Myalgic Encephalomyelitis (M.E.) or What? An Operational Definition by Frank Twisk (In Revision & in Reply to by Larrin Carney) - WORK IN PROGRESS -


ME-de-Patiƫnten Foundation, Zonnedauw 15, 1906 HB Limmen, The Netherlands; frank.twisk@hetnet.nl; Tel.: +31-72-505-4775

Received: 3 August 2018; Accepted: 6 September 2018; Published: 8 September 2018

(In Revised & In Reply to, 4th September 2025 by Larrin Carney)

Abstract: 

Myalgic Encephalomyelitis (M.E.), identified as a new clinical entity? with distinctive features in 1956, was originally considered to result in a "Neuromuscular Disorder". 



In 1988 the Centers for Disease Control (CDC) and Prevention...


Dr. Stephen Straus (American Physician, immunologist, virologist and science administrator) for the NIH

...introduced the ill-defined concept of Chronic Fatigue Syndrome (CFS). 

Chronic Fatigue Syndrome: A Working Case Definition - Gary Holmes, M.D. (Annals of Internal Medicine, 1988)


As predicted, CFS, unjustly considered to be a synonym for M.E., 

...pushed M.E. to the background. 

Dr. Dan Peterson and Dr. Paul Cheney (Physician of Internal Medicine)

To develop effective therapies for of M.E. and CFS, it is essential to investigate patients with M.E. specifically. 

For that reason, an operational definition of M.E. is indispensable. 

This article proposes an operational definition based on the most recent formal definitions and symptoms observed in M.E..

M.E. is a multi-systemic illness, which 

(1) has a sudden onset, in most cases a respiratory and/or gastrointestinal infection, and a dramatic onset is recognised; 


(2) has an epidemic and endemic form; 

(3) has an unique clinical pattern deviating from other post-viral states; 

(4) is distinguished by Muscle Fatigability/prolonged Muscle Motor Weakness after trivial exertion; 


(5) is accompanied by symptoms relating to "Neurological Disturbance", especially of Neurocognitive, Autonomic and Sensory functions; 

(6) can be accompanied by symptoms associated with cardiac and other systems; 

(7) is characterized by fluctuation of symptoms (within and between “episodes”); 

(8) has a prolonged relapsing course; and 

(9) has a tendency to become CHRONIC. 

In conclusion, a discriminative definition for M.E. contains four mandatory elements: 


(2) operational criteria for “Neurological Disturbance", especially of Neurocognitive, Autonomic and Sensory functions”; 

(3) Fluctuation of Symptoms; and 

(4) A prolonged relapsing course. 

This tentative definition of M.E. justifies the qualification “Neuromuscular Disorder”.


1. Introduction

Myalgic Encephalomyelitis (M.E.), in the literature also referred to as Epidemic Neuromyasthenia and Non-Paralytic or Atypical Poliomyelitis, and results in a...

...Neuromuscular Disorder, which was identified as a distinct clinical entity? for the first time in 1956 by Sir Donald Acheson. At that time it was evident that muscular symptoms (e.g., Paresis (Muscle Weakness) and Myalgia) and Neurological Dysfunction were the hallmark features of M.E..



Epidemic Myalgic Encephalomyelitis (also known as Enteroviral Encephalomyelitis) M.E. has been recognized by the World Health Organization as a 'Neurological Disease' since 1969, when it published the ICD-8 classification of diseases using (Code 323) for Myalgic Encephalomyelitis. 

The ICD-8 listing for M.E. is :

  • VI. DISEASES OF THE NERVOUS SYSTEM AND SENSE ORGANS
Inflamatory diseases of Central Nervous System (320-324)
Encephalitis, Myelitis, and Encephalomyelitis (except acute infectious as 343)
Encephalomyelitis (chronic) (disseminated, acute) (granulomatous)
(hemarrhagic necrotizing. acute)
(myalgic, benign)
(postexanthematous)
(postinfectious) (see also Encephalitis) 343)


Dr. Stephen Straus (American Physician, immunologist, virologist and science administrator) for the NIH

...introduced the ill-defined notion of Chronic Fatigue Syndrome (CFS). 

Chronic Fatigue Syndrome: A Working Case Definition - Gary Holmes, M.D. (Annals of Internal Medicine, 1988)


CFS was redefined in 1994. The only mandatory feature of CFS is (unexplained) CHRONIC FATIGUE. 

Dr. Keiji Fukuda (Japanese-American Physician and Epidemiologist)

The Chronic Fatigue Syndrome: A Comprehensive Approach to It's Definition and Study - Keiji Fukuda, M.D. (Annals of Internal Medicine, 1994)

Chronic fatigue must be accompanied by at least four out of a list of eight “minor” symptoms: sore throat; tender cervical or axillary lymph nodes; muscle pain, multi-joint pain without joint swelling or redness; headaches of a new type, pattern, or severity; unrefreshing sleep; and post-exertional malaise lasting more than 24 hours.

Infectious Mono-like Syndrome incorporated into the concept of Chronic Fatigue Syndrome. 

FATIGUE and 

01. Fever
02. Sore Throat (Pharyngitis)

03. Tender Lymph Nodes (Lymphadenopathy)

...other miscellaneous viral symptoms; such as Muscle Pain, Joint Pain, Headaches or Sleep Disturbances such as Unrefreshing Sleep, which are NOT uniquely attached to one infectious pathogenic group. 

