Chronic Fatigue Syndrome: A Presumptive Mitochondrial Disorder
| Status: | Completed |
|---|---|
| Conditions: | Neurology |
| Therapuetic Areas: | Neurology |
| Healthy: | No |
| Age Range: | 25 - 55 |
| Updated: | 3/16/2015 |
| Start Date: | September 2012 |
| End Date: | September 2014 |
| Contact: | Alfred E Slonim, MD |
| Email: | as2718@columbia.edu |
| Phone: | 212-305-5717 |
Chronic Fatigue Syndrome: Correction of Mitochondrial Dysfunction by Conditioning Exercise and Nutraceutical Therapy.
The pathogenesis of chronic fatigue syndrome (CFS) is poorly understood and no effective
therapy has been developed. Recent studies suggest that a preceding viral infection causes
mitochondrial dysfunction of the brain and skeletal muscle of genetically susceptible
individuals. There is no specific laboratory test to identify patients with CFS. However,
certain clinical manifestations are similar to those seen in mitochondrial disorders. Both
patients with mitochondrial disorders and CFS manifest elevated serum lactate levels after
exercise, and demonstrate elevated brain cerebrospinal fluid levels and decreased brain
glutathione levels on nuclear magnetic resonance (NMR) spectroscopy.
Therapy consisting of daily conditioning exercise, dietary recommendations, and
nutraceutical supplements (ENT) has been show to be beneficial in treating patients with
mitochondrial disorders. Similar therapy has been instituted in individual patients with CFS
and has been shown to also improve their clinical conditions.
A placebo-controlled trial will be undertaken in 24 CFS patients aged 25-55. Patients
fulfilling the CDC criteria for CFS will participate in this 6 month study. Other medical
causes for fatigue will be excluded. Half the patients will receive treatment consisting of
daily conditioning exercise plus nutraceutical supplements (ENT), that has been shown to be
beneficial for patients with mitochondrial dysfunction, while the other half will receive
daily conditioning exercise and placebo tablets. Response to ENT will be evaluated by
maximum oxygen consumption (VO2max) and circulating lactate levels during & after treadmill
exercise, a 6-minute walk test, and a fatigue questionnaire. In addition, whether ENT
corrects the elevated brain cerebrospinal fluid levels and decreased brain glutathione
levels will be measured. To ensure compliance to therapy patients will be monitored
frequently. The objective of this study is to assess the safety and efficacy of ENT and
whether ENT leads to sustained improvement of CFS patients compared to their baseline
status, and compared to an exercised group of patients not receiving supplements.
therapy has been developed. Recent studies suggest that a preceding viral infection causes
mitochondrial dysfunction of the brain and skeletal muscle of genetically susceptible
individuals. There is no specific laboratory test to identify patients with CFS. However,
certain clinical manifestations are similar to those seen in mitochondrial disorders. Both
patients with mitochondrial disorders and CFS manifest elevated serum lactate levels after
exercise, and demonstrate elevated brain cerebrospinal fluid levels and decreased brain
glutathione levels on nuclear magnetic resonance (NMR) spectroscopy.
Therapy consisting of daily conditioning exercise, dietary recommendations, and
nutraceutical supplements (ENT) has been show to be beneficial in treating patients with
mitochondrial disorders. Similar therapy has been instituted in individual patients with CFS
and has been shown to also improve their clinical conditions.
A placebo-controlled trial will be undertaken in 24 CFS patients aged 25-55. Patients
fulfilling the CDC criteria for CFS will participate in this 6 month study. Other medical
causes for fatigue will be excluded. Half the patients will receive treatment consisting of
daily conditioning exercise plus nutraceutical supplements (ENT), that has been shown to be
beneficial for patients with mitochondrial dysfunction, while the other half will receive
daily conditioning exercise and placebo tablets. Response to ENT will be evaluated by
maximum oxygen consumption (VO2max) and circulating lactate levels during & after treadmill
exercise, a 6-minute walk test, and a fatigue questionnaire. In addition, whether ENT
corrects the elevated brain cerebrospinal fluid levels and decreased brain glutathione
levels will be measured. To ensure compliance to therapy patients will be monitored
frequently. The objective of this study is to assess the safety and efficacy of ENT and
whether ENT leads to sustained improvement of CFS patients compared to their baseline
status, and compared to an exercised group of patients not receiving supplements.
Chronic fatigue syndrome (CFS), also known as myalgic encephalitis (ME), is clinically
characterized as a multisystem illness exhibiting debilitating fatigue, musculoskeletal
pain, disturbed sleep, and impaired memory and concentration. Its diagnosis is non-specific
and symptom based, with no real biomarkers yet identified. The etiology and pathophysiology
of CFS remain obscure. There is a long-standing hypothesis that individuals with CFS have
normal metabolism and their fatigue is psychological, with energy being wasted through the
processes of anxiety, stress, and depression. The more CFS is investigated, however, the
clearer it becomes that this is incorrect, and that it is probably a metabolic dysfunction
resulting in insufficient energy production. A number of studies have suggested that there
may be a genetic contribution to CFS. In addition, a severe viral illness frequently
predisposes the onset of CFS, while a number of pathogens have been linked to CFS (2, 3, 6).
