Myalgic encephalomyelitis

Myalgic Encephalomyelitis (ME) is a chronic, inflammatory, post-viral, primarily neurological disease that is multi-systemic. It affects the central nervous system (CNS), immune system, cardiovascular system, endocrine system, and musculoskeletal system. It has been classified by the World Health Organization (WHO) as a neurological disease since 1969 and has occurred in both epidemic and sporadic form since at least the 1930s, although is probably much older.

A hallmark symptom of ME, Post-exertional malaise, an intolerance to previously trivial cognitive or physical effort. Other key symptoms include muscle weakness and fatiguability, sleep disturbance, and cognitive dysfunction. Autonomic nervous system dysfunction is frequent, although specific symptoms vary from patient to patient and may include postural orthostatic tachycardia, orthostatic hypotension, cold intolerance and heat intolerance. Other common symptoms include muscle pain, neuropathic pain, neck and spine stiffness, and sensory symptoms including sensitivity to light, sound, touch, paraesthesia and hyperaesthesia.

Among adults, ME is more common in women than men. New onset has been observed in children as young as eight and in adults as old as eighty. Its course is usually relapsing-remitting with new symptoms occurring either in discrete relapses (or “crashes”) or accruing over time. There is a progressive form of ME but it is rarer than the relapsing-remitting type.

There are no approved treatments for ME in any country except for Argentina, which has approved Ampligen for the treatment of chronic fatigue syndrome.

Disease name
The name myalgic encephalomyelitis was coined by Dr. Melvin Ramsay following the 1955 Royal Free Hospital outbreak and is a portmanteau of several of the key signs and symptoms of the disease: myalgic (muscle pain), encephalo (brain), myel (spinal cord), itis (inflammation).

Several other names have been used or proposed throughout the history of the disease, including atypical polio, Icelandic disease, benign myalgic encephalomyelitis, epidemic neuromyasthenia, chronic fatigue syndrome, and systemic exertion intolerance disease. This has lead to much confusion as a variety of names have been used at different times to describe discrete outbreaks, a wider and potentially more heterogenous population of sporadic cases, and with a wide variety of case definitions.

A survey by The MEAction Network in 2016 found that the majority of patients prefer the name myalgic encephalomyelitis to other names including chronic fatigue syndrome. Most government agencies and researchers around the world use the term ME/CFS.

History
ME has occurred in both epidemic and sporadic form since at least the 1930s, although is probably much older. The first recorded outbreak of epidemic myalgic encephalomyelitis was in 1934 in Los Angeles and was thought to be an outbreak of atypical polio. After the outbreak in Akureyri, Iceland in 1946, the disease came to be called "Akureyri Disease" or Icelandic disease through much of the 1940s and 1950s. It was named myalgic encephalomyelitis after London's Royal Free Hospital outbreak in 1955. Other names included benign myalgic encephalomyelitis and epidemic neuromyasthenia.

After the Incline Village outbreak in Nevada in 1984, the disease came to be called and redefined as Chronic Fatigue Syndrome. The most recent was putative outbreak was in Arizona in 1996.

Signs and symptoms
Invest in ME outlines ME symptoms and notes symptoms can range from mild to very severe and can include:


 * Reaction to physical and mental activity and sensory input
 * Cardiovascular and Cardiac problems
 * Cognitive dysfunction
 * Gastrointestinal system Problems
 * Headache
 * Hormonal Imbalance
 * Immunological Problems
 * Muscle fatigability and Intense Pain
 * Neurological Problems
 * Sleep Problems (Sleep dysfunction)

Post-exertional malaise
A core symptom, Post-exertional malaise, is intolerance to previously trivial effort such as walking to the mailbox, running an errand or grocery shopping, taking a shower or brushing teeth, and deterioration of health from persistent or repeated exertion.

Over-exertion can make ME worse and the effects are often delayed and may not be seen within 24 hours.

It used in several ME, CFS, ME/CFS and SEID definitions of the disease.

The National Organization for Rare Disorders (NORD) states: "Symptoms and their severity can fluctuate over the course of the illness, even from hour to hour." The US National Institutes of Health notes that sensitivity to noise, light and chemicals may force patients to withdraw from society.

Diagnosis
The International Consensus Criteria (ICC) is thought to be the best tool for diagnosing ME while the Canadian Consensus Criteria (CCC) diagnoses both ME and Chronic Fatigue Syndrome (CFS) and is an ME/CFS diagnostic tool.