The case criteria for CFS define a heterogeneous group of patients with chronic fatigue (accompanied by 163 different combinations of “minor” symptoms).

The Chronic Fatigue Syndrome: A Comprehensive Approach to It's Definition and Study - Keiji Fukuda, M.D. (Annals of Internal Medicine, 1994)


M.E. and CFS are entirely different constructs: M.E. is an acute-onset, polio-like, diagnosable, and distinct neurological disease attributed to enteroviral infection; whereas CFS is an ill-defined syndrome encompassing a heterogeneous group of patients, characterized by chronic or profound fatigue, and treated as a “diagnosis of exclusion.”


Chronic fatigue has never been described as a distinctive feature of M.E....


Diffusion tensor imaging reveals neuronal microstructural changes in Myalgic Encephalomyelitis (2011 International Consenus Criteria) and Chronic Fatigue Syndrome (1994 Fukuda Criteria) - Kiran Thapaliya, Sonya Marshall-Gradisnik, Donald Staines and Leighton Barnden (European Journal of Neuroscience, Wiley, 6th August, 2021)


...specific neurological symptoms, discriminative features of M.E....

...are not required to meet the non-diagnosis of CFS.

The Chronic Fatigue Syndrome: A Comprehensive Approach to It's Definition and Study - Keiji Fukuda, M.D. (Annals of Internal Medicine, 1994)

Despite the fact that M.E., results in a typical Neuromuscular Disorder, and CFS, a Fatigue Syndrome, are two completely different clinical entities by definition, CFS has pushed M.E. completely to the background over the last decades.

Thus, the vast majority of studies into “ME/CFS” published since 1990 relate to patients fulfilling the case criteria for CFS.

The Chronic Fatigue Syndrome: A Comprehensive Approach to It's Definition and Study - Keiji Fukuda, M.D. (Annals of Internal Medicine, 1994)

The confusion with regard to diagnosis and abnormalities which has arisen as a result of the introduction of the "non-diagnosis" of CFS was forecasted in 1988 by the renowned M.E. expert Dr. Betty Dowsett, who stated; 

"The introduction of ‘Chronic Fatigue Syndrome’ to designate M.E. does nothing to indicate the unique epidemiological, geographical, clinical, and laboratory findings in M.E. and can only add to the confusion", surrounding the diagnosis, therapy, and prognosis of the condition”.

One of the last important studies investigating M.E. patients dates back to 1990, just prior to the death of Melvin Ramsay, the recognized authority in M.E.

Myalgic Encephalomyelitis --- a persistent enteroviral infection? - Elizabeth Dowsett, Melvin Ramsay, Robert McCartney & Eleanor Bell (Postgraduate Medical Journal, Oxford Academic, 1st July, 1990)

Studies adopting "CFS" research criterias have become much more prominent, since his death.

The Chronic Fatigue Syndrome: A Comprehensive Approach to It's Definition and Study - Keiji Fukuda, M.D. (Annals of Internal Medicine, 1994)


Dr. Bruce Carruthers (Internal Medicine Physician)

M.E. Definition Booklet, September 2011, by Byron Hyde, MD

"At the first meeting on the 27th of October 2005, the Chairman of the Joint Committee, Dr. Ian Gibson, asked me to prepare a report and definition that might assist the committee in its further deliberations. The following are my original recommendation. Dr. Bruce Carruthers, who chaired the 2003 Canadian Clinical Case Definition for ME/CFS, was also present when I gave this definition. I strongly disagreed with Dr. Carruthers in the merging of the definitions of M.E. and CFS since on basis of the physical total body assessment of both M.E. and CFS patients; these two names represent two entirely different spectrums of illnesses. The present 2016 definition is confined to the defining of Myalgic Encephalomyelitis (M.E.). The term CFS is mentioned from time to time to clarify differences.

It is increasingly obvious that too much importance was being placed upon the definitions of Chronic Fatigue Syndrome (CFS), and not enough upon the actual disease, Myalgic Encephalomyelitis (M.E.). These two illness spectrums are not the same and shouldn't be considered the same. Nor is there any doubt in my mind that the various definitions of CFS actively impede physicians' ability to make a rapid and rational diagnosis as well as a scientific confirmation of any testable illness. Such is not true of M.E. where a rapid and rational diagnosis can be confirmed by laboratory and other technological testing."

"In my 27-year investigation of M.E. and CFS patients, I can state with clarity that there is less psychiatric among M.E. or CFS patients than in the general public"

"Garbage Bag Disease: Unfortunately, many physicians appear to be using CFS (currently erroneously labelled ME/CFS) as a convenient garbage bag disease, simply telling patients whom they have no time to investigate, "Oh, you have Chronic Fatigue Syndrome". It is most unfortunate that the Americans, who have now promoted the idea that CFS is the same as M.E. have only compounded the disaster. Due to this garbage bag phenomena mentality many CFS patients are never properly investigated for serious disease and most CFS patients have significant and often treatable pathologies."

