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Chronic Fatigue Syndrome 101

What is Chronic Fatigue Syndrome (CFS) 101

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Dr. DePace, MD, FACC

Symptoms of Chronic Fatigue Syndrome

Chronic diseases usually last for over 6 months. In Chronic Fatigue, we see post-exertional fatigue, unrefreshing sleep, and “Brain Fog” ( memory and cognitive disturbances).

The Autonomic Nervous System (Parasympathetic and Sympathetic balance) is often abnormal in Chronic Fatigue Syndrome (CFS). This affects blood pressure (BP) and heart rate (HR) regulation.

That’s why we see Orthostatic Intolerance in most cases like Postural Orthostatic Tachycardia Syndrome (POTS). In this condition they experience worsening symptoms when are in an upright position and improve when they lie down. Females are more affected than males. As many as 8 million Americans may be affected. Patients are affected at different ages and have different presentations.

What Causes Chronic Fatigue Syndrome?

Chronic Fatigue Syndrome is a group of disorders that consists of many different causes. Let’s take them separately;

  1. Infection (viral or bacterial) that causes autoantibodies and oxidative stress to dysregulate cellular and specifically mitochondrial energetics. This may lead to exercise intolerance.
  2. Disturbed gut microbiota (abnormal bacterial colonization) possibly leading to “leaky-gut” leads to autoimmunity. Irritable Bowel Syndrome is seen in many Chronic Fatigue patients.
  3. Microglial activation of the nervous system, including the Central nervous System (CNS), possibly leading to chronic pain due to allodynia (pain due to stimuli that is usually not painful) and hyperalgesia (abnormally heightened sensitivity to pain).
  4. Neuronal inflammation is important in the pathophysiology of many disabling symptoms.
  5. High levels of pro inflammatory cytokines (chemicals produced by cells) and low level of antioxidants, such as Coenzyme Q-10 (CoQ10) or Glutathione
  6. Abnormalities of the Hypothalamus-Pituitary-Adrenal Axis possibly leading to “delayed cortisol awakening”, possibly leading to unrefreshing sleep. In some cases we see low cortisol levels. Cortisol is a hormone that helps the body handle stress.
  7. Physical or emotional trauma, including form an accident, concussion, immobilization, surgery, trauma, or even emotional stress such as loss of a loved one.
  8. Genetics may contribute, with identical twins having a higher incidence then fraternal twins. There has also been familial aggregations note of CFS.
  9. Environmental factors like mold or toxins may also be a triggers.

While mitochondrial dysfunction is implicated as an immediate cause of CFS, it is not determined what the damage to mitochondrial function is from.

Mitochondria are components of cells that are called organelles and they produce energy in the form of a molecule called ATP. Cellular hypoxia and oxidative stress happen during stressful situations.

Treatments For Chronic Fatigue Syndrome

The end result is disturbing muscle and nerve function. Exercise is the hallmark treatment for improving CFS. “Low and slow” exercise is where patients exercise 2-5 minutes followed by 5 minutes of rest so as not to damage skeletal muscle. Another such exercise is walking slowly, no more than 2 MPH for 40 minutes daily.

Even if biking or rowing, no more than 2 MPH. This may be too stressful for some patients, who on some days cannot lift their heads off the pillow. Supine exercises can be used for them. More work is required to assess the types of exercise programs that are most effective.

Diets high in processed foods and full of chemicals may be a cause of CFS and should be avoided. Cocktails of antioxidants that work on the mitochondria and immune system modulation are current areas of investigation. Currently, we are working on ways to categorize the different patients to determine which treatments work best.

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

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ME/CFS is a common and very debilitating disease for which the origin, or etiology, is unknown. While there is some controversy about the exact cause or causes, much has been learned in the last 20 years.  One widely held theory is that patients with a genetic predisposition and abnormal bacteria colonization, or dysbiosis, experience a gradual development of lymphocytes which are known as B cell clones which are susceptible to autoreactivity.  Normally these B cells produce normal antibodies in the body.  However, during unusual circumstances a triggering event such as a viral or a bacterial infection can cause these B cells to become autoreactive and produce autoantibodies.  Therefore, there was some belief there may be an autoimmune mechanism which begins evolving and causes this disease process.