The original criteria developed by Melvin Ramsay, the Ramsay definition, is not used for diagnosing ME today.

Other diagnostic criteria
The UK Oxford criteria (the US Institute of Medicine report has called for its retirement) and the US CDC Fukuda criteria (used in some research worldwide) are not describing ME but instead describe chronic fatigue (CF). CF should not be confused with CFS. Many patients and ME organizations believe CFS must not be confused with ME nor its diagnostic criteria used to describe, diagnose or research ME.

Differential diagnosis
The signs and symptoms of ME can be similar to other medical problems, "such as cancer, multiple sclerosis, lupus, brucellosis, or another condition." Additional testing may be needed to help distinguish ME from these other problems.

Disease course and clinical subtypes
Primary Phase

"The first phase is an epidemic or endemic (sporadic) infectious disease generally with an incubation period of 4 to 7 days; in most, but not all cases, an infection or infectious process is evident."

Secondary Chronic Phase

"The second and chronic phase follows closely on the first phase, usually within two to seven days; it is characterized by a measurable diffuse change in the function of the Central Nervous System. This second phase is the persisting disease that most characterizes M.E."

Presentation

"The initial presentation takes one of two forms: a severe, incapacitating prolonged illness, or an apparent remission followed by increasing relapses until the patient is forced to recognize exertional limitation. The most common initial symptoms reported are: Pain in the spine, neck or head; mild fever and flu-like symptoms; nausea or vomiting; flaccid muscle weakness; and muscle pain or tenderness." For some people, ME is triggered by Hepatitis B vaccination, blood transfusion , or chemical poisoning (See: Countess of Mar), although it is now thought organophosphate poisoning is a different illness.

Later course

"The later course of ME. is difficult to predict, and may either become consistently severe, improve to a plateau, or be markedly relapse-remitting. In some, even prolonged severe incapacitation can be relieved by unpredictable remission, although relapse is always possible. The degree of impairment and complexity depends on the degree of diffuse brain injury and end organ involvement."

Subgroups/types

"The evidence for subgroups is strengthened by research using heterogeneous CFS criteria, although this artificial heterogeneity also hampers consensus. It is likely that subtypes exist within the ME milieu based on the clinical findings, history, and perhaps gender of patients."

Subtypes proposed
Kerr et al proposed 7 different subsets for “CFS” as it is defined today:


 * Subtype 1 This is one of the more severe subtypes. Effects are cognitive, musculoskeletal, sleep-related and anxiety/depression.


 * Subtype 2 This is one of the more severe subtypes. Effects are musculoskeletal, pain and anxiety/depression.


 * Subtype 3 This subtype has the mildest symptoms.


 * Subtype 4 This subtype is dominated by cognitive issues.


 * Subtype 5 Effects are musculoskeletal and gastrointestinal.


 * Subtype 6 This subtype is dominated by post-exertional malaise (extreme crash after exercise or exertion.)


 * Subtype 7 This is one of the more severe subtypes. Effects are pain, infections, musculoskeletal, sleep-related, neurological, gastrointestinal, neurocognitive and anxiety/depression.

Factors triggering a relapse
ME relapses are often a result of over-activity, but can occur without warning with no obvious inciting factors. Exposure to increased sensory information in light, sound, and movement can provoke a sensory storm.

Infections, such as the common cold, influenza and gastroenteritis, also increase the risk for a relapse. Heat and cold can transiently increase symptoms.

Pregnancy can directly affect the susceptibility for relapse. Later pregnancy appears to offer a natural protection against relapses, and there are anecdotal reports of postpartum remission. However, pregnancy does not seem to influence long-term disability.

Pathophysiology
Although much is known about abnormalities in ME., the reasons why they occur are not known. There are two ME. conferences held in the UK each year attended by international research luminaries, and other conferences held worldwide.

ME is a complex disease in which the immune and neurological systems appear dysregulated and in conflict, producing a wide variety of findings.

The problem is that most of the research in recent years has been conducted on people with CFS. This is a heterogeneous population, and includes patients with psychiatric disorders, as well as vitamin and nutritional deficiencies (especially vitamin D) and post-viral states such as ME.

According to a strictly immunological explanation of CFS, the inflammatory processes triggered by T cells create leaks in the blood-brain barrier (a capillary system that should prevent entrance of T-cells in the nervous system). These leaks, in turn, cause a number of other damaging effects such as swelling, activation of macrophages, and more activation of cytokines and other destructive proteins such as Rnase-L. A reduced ability to move metabolites in and out of cells (channelopathy) has been implicated in this process. This may also be applicable to ME.