"This document is an excellent and timely antidote to the scientifically unsupportable ICC - the latest unhelpful CFS redefinition being endlessly promoted by "ME/CFS" advocates - and so is highly recommended by HFME" - Jodi Bassett

Canadian Consensus Criteria (CCC) - MEPedia


Myalgic Encephalomyelitis and Chronic Fatigue Syndrome - Clinical Working Case Definition, Diagnostic and Treatment Protocols - Bruce Carruthers (Journal of Chronic Fatigue Syndrome, Taylor & Francis Online 2003)


Ellen Wright Clayton (with Dr. Peter Rowe and Dr. Lucinda Bateman) are some of the authors of the bogus SEID (Currently erroneously known as "ME/CFS" Criteria)



Beyond Myalgic Encephalomyelitis and Chronic Fatigue Syndrome - Redefining an illness - Ellen Wright Clayton, Margarita AlegrĆ­a, Lucinda Bateman, Lily Chu, Charles Cleeland, Ronald Davis, Betty Diamond, Theodore Ganiats, Betty Keller, Nancy Klimas, Martin Lerner, Cynthia Mulrow, Benjamin Natelson, Peter Rowe and Michael Shelanski (Institutional Medicine of Medicine (IOM) / The National Academy Press, 2015)


Dr. Ramsay was a consultant physician in infectious diseases at the Royal Free Hospital in London (United Kingdom) during an outbreak of M.E. in 1955.

From that date until his death Ramsay was closely involved in M.E. cases.

To unravel the aetiology and pathophysiology and to develop effective therapies for M.E., it is essential to study patients with M.E. as described in the medical literature.

For that reason an operational definition of M.E. is indispensable.

The aim of this study was to compose an operational definition of M.E. based on the definition and description in the most recent relevant articles, the symptoms and signs observed in the various epidemics (1934–1983) and endemic cases of M.E., and the symptoms often and less-often experienced by 420 patients with M.E..


2. Method

The starting point of the search of an operational definition of M.E. are the last two formal descriptions of M.E.. 

As can be seen from Tables 1 and 2, the definitions of M.E. in these two publications are essentially the same. 

The elements were classified as symptomatic features or characteristic features of the disease (Figure 1, Step 1). 

Based on the text, elements were classified as mandatory or optional (Step 2). 

For example the phrase “a tendency to chronicity” implies it does not apply to all patients: it is an optional feature. 

This also applies to “variable involvement of cardiac and other systems”.

Table 1. The most recent formal definitions of M.E. (1990)

Definition of M.E. (1990)

“A disease commonly initiated by respiratory and/or gastrointestinal infection but an insidious or more dramatic onset following neurological, cardiac or endocrine disability occurs.


The pathognomonic features (of M.E.) are:

1. Complaint of general or local muscular fatigue following minimal exertion with prolonged recovery time.

2. "Neurological Disturbance", especially of neurocognitive, autonomic and sensory functions.

3. Variable involvement of cardiac and other systems.

4. A prolonged relapsing course.

Other characteristics include a prolonged relapsing course and variation in intensity of symptoms within and between episodes, tending to chronicity.

Definition of M.E. (1992)

“A syndrome initiated by a viral infection commonly described as a respiratory/gastrointestinal illness but a gradual or more dramatic onset following neurological, cardiac or endocrine disability is recognised.

The cardinal features, in a patient who has previously been physically and mentally fit, with a good work record are:

1. Generalised or localised muscle fatigue after minimal exertion with prolonged recovery time.

2. "Neurological Disturbance", especially of neurocognitive, autonomic and sensory functions, often accompanied by marked emotional lability and sleep reversal (hypersomnia followed by insomnia).


3. Variable involvement of cardiac and other bodily systems.

4. An extended relapsing course with a tendency to chronicity.

5. Marked variability of symptoms both within and between episodes.”

The symptoms mentioned in epidemic and endemic cases of M.E. were analysed and classified (Steps 3 and 5). 

The symptoms and symptom categories were checked against symptoms observed in 420 patients with well-defined M.E. (Step 4).

Myalgic Encephalomyelitis—a persistent enteroviral infection? - Elizabeth Dowsett, Melvin Ramsay, Robert McCartney & Eleanor Bell (Postgraduate Medical Journal, Oxford Academic, 1st July, 1990)

In Step 2a it was learnt that in addition to Muscle Fatigability/prolonged Muscle Motor Weakness after exertion, “Neurological Disturbance", especially of Neurocognitive, Autonomic and Sensory functions is a mandatory symptomatic feature in the definition of M.E..

To define operational criteria, the 50 neurological symptoms mentioned in cases of M.E. were divided into five categories (Step 6): Neurocognitive Dysfunction, Autonomic Dysfunction, Sensory Dysfunction, Motor Dysfunction, and Unclassified Symptoms.

The basic assumption was that a patient should experience at least one symptom related to neurocognitive dysfunction, at least one symptom related to autonomic dysfunction, and at least one symptom associated with sensory dysfunction in order to meet this operational criteria of M.E.. 

However, considering the frequency of the symptoms reported by 420 patients with M.E. and the number of times specific symptoms were mentioned in the description of cases of M.E., two changes were made (Step 7a). 

