Myalgic Encephalomyelitis (ME) / Chronic Fatigue Syndrome (CFS)

Myalgic Encephalomyelitis (ME), also known as Chronic Fatigue Syndrome (CFS), is a neglected, serious debilitating disease with no proven diagnostic marker and specific therapy. While there is evidence for several pathophysiological abnormalities including the neurological, immunological, infectious, mitochondrial, and endocrine systems, the underlying etiology and sequence of events remain unknown. 

The role of the microbiome in ME/CFS has been discussed more and more over the past years, as many patients suffer from gastrointestinal symptoms and there is very frequent comorbidity with irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD).

Clinical Manifestations

ME/CFS is a severe multisystem disease with a high degree of the physical disability that can lead to a completely bedridden condition with a high need for care. The disease is characterized by debilitating fatigue with unrefreshing sleep, neurocognitive impairments, and flu-like symptoms such as muscle weakness and pain, headaches, sore throat, and tender lymph nodes, among others. The malaise and the accompanying symptoms are worsening dramatically after a minimal physical, or cognitive activity, which is referred to as PEM. PEM is the cardinal symptom and mostly comes with a delay of 24 hours after the overexertion leading to a significant reduction (at least 50%) of the patient’s energy and activity level. The recovery period of such exhaustion usually takes more than 24 hours and can be prolonged to weeks. The course of the disease is fluctuating, and the severity of symptoms can change drastically only in a few days. Patients often describe allergies, intolerance to any sort of stimulation such as temperature extremes, light, noise, specific odors or chemicals, and simple conversations. Patients often suffer from gastrointestinal symptoms, including constipation, diarrhea, and intestinal discomfort. There is a frequent comorbidity of ME/CFS with irritable bowel syndrome (IBS) ranging from 38% up to 92%.

The illness, which can be as disabling as multiple sclerosis (MS) or systemic lupus erythematosus (SLE), is defined by the WHO in the ICD-10 as a disorder of the nervous system. However, considering the fact that there still exist different assumptions about the pathogenesis and etiology, it is debated whether this is the right classification.

Progression

ME/CFS usually tends to develop in the middle years of life, typically with two different onset patterns: a sudden onset that patients can usually remember or a more gradual onset with a slow worsening. A majority of the patients reported having been healthy before, fully functional, and with an active social life. 

A cohort study in the United States in 2019 reported that most patients experienced infectious episodes before the disease onset (64%), followed by stressful incidents (39%) and exposure to environmental toxins (20%), from which they never recovered. 

Diagnosis

Currently, there is no diagnostic test or validated biomarker for ME/CFS available.

As mentioned, PEM is the most distinct symptom for differentiating ME/CFS from other diseases with chronic fatigue. A meta-analysis reported PEM 10.4 times more common with a ME/CFS diagnosis than in healthy controls. Patients often describe these cognitive and physical exacerbations as “crashes” or “collapses”. The worsening after physical activity or even normal daily activities also helps to exclude depression or other diseases, because in most other diseases physical activity normally leads to an improvement of fatigue. Disease onset with an infection is another important clue to the diagnosis.

Even though ME/CFS is a common disease, it is often ignored in medical education and research. Various studies show that around 80% of the patients are not diagnosed correctly due to deficits in medical education. 

Etiology and Pathophysiology

The underlying etiology or a specific cause of ME/CFS is currently not known. However, over the past years, multiple studies have shown elementary evidence of a multi-factorial etiology involving neuro-immuno-endocrinological patterns, metabolic alterations, and also genetic components.

Dysfunctional Immune System 

The role of acute infection as the most reported onset is not yet fully understood, but there is a lot of evidence to support the hypothesis of a dysfunctional immune mechanism that is followed by fatigue and results in chronic low-grade systemic inflammation. 

investigating 192 ME/CFS patients and 392 controls, a research team using high-throughput methods found 17 cytokines to be significantly abnormal and consistent with the severity, 13 of these being pro-inflammatory. TGF-β, an anti-inflammatory cytokine, was significantly elevated, which was interpreted as a backlash of the body against a long-standing chronic inflammation with which patients struggle. This suggests a correlation between inflammation and ME/CFS.

Besides a wide range of ME/CFS-associated infectious agents such as human herpesviruses (HHV-6, HHV-7, HHV-8), Borrelia burgdorferi, Enterovirus, Lentivirus, Parvovirus, retroviruses, mycoplasma and many more, scientists have long debated the association between EBV infection and ME/CFS. Up to 37% of patients reported a past symptomatic EBV infection. Altered EBV-specific antibodies and a lack of B-cell memory response to EBV have been detected and provide serological evidence of a deficiency of EBV-specific immune response in a subset of ME/CFS patients. 

