2012 - Dr. Hyde stated that if sudden onset patients had both a blood test and cerebrospinal fluid checked at the same time for this oligoclonal banding, and the banding is positive, then they either had MS or ME. What is important about this finding is that oligoclonal banding occurs when there is neuron breakdown—nerve cells in the brain being injured on an ongoing, chronic basis.



Comparing and Contrasting Consensus versus Empirical Domains

Since the publication of the CFS case definition [1], there have been a number of other criteria proposed including the Canadian Consensus Criteria [2] and the Myalgic Encephalomyelitis: International Consensus Criteria. [3]. Purpose: The current study compared these domains that were developed through consensus methods to one obtained through more empirical approaches using factor analysis. Methods: Using data mining, we compared and contrasted fundamental features of consensus-based criteria versus empirical latent factors. In general, these approaches found the domain of Fatigue/Post-exertional malaise as best differentiating patients from controls. Results: Findings indicated that the Fukuda et al. criteria had the worst sensitivity and specificity. Conclusions: These outcomes might help both theorists and researchers better determine which fundamental domains to be used for the case definition.





ME Research UK

An audit study was designed to examine correctness of GP diagnosis and usefulness of outpatient screening. We examined 100 consecutive referrals to the Outpatient clinic from August 1990 to June 1992 inclusive. All patients studied had been diagnosed by the general practitioner as PVFS. The patients were then assessed and the diagnosis of PVFS confirmed if the patients met the classic case definition of CFS (Rev Infect Tis 1991; 13 (Suppi 1): 53-55. 107 diagnoses were made in 100 serially screened patients. 67% fulfilled the criteria for PVFS, 12% were diagnosed as having a psychiatric disorder alone, 7% met the criteria of flbromyalgia and there were 21 other organic diagnoses. The organic diagnoses made included muscle disease, connective tissue diseases and endocrine disorders. There was one patient found to have a brain tumour and one patient found to have HIV infection. In conclusion, therefore, there was a 20% incidence of organic pathology in this series, 7% incidence of fibromyalgia and 12% incidence of psychiatric disease.



February 6, 2019

Expert reaction to letter from the HRA to Norman Lamb regarding the S&T Committee’s

inquiry on Research Integrity and the PACE trial.  Reactions to a letter from the Health Research Authority (HRA) to Norman Lamb MP on an inquiry into the PACE trial.

Who Reviews ME/CFS Applications for NIH?                                                                                                                                 Posted on February 5, 2019 by Jennie Spotila.                                                                                                                                 There is no question that NIH’s funding of ME/CFS research has been minuscule relative to the size of the public health crisis. Review of ME/CFS grant applications at NIH has drawn scrutiny from the public as one contributing factor. The public perception is that the grant review panelists have not been ME/CFS experts, and that this has led to the unfair denial of qualified applications.           
In a new study, published today (March 5, 2019) in the journal Nature Communications, researchers at Bar-Ilan University in Israel reveal a novel and unexpected function of sleep that they believe could explain how sleep and sleep disturbances affect brain performance, aging and various brain disorders.
NICE CFS/ME consultation draft 29 September – 24 November 2006 Comments from stakeholders
2017 Theses, Dissertations & Project
Patient perspectives on mental health therapy formyalgic encephalomyelitis (ME) and chronicfatique syndrome (CFS)Brooke




Feb 2019
A model of the development and progression of chronic fatigue syndrome (myalgic encephalomyelitis), the aetiology of which is currently unknown, is put forward, starting with a consideration of the post-infection role of damage-associated molecular patterns and the development of chronic inflammatory, oxidative and nitrosative stress in genetically predisposed individuals. The consequences are detailed, including the role of increased intestinal permeability and the translocation of commensal antigens into the circulation, and the development of dysautonomia, neuroinflammation, and neurocognitive and neuroimaging abnormalities. Increasing levels of such stress and the switch to immune and metabolic downregulation are detailed next in relation to the advent of hypernitrosylation, impaired mitochondrial performance, immune suppression, cellular hibernation, endotoxin tolerance and sirtuin 1 activation. The role of chronic stress and the development of endotoxin tolerance via indoleamine 2,3-dioxygenase upregulation and the characteristics of neutrophils, monocytes, macrophages and T cells, including regulatory T cells, in endotoxin tolerance are detailed next. Finally, it is shown how the immune and metabolic abnormalities of chronic fatigue syndrome can be explained by endotoxin tolerance, thus completing the model.