Myalgic Encephalomyelitis --- a persistent enteroviral infection? - Elizabeth Dowsett (Postgraduate Medical Journal, Oxford Academic 1990)

First, since only three symptoms observed relate to cognitive disturbance, and not all patients experience these three symptoms, it was decided that Neurocognitive Dysfunction symptoms should be combined with three other symptoms often reported by patients with M.E. (two unclassified neurological symptoms related to sleep and headaches) in order to meet the first operational criterion for “Neurological Disturbance”. Second, because symptoms related to "Sensory Dysfunction" are diverse and this category contains various symptoms often experienced by patients, it was decided that a patient should report at least two symptoms of the “Sensory Symptoms” subcategory to meet the minimal requirement for “Sensory Dysfunction”.

3. Results

3.1. Characteristics

3.1.1. An Epidemic and an Endemic Form


M.E. has been described since 1905...


...and 1934 respectably. 


This was often on account of outbreaks, the two most well-known being the epidemic in Akureyri district in Iceland (1948–1949) and... 


...the outbreak in the Royal Free Hospital (London, UK) in 1955.


However, in the 1950's it became evident that M.E. can also occur in sporadic form : “Endemic prevalence alternates with periodic epidemics, showing a curious predilection for female staff of health care and teaching institutions”.

3.1.2. Sudden Onset

M.E. has a "sudden onset"; in most cases an infection described as a respiratory and/or gastrointestinal illness preceded, “but a gradual or more dramatic onset following neurological, cardiac or endocrine disability is recognised.”. 




It could be describing having an earlier encephalitic illness, and having a relapse into another 'acute onset' encephalitic or encephalomyelitic illness. 


Gradual could be mistaking an underlying asymptomatic carrier from a previous infection, in which didn't completely clear, but becomes more symptomatic over time, and in which the infection remained more asymptomatic to the patient, to then becoming more symptomatic upon a new immune system challenge. (e.g. maybe a previous enterovirus infection from childhood, upon catching a later one in adolescence, or adulthood, and then developing a more substantial illness as a result, later on at some point. Enterovirus Persistence has been demonstrated by Dr. John Chia and others) (e.g. Andrew Chia)


3.1.3. An Acute and a Chronic Phase (Biphasic)

“The onset is usually acute with systemic prodromata such as are common in poliomyelitis.”. 

In the outbreaks, the prodromal phase was usually followed by improvement for a few hours, days or weeks, after which the symptoms returned more severely with additional symptoms, including marked muscle weakness.

In many cases the symptoms become chronic with a periodic relapsing course.

3.1.4. Not Just Like Other Post-Viral Fatigue States

M.E. should be distinguished from other forms of “post-viral debility following Epstein-Barr mononucleosis, influenza and other common fevers” since M.E. has “an unique clinical and epidemiological pattern” and these other post-viral states “lack the dramatic effect of exercise upon muscle function, the multisystem involvement, diurnal variability of symptoms and prolonged relapsing course”. 

Postviral Fatigue Syndromes (PVFS) (also known as Chronic Fatigue Syndromes) - Verywell Health


This is also one of the many reasons why M.E. should not be confused with CFS, an ill-defined syndrome which can be initiated by various infections, e.g., the Epstein-Barr virus (Mononucleosis), Coxiella Burnetii (Q-Fever), or Ross River virus, Coronavirus (COVID-19) infections.



3.1.5. A Prolonged Relapsing Course

A distinctive feature of M.E. is a prolonged relapsing course. Years can pass between two relapses.

Relapses can be caused by physical and mental stress (very often) and intercurrent infection (often). 

Although outbreak patients appear to recover much often than sporadic patients, the illness often lasts for years or even decades.

3.1.6. Diurnal Variability of Symptoms

In addition to periodic relapses or partial remission, M.E. is characterized by a strong fluctuation of symptoms during the course of the day, and over time. 

Physical and/or Mental Stress can have a (prolonged) Negative Effect on the symptoms.

3.2. Symptoms

Although M.E. is a multi-systemic disease with a large range of symptoms that can vary greatly per patient per day, the distinctive features of M.E. are limited to Muscle Fatigability/post-exertional Muscle Motor Weakness,...

...and specific neurological symptoms.

Patients often report various other symptoms relating to the "muscles" and “variable involvement of cardiac and other bodily systems”, e.g., myalgia (80%),



3.2.1. Muscle Fatigability / Prolonged Muscle Motor Weakness after Exertion is a Mandatory Feature of M.E.


“Muscle fatigability is the dominant and most persistent feature of the disease, and a diagnosis should not be made without it" - Dr. Melvin Ramsay


"Restoration of muscle power after exertion can take three to five days or even longer.”. This implies that muscle fatigability/prolonged muscle motor weakness after exertion is a discriminative feature of M.E.. Long-lasting 'muscle weakness' after exertion can be validated objectively by measuring muscle power of the arms, hands, legs, etc., during repeated 'muscle contractions' on two consecutive days using 'dynamometers'.

3.2.2. "Neurological Disturbance" is an Essential Feature of M.E. 


...neurological symptoms are distinctive for M.E.. 

"Neurological Disturbance" in M.E. especially relates to “Neurocognitive, Autonomic and Sensory functions”

Many symptoms observed in epidemic and endemic cases of M.E. are related to Neurological Dysfunction. 

The neurological symptoms relate to neurocognitive dysfunction (n = 3), autonomic dysfunction (n = 11), sensory dysfunction (n = 19), and motor dysfunction (n = 4), while three symptoms (headache and symptoms related to sleep) are unclassified (Table 3). 