One hypothesis of infectious related pathogenesis is that a virus as a trigger infection interacts with a dysfunctional cellular immunity including T and B cells as well as altered activity of NK cells leading to viral reactivation. Morris and colleagues suggested this consequently might cause mitochondrial dysfunction and decreased ATP productions that result in symptoms like fatigue, aching, disturbances of sleep, and inactivity, which are all present in ME/CFS patients.

ME/CFS as an autoimmune disease and the possible role of the gut in these models have been major subjects of recent research. Results from a study of 268 ME/CFS patients revealed that a subset (29%) of patients had elevated levels of autoantibodies against neurotransmitter receptors, supporting the hypothesis of an autoimmune disease.

Of interest, in a cohort study of 1309 ME/CFS patients more men reported an initial infection as a trigger, and more women prior to ME/CFS suffered from fibromyalgia and immune symptoms such as Raynaud’s phenomenon, drug or metal allergies. As more women than men are affected by ME/CFS, this sex difference might reflect a gender-differential immune response. A similar distribution is present in many other immunoinflammatory and autoimmune diseases where women are more affected than men. A possible reason for the gender-dependent factors in immunity might be sex hormones themselves, alterations in the sex-dependent immune cells such as dendritic cells, macrophages, invariant natural killer T cells, and CD4+ T cells, the influence of sex hormones on the microbiome, X-chromosome-located immune genes escaping X-inactivation and of course the vast hormonal changes during the menstrual cycle or pregnancy. 

Energy Production Impairments and Oxidative Stress 

Since energy loss is an important symptom of ME/CFS, various research teams focused on the hypothesis that cells of ME/CFS patients might have problems with energy generation, including impaired mitochondrial energy production. 

They suggested that an initial infectious process with a cytokine response (IL-1, IL-6, TNF-α, etc.) leads to increased levels of free radicals like NO and reactive oxygen species (ROS), a harmful pro-inflammatory form of oxygen, which can cause oxidative stress in cells. ROS elevate also blood levels of the oxidative stress marker and vasoconstrictor isoprostane. They concluded that the resulting cerebral hypoperfusion leads to anaerobic metabolism and therefore the higher lactate in cerebrospinal fluid can be explained.

Decreased levels of the antioxidant vitamin alpha-tocopherol (vitamin E) found in studies with ME/CFS patients further support the potential role of increased oxidative stress.

Furthermore, abnormal levels of oxidative stress in the post-exercise period have been found, which might explain the typical post-exertional malaise. 

Chronic immune activation and an increased oxidative and nitrosative stress might lead to an inhibition of mitochondrial function and a defective ATP production, including mitochondrial DNA and electron transport complex damage, reductions of the membrane potential, and an increase in the mitochondrial permeability, which may play a role in the central metabolic disorders as seen in these patients.

Another hypothesis is that especially propionate, as a product of gut fermentation, penetrates the intestinal barrier and passes into the blood circulation where it results in oxidative stress and mitochondrial dysfunction, though this metabolite has been more frequently discussed as a health marker. Furthermore, it has been shown that mitochondrial DNA genome variation does not seem to play a role in susceptibility or resistance to ME/CFS but might affect the type and severity of symptoms.

Genetic Predisposition 

Some studies provide support for the suggestion that genes might play a role in ME/CFS, as the disease shows higher concordance in identical monozygotic twins. The rates of ME/CFS for first-degree relatives vary from 2.7% to 13%. A monozygotic twin study in which more than half (55%) of both identical twin pairs showed ME/CFS symptoms support the evidence of a genetic component, at least in a subgroup of ME/CFS.

Therapy

There is currently no pharmacological or non-pharmacological therapy available with clear evidence for the management of ME/CFS. Pacing, the careful dosing of all types of activities as an energy self-management method, is one of the most recommended strategies to avoid relapses due to overexertion. But it is not curative. Patients should learn to read their fluctuating symptoms, pay attention to early signs of PEM and trust their own experiences. They have to learn to manage their cognitive, physical, emotional and social activities to reduce a worsening of their symptoms 

Tests for Chronic Fatigue Syndrome

Although there are, as already mentioned, specific tests that can help diagnose and monitor chronic fatigue syndrome, some tests can be very helpful in controlling the symptoms in some patients’ groups:

• EnteroScan® Comprehensive
• EnteroScan® Neuro
• Short Chain Fatty Acids (SCFA)
• Neurotransmitters
• EBV Immunity Test
• Th1 / Th2 / Th17 Balance Check
• Serum lipopolysaccharide (LPS)
• Chronic Inflammation Control
• Vitamin E, Vitamin B1
• Total Plasma Antioxidant Capacity (TAC)
• Active Plasma Oxygen Roots (ROS)
• Basic Antioxidant Test - DetoxScan®