Some evidence shows viral infection of muscle and brain in at least a proportion of sufferers. This triggers inflammatory processes, stimulating other immune cells and soluble factors like cytokines and antibodies. A model for late ME has been proposed analogously to post-polio syndrome in which repaired nerve tissue forms inappropriately [The Late Effects of ME: Can they be distinguished from the Post-polio syndrome?]. Radiological research on ME has shown hypoperfusion of the brain stem and an abnormal response to exertion, but research on CFS is often inconsistent and must be interpreted with caution. For example, a reduced volume of grey matter may be a result of a lack of activity and is reversible with cognitive behavior therapy.

An inquest into the death of Sophia Mirza from ME found inflammation of the dorsal spine ganglia and liver abnormalities. However, she had co-morbid disorders.

Hemodynamic abnormalities are widely found, including serum and RBC hypovolemia, NMH, and cerebral hypoperfusion. Vascular and endothelial abnormalities have been published by MERUK. However, none of these studies used research criteria for ME so the results may not be applicable to ME.

Some cardiologic features such as cardiac insufficiency, inverted T-waves and myofiber disarray have been reported in CFS and recently added to by findings of reduced Q-value. This has led clinician and researcher Dr. Paul Cheney to posit that CFS is form of partially compensated cardiomyopathy in which orthostatic intolerance and rapid fatiguability are secondary protective mechanisms. Due to the heterogeneity of the population, a single cause is unlikely, but one-third of people with ME have abnormalities when tested with Holter monitors.

Sex differences
A CFS/ME Norwegian study shows the disease affects all ages, with two peak ages of 10-19 years and 30-39 years; it is more common in women than in men. Research by the Open Medicine Foundation cited in its paper, Metabolic features of chronic fatigue syndrome which studied severe CFS, found that the disease is different in men and women but this is not related to testosterone or estrogen. Michael VanElzakker notes there are male and female differences in neuropathic pain. A study of UK and Dutch co-horts found "younger children had a more equal gender balance compared to adolescents and adults."

Potential causes
Although risk factors for myalgic encephalomyelitis have been identified, no single definitive virus has been found in all cases, which has led to the claim that ME is a common end path of a variety of infectious insults. It is still possible ME involves some combination of both environmental and genetic factors. Various theories try to combine the known data into plausible explanations. Several theories suggest that ME is an inappropriate immune response to an infection, a theory bolstered by the observation that there is sometimes a family history of autoimmune disease. There is also a shift from the Th1 type of helper T cells, which fight infection, to the Th2 type, which are more active in allergy and more likely to attack the body.

Viruses
Other theories describe ME as an immune response to a chronic infection. The association between ME and the Coxsackie B, HHV-6, and HHV-7 viruses  suggests a potential viral contribution in at least some individuals. Evidence from epidemic myalgic encephalomyelitis strongly point to an enterovirus, however, in most outbreaks, no virus was successfully isolated.

Bacteria
Others believe ME may sometimes result from a chronic infection with spirochetal bacteria, such as Lyme disease. Another bacterium that has been implicated in ME is Chlamydia pneumoniae. Protein findings relating to several infections have seen found in the oligoclonal bands ME patients.

The Vagus nerve infection hypothesis accounts for why so many different infectious onsets could be responsible. The Vagus nerve runs from the brain stem and throughout the body and has an impact on many body systems.

Given the uncertainty regarding the cause, ME and CFS patients are barred from donating blood or organs in the United Kingdom, United States and New Zealand while symptoms persist.

Treatments
There is no known cure for ME. Treatments for sleep problems, headaches and pain are utilized by some doctors for some patients although these are treating symptoms and not ME itself. Success of treating symptoms of ME is not well researched or documented.

Ampligen (Approved for ME/CFS in Argentina) and Rituximab are being trialled.

ME does not have a cure, though treatments including the antiviral Ampligen (now approved for use on ME/CFS patients in Argentina) and immune system modulator Rituximab are being trialled.

Epidemiology
ME has been found world-wide, in at least 75 epidemics documented in published papers from the 1930s to the 1980s. Epidemics often occur in enclosed communities such as schools and hospitals.

As observed in many autoimmune disorders, ME is more common in females than males; the mean sex ratio is approxmately 2-3 females for every male. In children the sex ratio is approximately equal.

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