Considering the most recent definitions of M.E. and the frequency of symptoms reported by 420 patients, a patient should experience at least one symptom related to "neurocognitive dysfunction" (n = 3) or "one unclassified neurological symptom" (n = 3), "one symptom related to "autonomic dysfunction" (n = 11) and two symptoms related to sensory dysfunction (n = 19) to meet the proposed operational definition of M.E.

Myalgic Encephalomyelitis --- a persistent enteroviral infection? - Elizabeth Dowsett, Melvin Ramsay, Robert McCartney & Eleanor Bell (Postgraduate Medical Journal, Oxford Academic, 1st July, 1990)

Table 3. Neurological symptoms of patients observed in endemic and epidemic cases.


Neurocognitive impairment (impaired memory) or concentration, impaired ability in calculation, Aphasia (Both Receptive and Expressive) (e.g. using wrong words), forgetfulness, etc.);

Mental confusion.


Dizziness/giddiness/vertigo (when standing);




Postural orthostatic Tachycardia Syndrome (PoTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed);

Neurogenic Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), overactive bladder and pollakiuria (often urinating small amounts), etc.;

Symptoms related to "impaired circulation": cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.;

Symptoms related to thermoregulation: feeling cold (hands and feet), chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.;

Intolerance of extremes of temperature/hypersensitivity to climatic change;

Abnormal dryness of the skin of the extremities (head, arms and feet);

Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue;

Brittle nails (onychorhexis); and

Hypertrichosis (abnormal amount of hair growth over the body).

Sensory Dysfunction

Paraesthesia (abnormal sensations such as tingling, tickling, pricking, “pins and needles”, numbness, itching or burning of the skin with no apparent cause);

Hypoesthesia (reduced sense of touch or physical sensation/local numbness);

Hypoalgesia (decreased sensitivity to painful stimuli);

Diminished or absent position sense of hands/fingers and feet/toes;

Diminished or absent vibration sense of hands/fingers and feet/toes;

Dysesthesia is the term for symptoms that disrupt how you experience touch-based sensations. What you feel with your sense of touch can be unpleasant, unusual or painful?;


Hyperesthesia (increased sensitivity to stimulation);

Hyperalgesia increased sensitivity to painful stimuli);

Muscle tenderness (pressure induces pain);

Blurring of vision; with a sensory cause from virus or inflammation associated with optic nerve/visual tracts (less common)

Photophobia/defective response to light (sluggish pupils)/light hypersensitivity;

Hyperacusis (intolerance of loud noise);



Deafness (Hearing Loss).

Sensory Ataxia (lack of coordination of muscle movements, including gait abnormality); and tendency to stumble when walking, unsteady gait.

Postive Romberg Test for Sensory Ataxia (Eyes Closed) is a simple physical test to see if you have balance problems that are related to proprioception - your body’s ability to sense your movements and position.

Motor Dysfunction (Motor Disorder)

Muscle Fatigability (Lower Motor Neuron Lesion) in M.E. is a symptom in which muscles become weaker (motor weakness) after minor exertion and a long period (3-5 days or longer) may elapse before full muscle power is restored. According to Melvin Ramsay, it is the defining feature of Myalgic Encephalomyelitis, without which a diagnosis of M.E. should not be made; 

Hyporeflexia (Lower Motor Neuron Lesion or Peripheral Nerve Involvement) : Depressed tendon reflexes of the upper and lower limbs (decrease in amplitude and duration of muscle contraction in response to an impulse);

Paralysis of the limbs (arms and legs);

Flaccid Paralysis (Lower Motor Neuron Lesion) : complete loss of voluntary muscle movement with reduced tone; limb hangs limp; 

Flaccid Weakness (Lower Motor Neuron Lesion) : partial loss of muscle strength with reduced tone; limb movement is weak and floppy; 

Neurogenic Muscle Atrophy (Lower Motor Neuron Lesion) is the wasting or thinning of muscle mass. It can be caused by disuse of your muscles or neurogenic condition; 


Muscle Weakness of voluntary muscles (arms and legs, e.g., gastrocnemii);

Local Muscle Weakness (e.g., trapezii);

Paralysis of the face (Peripheral Facial Palsy) (Lower Motor Lesion Neuron);


"Peripheral" Facial Palsy

Paralysis of swallowing (Dysphagia);

Poor movement of the soft palate;

Nystagmus (involuntary eye movements, “dancing eyes”);

Loss of Accommodation (depth perception);

Diplopia (simultaneous perception of two images of a single object);

Blurring of Vision; with a motor cause from virus or inflammation associated with brainstem/ocular motor nerve pathways affected

Fasciculation of Muscles (Lower Motor Neuron Sign) (local, involuntary muscle contraction and relaxation);

Muscle Spasms (often in limbs) (More classically associated with Upper Motor Neuron Sign but Lower Motor Neuron Sign can also apply in M.E.);

Muscle twitches/jerking of the limbs/Myoclonus;

Hyperreflexia (Upper Motor Neuron Lesion) : Exaggerated tendon reflexes of the upper and lower limbs (increase in amplitude and duration of muscle contraction in response to an impulse).

Spasticity (Upper Motor Neuron Symptom) is a symptom and characteristic of certain neurological conditions. It causes certain muscles to contract all at once. It ranges in severity and can affect movement and speech; 

Spastic Paralysis (Upper Motor Neuron Lesion) : complete loss of voluntary movement with spasticity, stiffness, hyperreflexia.