ME/CFS is a chronic disease that usually has lasted for more than six months.  The result is post-exertional fatigue, unrefreshing sleep, memory and cognitive disturbances (“Brain Fog”), and oftentimes Autonomic Nervous System dysfunction (typically involving Parasympathetic Excess, an abnormal increase in Parasympathetic activity in response to a Sympathetic challenge or stress).  Usually the stricken individual was very active prior to the onset of the disease.  The disease usually persists as a chronic condition.  Females are affected more than males.  As many as 8 million Americans may be affected.  While the cause of ME/CFS is unknown, many factors are through to contribute to the development of the illness, such as:  (1) bacterial or viral infections, or (2) physical or emotional trauma, including from an accident, concussion, immobilization, surgery, trauma, or even a significant emotional stress such as loss of a loved one.  Genetics may also contribute, and a genetic link with common environmental exposures, such as infectious or toxic has been postulated.  Identical twins have a higher incidence then fraternal twins.  Environmental factors, such as molds or toxins may also be a trigger to ME/CFS.  However, no one common cause has been identified.  This is because the population is heterogenous.  Patients are affected at different ages and have different presentations.

Dysfunctional energetics at the cellular level is believed to be a common mechanism.  Disturbed muscle function, metabolism, mitochondrial function, immunity, signaling, neurological, and adrenal and gut health are involved.  Specifically, abnormal metabolism regarding the mitochondria has been demonstrated.  Urea Cycle dysregulation, Tricyclic Carboxylic Acid (TCA) Cycle disturbances, and dysregulation of Amino Acid metabolism are also involved.  Also, gut microbiota disturbances have been identified.  In regard to Mitochondrial dysfunction, studies state that ATP8 levels have been both noted to be reduced and elevated, and resting ATP8 synthesis rates have been variable.  However, studies on isolated Peripheral Blood Mononuclear Cells have shown that under stress such as Hypoglycemia there is inefficient ATP8 production in Chronic Fatigue patients but not in normal controls.  This was demonstrated by Tomas and coworkers in 2017.  Therefore, while resting ATP studies show that production may not be significantly abnormal in ME/CFS patients as compared with controls, it appears that under stressful situations, such as Hypoglycemia, the situation is different when one analyzes peripheral blood mononuclear cell ATP production.  ATP is the energy molecule of the cell and of the body and is produced in the Mitochondria, which are the energy factories of the body.

Mitochondria are organelles, or components of cells, which are very active and contain their own DNA contents separate from the nucleus of the cell.  Elevated oxidative stress has also been demonstrated in many subpopulations of patients with ME/CFS.  Increasing oxidative stress has been demonstrated with testing products which are the result of oxidative stress, which include increased isoprostane, increased oxidized LDL levels, and increased iso-prostaglandin F2 levels. Also, reduced protective antioxidants, such as glutathione levels have been reduced in populations of patients with ME/CFS.  Oxidative stress is produced when free radicals are produced in the mitochondria of cells in abundance during stressful situation and in essence cause a chemical burning reaction in damaged tissues.

Figure Legend: Schematic diagram showing various viral pathogens potentially associated with ME/CFS and possible molecular mechanisms altered by these pathogens that can contribute to ME/CFS development [[i]].

Plioplys and coworkers demonstrated lower levels of serum total Carnitine, free Carnitine, and Acetylcarnitine compared to healthy controls, and the lower level correlated with the more severe disease and ME/CFS patients.  Carnitine is an important natural component in transporting Fatty Acids across the Mitochondria cell membrane to continue the process of fatty acid oxidation, which also produces ATP molecules.