Although some patients develop CFS after an acute infection such as mononucleosis, some
investigators believe it arises from the reactivation of a latent virus in the host, both
resulting in a chronic low-level activation of the immune system.
As more data are acquired, we and others believe that CFS is actually a metabolic
mitochondrial dysfunction resulting in insufficient energy production. Mounting evidence
indicates that viral infections in genetically susceptible individuals can cause changes in
mitochondrial function. Many features observed in CFS are similar to those seen in genetic
mitochondrial disorders. Firstly, some muscle biopsies in patients with CFS have shown both
abnormal mitochondrial degeneration and severe deletions of mitochondrial DNA genes.
Mitochondrial dysfunction increases the production of free radicals and reactive oxygen
species (ROS), which cause oxidative damage, believed to contribute to CFS pathogenesis.
Carnitine is required for metabolic reactions including mitochondrial fatty acid oxidation.
A deficiency of serum acylcarnitine has been observed in CFS patients, suggesting that there
is increased utilization of carnitine in CFS, thereby decreasing energy production. In
mitochondrial disorders, utilization of pyruvate is decreased, resulting in higher
circulating and muscle levels of lactate, as well as decreased oxidative phosphorylation and
energy production. Brain ventricular cerebrospinal lactate is elevated, and brain
glutathione is decreased, in both mitochondrial disorders and CFS. In CFS patients
cerebrospinal lactate is increased by approximately 300% compared to that found in
generalized anxiety disorder and healthy individuals. Using brain NMR spectroscopy, the
distinction between CFS and psychological disorders can be demonstrated.
characterized as a multisystem illness exhibiting debilitating fatigue, musculoskeletal
pain, disturbed sleep, and impaired memory and concentration. Its diagnosis is non-specific
and symptom based, with no real biomarkers yet identified. The etiology and pathophysiology
of CFS remain obscure. There is a long-standing hypothesis that individuals with CFS have
normal metabolism and their fatigue is psychological, with energy being wasted through the
processes of anxiety, stress, and depression. The more CFS is investigated, however, the
clearer it becomes that this is incorrect, and that it is probably a metabolic dysfunction
resulting in insufficient energy production. A number of studies have suggested that there
may be a genetic contribution to CFS. In addition, a severe viral illness frequently
predisposes the onset of CFS, while a number of pathogens have been linked to CFS (2, 3, 6).
Although some patients develop CFS after an acute infection such as mononucleosis, some
investigators believe it arises from the reactivation of a latent virus in the host, both
resulting in a chronic low-level activation of the immune system.
As more data are acquired, we and others believe that CFS is actually a metabolic
mitochondrial dysfunction resulting in insufficient energy production. Mounting evidence
indicates that viral infections in genetically susceptible individuals can cause changes in
mitochondrial function. Many features observed in CFS are similar to those seen in genetic
mitochondrial disorders. Firstly, some muscle biopsies in patients with CFS have shown both
abnormal mitochondrial degeneration and severe deletions of mitochondrial DNA genes.
Mitochondrial dysfunction increases the production of free radicals and reactive oxygen
species (ROS), which cause oxidative damage, believed to contribute to CFS pathogenesis.
Carnitine is required for metabolic reactions including mitochondrial fatty acid oxidation.
A deficiency of serum acylcarnitine has been observed in CFS patients, suggesting that there
is increased utilization of carnitine in CFS, thereby decreasing energy production. In
mitochondrial disorders, utilization of pyruvate is decreased, resulting in higher
circulating and muscle levels of lactate, as well as decreased oxidative phosphorylation and
energy production. Brain ventricular cerebrospinal lactate is elevated, and brain
glutathione is decreased, in both mitochondrial disorders and CFS. In CFS patients
cerebrospinal lactate is increased by approximately 300% compared to that found in
generalized anxiety disorder and healthy individuals. Using brain NMR spectroscopy, the
distinction between CFS and psychological disorders can be demonstrated.
Inclusion Criteria:
Subjects must meet the criteria for CFS of the US Centers for Disease Control and
Prevention (CDC), which requires persistent, unexplained fatigue for at least 6 months,
concurrent with four of the following:
- impaired memory/concentration
- sore throat, new headaches
- unrefreshing sleep, muscle pain
- multi-joint pain
- tender lymph nodes
- post-exertional malaise
As well, due to the frequency of visits subjects must currently reside in the greater New
York area.
Exclusion Criteria:
- shortness of breath
- heart disease
- high blood pressure
- other severe chronic illnesses
- clinical depression
- generalized anxiety disorder
- insomnia
- inflammatory arthritis
- anemia
- hypothyroidism
- other conditions associated with significant fatigue
- history of alcohol, tobacco, or drug abuse
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