Central (spastic) Weakness (Upper Motor Neuron Lesion) : weakness with increased muscle tone and exaggerated reflexes, due to upper motor neuron pathway damage.

Ankle clonus (Upper Motor Neuron sign) (series of involuntary, rhythmic, muscular contractions and relaxations usually initiated by a reflex);

Extensor plantar responses (Babinski reflex) (Upper Motor Neuron sign);

Cereballar Ataxia (lack of coordination of muscle movements, including gait abnormality); and tendency to stumble when walking, unsteady gait.

Motor Clumsiness, Fumble (Dysmetria) with simple manoeuvres; and

Unclassified Neurological Symptoms

Reversal of sleep rhythm (Hypersomnia followed by Insomnia) (not sleepy at night, sleeping in the day);


Vivid dreams/nightmares (often in colour); and

Headaches (often frontal or occipital, sometimes accentuated by movement).

3.2.3. M.E. often coincides with a number of symptoms Related to Other Body Systems

In addition to the two mandatory features, muscle fatigability/prolonged post-exertional muscle motor weakness after,...

...and neurological dysfunction, M.E. patients often, but not always, suffer from many other symptoms related to other bodily systems, including musculoskeletal symptoms, e.g., myalgia (with or without exercise), paresis and joint pain, immunological symptoms, e.g., sore throat, tender lymph nodes (lymphadenopathy), gastrointestinal symptoms, e.g., nausea, anorexia, diarrhoea, constipation and abdominal pain, and respiratory symptoms, e.g., respiratory distress, intercostal myalgia (often made worse on breathing) and exertional chest pain, with or without palpitations. 

M.E. patients can experience “extreme physicial exhaustion" after physical or cognitive exertion and emotional strain, but looking at the definitions and symptoms reported, the abstract concept of post-exertional “malaise”, cannot be considered a mandatory feature for the diagnosis of M.E..

3.2.4. M.E. is often accompanied by emotional problems, but is not caused by those symptoms

Emotional lability is a characteristic feature of M.E.. According to the last patient population study, 98% of the 420 M.E. patients reported experiencing “emotional disability”. 

Myalgic Encephalomyelitis—a persistent enteroviral infection? - Elizabeth Dowsett, Melvin Ramsay, Robert McCartney & Eleanor Bell (Postgraduate Medical Journal, Oxford Academic, 1st July, 1990)

Other emotional symptoms reported in cases of M.E. include “outbursts of irritability”, impatience, frustration, anxiety, and reactive depression (adjustment disorder). 

However, it should be emphasized that “emotional lability” and other psychological features are caused by M.E.-related dysfunction and related to cerebral dysfunction, and do not cause the symptoms in M.E. (e.g. M.E. is not a psychosomatic disorder)

3.3. An Operational Definition of M.E.

Based on the most recent definitions, definitions, the symptoms experienced by 420 patients, and the symptoms observed in endemic and epidemic cases of M.E., a discriminative operational definition comprises the following four elements:


2. Neurological Disturbance (see Table 3):

a. at least one symptom related to neurocognitive dysfunction or one unclassified neurological symptom;

b. at least one symptom related to autonomic dysfunction; and

c. at least two symptoms related to sensory dysfunction;

3. Fluctuation of Symptoms (within and between “episodes”); and

4. A prolonged relapsing course.

This definition contains the basic requirements to comply with the diagnosis of M.E.. The tentative case definition described above should be used in conjunction with a full clinical assessment, with consideration of differential diagnoses.

Future surveys should make clear if stricter requirements can be imposed on the three neurological criteria, and if symptoms not mentioned in the original description of endemic and epidemic cases can be added to these neurological symptoms clusters, without excluding patients meeting the minimal requirement for “Neurological Disturbance”.

Forthcoming studies should also establish the frequency of the (optional) symptoms related to other bodily systems observed in endemic and epidemic cases of M.E. and mentioned in other diagnostic criteria, e.g., the International Consensus Criteria (ICC), the Fukuda Criteria for CFS, and the Criteria for Systemic Exertion Intolerance Disease (SEID) (Currently 'erroneously' known as "ME/CFS")


Prospective studies should also investigate the overlap and differences between patients meeting the four different system clusters within this operational definition of M.E. and with non-diagnoses of ICC, CFS, and SEID, and the relative numbers of patients fulfilling one, or more of these criterias.

Review of case definitions for Myalgic Encephalomyelitis (M.E.) and Chronic Fatigue Syndrome (CFS) - Eun-Jin Lim & Chang-Gue Son (Journal of Translational Medicine, 2020)

Future research should also clarify which signs are exhibited by all patients meeting the operational definition (the “minimum criteria”) of M.E. and can be included in the definition, and which comorbidities (symptom patterns) are often present in M.E.

4. Discussion

M.E. results in a "distinct" Neuromuscular Disorder with specific features. 

Based on the definitions, M.E. is not an equivalent of CFS, an ill-defined fatigue syndrome. 

This observation is completely independent of the question whether the name “M.E.” is appropriate or not. 

The discussion with regard to the definition (case criteria) should be separated from the discussion with regard to the most accurate label.