In regard to ATP molecules, Mayhill and coworkers measured Mitochondria function and ATP production in Neutrophils and developed an ATP profile test.  More elements of the ATP profile are abnormal in patients with ME/CFS.  Again, this reinforces the fact that there are abnormal energetics occurring within the Mitochondria of cells.  They state “our observations strongly implicate Mitochondrial dysfunction as the immediate cause of chronic fatigue symptoms.  However, we cannot tell whether the damage to Mitochondria function is a primary effect or a secondary effect to one or more of a number of comorbidities, for example, cellular hypoxia or oxidative stress, including excessive peroxynitrates.”

[i] Rasa S, Nora-Krukle Z, Henning N, Eliassen E, Shikova E, Harrer T, Scheibenbogen C, Murovska M, and Prusty BK.  Chronic viral infections in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).  J Translational Med.  2018; 16: 268, doi:10.1186/s12967-018-1644-y.

 

Figure Legend:  Main stages and location of energy metabolism in a human cell (left), and simplified details of a mitochondrion showing the main metabolic cycles and the oxidative phosphorylation respiratory chain (right). The outer mitochondrial membrane is highly permeable whereas the inner membrane is permeable only to water and gases. Special carrier and Translocator proteins pass reactants through it. At the top are the proteins involved in the respiratory electron transfer chain (ETC) and in the transfer of ATP and ADP between the cytosol and mitochondrion. ADP and Pi are combined by ATP synthase to make ATP. The ADP/ATP Translocator opens OUT to transfer ADP into the matrix and opens IN to transfer ATP to the cytosol. Nicotinamide adenine dinucleotide plays a key role in its oxidized form NAD+ and its reduced form NADH + H+ in carrying and transferring protons (H+) and electrons (e−) [[i]].

Key reports on ME/CFS have shown abnormal metabolites produced which demonstrate disturbed Amino Acid metabolism, dysregulated lipid metabolism with possible glycolysis impairment, possible Pyruvate Dehydrogenase (PDH) impairment, Urea Cycle dysregulation and overall TCA cycle substrates provision deficiency and reliance these cells for alternate fuel sources.  As noted, Mitochondria function has been shown to be abnormal and the Electron Transport Chain, specifically if Complex IV is inefficiently compensated for the up-regulation of supporting pathways.

[i] Myhill S, Booth NE, McLaren-Howard J. Chronic fatigue syndrome and mitochondrial dysfunction.  Int J Clin Exp Med. 2009; 2(1): 1–16. 

Abnormalities in B cells have been linked to mitochondrial disturbances and as gut microbiota and physiology.  Autoimmunity has been little researched but has been performed on a subtype that is especially comorbid with Irritable Bowel Syndrome, which is seen in many Chronic Fatigue patients.   Autoimmune evidence has been strengthened by the fact that there is a decrease in the natural killer cell cytotoxicity in patients with ME/CFS.  Natural killer cells are Granular Lymphocytes which attack viruses and bacteria foreign to the body.  In addition, the autoimmune evidence is supported by autoantibodies which have been noted against various transmitter receptors, both Muscarinic receptors and Beta receptors.  A high incidence of these receptors has also been found in patients with Postural Orthostatic Tachycardia.  Specifically, autoantibodies against the Muscarinic and Cholinergic receptors #3 (M3) and autoantibodies against the Muscarinic and Cholinergic receptor #4 M4) are elevated in 20-30% of all patients suffering from ME/CFS.  Other studies have shown Beta-1 Adrenergic Receptor Autoantibodies and Beta-2 Adrenergic Receptor Autoantibodies along with Alpha-1 Adrenergic Receptor Autoantibodies, the same autoantibodies which we find in a significant number of patients with Postural Orthostatic Tachycardia Syndrome.