Since the cause of M.E. is now known, the operational definition of M.E. proposed in this original article, initially depended on the self-report of symptoms. 








Beyond Myalgic Encephalomyelitis and Chronic Fatigue Syndrome - Redefining an illness (Read Online, Page 28) - Ellen Wright Clayton, Margarita AlegrĆ­a, Lucinda Bateman, Lily Chu, Charles Cleeland, Ronald Davis, Betty Diamond, Theodore Ganiats, Betty Keller, Nancy Klimas, Martin Lerner, Cynthia Mulrow, Benjamin Natelson, Peter Rowe and Michael Shelanski (Institutional Medicine of Medicine (IOM) / The National Academy Press, 2015)



MRI findings of Enteroviral Encephalomyelitis - Mohamed Saied Abdelgawad, Abd El-Aziz El-Nekidy, Rania A.M. Abouyoussef & Amr El-Fatary (The Egyptian Journal of Radiology and Nuclear Medicine, ScienceDirect, September 2016)








However, various symptoms, including muscle fatigability/prolonged muscle motor weakness (the distinctive symptom) and... 

...several neurological symptoms, can be assessed with objective tests.

In 2011 a panel of so called experts proposed using the International Consensus Criteria (ICC) for M.E. 

Myalgic Encephalomyelitis: International Consensus Criteria - Bruce Carruthers (Journal of Internal Medicine, Wiley, 2011)

According to the ICC, Post-Exertional Neuroimmune Exhaustion (PENE) is the hallmark feature of M.E. (e.g. Central Nervous System Exhaustion) was originally described by Dr. Elizabeth Dowsett, a similar sounding concept, but a more credible sounding terminology. 

"Long-lasting" post-exertional motor muscle weakness is NOT a mandatory operational feature of M.E. according to the ICC.

Myalgic Encephalomyelitis: International Consensus Criteria - Bruce Carruthers (Journal of Internal Medicine, Wiley, 2011)

This is a major departure from the original descriptions according to the original definition. 

On the other hand, diagnosis of M.E. and ICC based upon a positive family history is not mentioned in the 'original description'.

Myalgic Encephalomyelitis: International Consensus Criteria - Bruce Carruthers (Journal of Internal Medicine, Wiley, 2011)

How big the overlap is between the original definition of M.E. and that of the ICC and whether the latter can adequately be used in studies of patient cohorts by itself to study the exact same grouping of original M.E. patients. Is the 2011 ICC close enough to isolate the 'original M.E. Patient Group' and ONLY the original patient group?



Review of case definitions for Myalgic Encephalomyelitis (M.E.) and Chronic Fatigue Syndrome (CFS) - Eun-Jin Lim & Chang-Gue Son (Journal of Translational Medicine, 2020)


According to the definition of “ME/CFS” proposed by the Institute of Medicine (now the National Academy of Medicine) in 2015, 

Ellen Wright Clayton (with Dr. Peter Rowe and Dr. Lucinda Bateman) are some of the authors of the bogus SEID (Currently erroneously known as "ME/CFS" Criteria)

Beyond Myalgic Encephalomyelitis and Chronic Fatigue Syndrome - Redefining an illness (Read Online, Page 60) - Ellen Wright Clayton, Margarita AlegrĆ­a, Lucinda Bateman, Lily Chu, Charles Cleeland, Ronald Davis, Betty Diamond, Theodore Ganiats, Betty Keller, Nancy Klimas, Martin Lerner, Cynthia Mulrow, Benjamin Natelson, Peter Rowe and Michael Shelanski (Institutional Medicine of Medicine (IOM) / The National Academy Press, 2015)


Frank Twisk (2017) stated that M.E. and CFS are different illnesses, with M.E. resulting in a "specific" Neuromuscular Disorder, and CFS being a partially overlapping "Fatigue-based illness", and that it was not possible to replace both M.E. and CFS with a single diagnostic entity. Frank Twisk also stated that SEID included some patients that did not meet either M.E. or CFS diagnostic criteria.


(Post-Exertional “Malaise”) is a different feature of “ME/CFS” 

(in addition to 'Fatigue' and 'Unrefreshing Sleep'). 

However, Post-Exertional “Malaise”, an ill-defined notion, has NEVER been described as a distinctive feature of M.E. in the literature

"Frank Twisk is right that it hasn't been 'directly' attached/attributed to Myalgic Encephalomyelitis (also known as Enteroviral Encephalomyelitis) M.E. which Post-Exertional Muscle Fatigability followed by Motor Weakness as described by Dr. Melvin Ramsay historically as the hallmark symptom which IS NOT A SYNONYM for 'Post-Exertional Malaise (PEM)' which is a 'different concept'"

"Long-lasting" post-exertional muscle motor weakness, the distinguishing feature of M.E., is a very specific symptom which can be assessed objectively...

...(and is not a synonym of Post-Exertional “Malaise”)

This operational definition proposal interprets muscle fatigability/post-exertional muscle motor weakness, and... 

..post-exertional “malaise”, as two different concepts.

Frank Twisk is wrong to imply that it is not a term within the Enteroviral and M.E.-related literature. But the terminology itself has been associated with a chronic enterovirus infection within the scientific research, which could lead up to Myalgic Encephalomyelitis (also known as Enteroviral Encephalomyelitis) M.E. or persist after an acute illness such as in any of those within the first 'blue box' above (e.g. Encephalitis) leading onto an Encephalomyelitis in cases, or even after an Encephalomyelitis. 

"The John Richardson Research Group (Dr. John Richardson and Dr. Irving Spurr) and Dr. John Chia has researched the effects of a persistent enteroviral infection in association with original CFS (also known as Enteroviral Encephalitis) and... 


...M.E. (also known as Enteroviral Encephalomyelitis) in patient cohorts"


Myalgic Encephalomyelitis—a persistent enteroviral infection? - Elizabeth Dowsett, Melvin Ramsay, Robert McCartney & Eleanor Bell (Postgraduate Medical Journal, Oxford Academic, 1st July, 1990)

I myself fell ill with Hand, Foot & Mouth Disease (HFMD),...

...Diarrhoea and Vomiting, Bornholm Disease, Labyrinthitis and Encephalitis and then developed a "severe" Persistent Viral Fatigue Syndrome (involving a persistent Non-Cytolytic Enterovirus Infection) following on from the Enterovirus Encephalitis. This so called GENERAL FATIGUE felt more like "EXTREME PHYSICAL EXHAUSTION", after the acute onset Encephalitis with Sleep Disturbances such as Sleep Reversals, Disruptions, Waking Unrefreshed which were horrible, and with so called Post-Exertional Malaise (PEM) upon exertion and after activity <---> Persistent Enteroviral Infection <---> leading up to Myalgic Encephalomyelitis (also known as Enteroviral Encephalomyelitis) M.E. in which Post-Exertional Muscle Fatigability followed by Muscle Motor Weakness... 

...I did and do experience it to be the hallmark symptom as Dr. Melvin Ramsay had historically described. But Frank Twisk is correct in calling them two different concepts. 


The tentative definition described here deviates from the London criteria on two crucial points. 

Exercise-induced Fatigue, the first criterion of the London Criteria, has never been described as a distinctive feature of M.E. in the literature, while on the other hand, Muscle Fatigability/long-lasting post-exertional Muscle Motor Weakness, the hallmark feature of M.E.,...

...is NOT required to meet the London Criteria.

This operational definition of M.E. also deviates from the definition proposed by Hyde, since the proposed operational definition ONLY incorporates discriminative features of M.E. and "not symptoms" related to “variable involvement of cardiac and other systems”, and does not include “testable brain changes” as described within the Nightingale Research Foundation Definition. 





M.E. (results in) a specific Neuromuscular Disorder and is not equivalent to CFS or “SEID (also erroneously known as ME/CFS)” or even the ICC. 

M.E. was described in the literature from 1938  until 1992, after which CFS, a fatigue syndrome, pushed M.E. to the background.

The Chronic Fatigue Syndrome: A Comprehensive Approach to It's Definition and Study - Keiji Fukuda, M.D. (Annals of Internal Medicine, 1994)

To unravel the aetiology and pathophysiology and to develop effective therapies for M.E. as described in the literature, it is essential to investigate patients with M.E. (and M.E. only). 

Myalgic Encephalomyelitis --- a persistent enteroviral infection? - Elizabeth Dowsett, Melvin Ramsay, Robert McCartney & Eleanor Bell (Postgraduate Medical Journal, Oxford Academic, 1st July, 1990)

For that reason, an operational definition is indispensable.

This article proposes an operational definition of M.E., based on the last formal definitions of M.E., and the symptoms observed in the epidemic and endemic cases of M.E. and reported by a large group of patients with well-defined M.E..

A discriminative operational definition of M.E. should consist of the four mandatory features (minimum criteria for the diagnosis M.E. :


2. "Neurological Disturbance", especially of Neurocognitive, Autonomic and Sensory functions;

3. Fluctuation of Symptoms (within and between ‘episodes’); and

4. A prolonged relapsing course.

The first two criteria of this tentative definition of M.E. justify the qualification “Neuromuscular Disorder”, with specific characteristic and discriminative symptoms.

Muscle fatigability/post-exertional Muscle Motor Weakness (criterion 1) should be assessed objectively. 

This article proposes the tentative criteria to operationalize “Neurological Disturbance” (criterion 2): at least 'one symptom' related to Neurocognitive Dysfunction or 'one' Unclassified Neurological Symptom, 'one' symptom related to Autonomic Dysfunction (Dysautonomia), and 'two symptoms' related to Sensory Dysfunction (listed in Table 3). 

Several neurological symptoms can be confirmed objectively by medical tests.

The third and fourth criteria, “fluctuation of symptoms” and “a prolonged relapsing course” (criterion 3 and 4), will largely depend on self-report. 

The notion “prolonged” is not operationalized in the literature. However, since an early diagnosis is crucial, future experiments (surveys) should make stricter requirements for fluctuation and prolonged relapsing course.

Based on the (proposed) minimum criteria for M.E., which discriminate M.E. from CFS and other disorders, future studies into the criteria for “Neurological Disturbance” and the frequency of optional symptoms can be conducted.

Acknowledgments: This article is dedicated to Melvin Ramsay, Elizabeth Dowsett, Donald Acheson, Gordon Parish, and other renowned researchers who have dedicated their professional career to Myalgic Encephalomyelitis and patients suffering from M.E.

Conflicts of Interest: The author declares no conflict of interest.

Larrin Carney

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