Testing for these autoantibodies is expensive, and it is not proven that immunomodulating therapy or steroids may be effective in these patients although there is some data that low-dose Hydrocortisone does improve patients with ME/CFS.  There is also data that B lymphocyte cell depletion with a drug known as Rituximab can result in clinical benefit also.  Also, an immunoabsorption technique which removes Beta 2 receptors and depletes them has been shown to be effective.  This supports a cause and effect relationship with autoantibodies against receptors and removing them as a clinical response.  This improvement in patients has been seen with Chronic Fatigue.  In one study, immunoabsorption removed Beta 2 Adrenergic Receptor Antibodies in patients with ME/CFS and showed clinical improvement in memory in symptoms. Some of these patients had long-lasting improvements, while others had short lasting improvements.  These are only pilot studies and more research is needed.  Other studies have also shown higher autoantibody levels against M1, M3 and M4 Acetylcholine receptors and Beta 2 Adrenergic receptors compared to controls.

Impairments of the Hypothalamic-Pituitary-Adrenal system (considered a portion of the Autonomic Nervous System) have also been reported.  There has been noted decrease in Adrenocorticotropic Hormone sensitivity of Adrenal cells expression of negative feedback mechanisms.  Some patients with ME/CFS have low Cortisol levels and improvement with low-dose Hydrocortisone has been shown in these patients.  In and to hormonal dysregulation, Autonomic dysregulation shows a strong association with ME/CFS.  Some studies have shown that more than 90% of patients with ME/CFS have Orthostatic Intolerance.  This is strengthened by the fact that many patients with Postural Orthostatic Tachycardia Syndrome (POTS) have similar autoantibodies to patients with ME/CFS.  Blood pressure or heart rate regulation abnormalities are seen particularly in adolescents with ME/CFS and many experience symptoms of Orthostatic Intolerance as noted.  These patients have worsening symptoms when they get upright posture and improvement when they lie down.

The association of Ehlers-Danlos Syndrome and Autonomic Dysfunction with high frequency of ME/CFS has been intriguing.  We believe that there is a genetic predisposition to patients with Ehlers-Danlos Syndrome and Hypermobility spectrum disorders, and they are susceptible to develop Autonomic Dysfunction and Chronic Fatigue after exposure to certain triggers, such as viruses, bacterial infections, emotional stress, trauma, and concussions.  Indices of inflammation are also noted to be increased in the populations of patients with ME/CFS.  Increased production of various proinflammatory cytokines produce symptoms of fatigue, fevers, adenopathy, myalgias, and arthralgias, sleep disturbances, cognitive impairment and mood disturbances.  Infections can trigger or initiate an autoreactive process affecting brain and energy metabolism in people genetically predisposed and patients with abnormal dysbiosis.  Patients experience a gradual development of a B cell clone prone to autoregulation, and this may lead to autoimmunity.

Some patients have abnormalities of levels of immunoglobulins.  Increased levels of IgA and in some cases, IgM have been noted, and these have been directed against endotoxin components of gram negative bacteria and may be the cause of increased gut permeability noted in many people with ME/CFS.

Exercise is the hallmark treatment for improving patients with ME/CFS.  Given that Parasympathetic Excess is a typical Autonomic Dysfunction, usually “low-and-slow” exercise is recommended.  Some experts in the field feel patients should exercise no more than two to five minutes at a time followed by five minutes of rest so not to damage skeletal muscle.  However, “low-and-slow” exercise, such as walking slowly at no more than 2 mph for 40 minutes, every day for 6 months.  No running or jogging or weight lifting or anything else that would raise heart rate too fast.  Even if biking or rowing, the motion is still as if walking at no more than 2 mph.  This is to re-train the Parasympathetic nervous system to accept small stresses, then larger stresses may be (re-)introduced.  For some patients, this is still too stressful.  For those days in which a patient simply cannot lift their head off the pillow, supine exercises are recommended, see figure below.

Antimitochondrial cocktails with antioxidants, such as Alpha Lipoic Acid, Coenzyme Q10 and L-carnitine have also been proposed by many experts and some patients are significantly benefited by these cocktails.

In regard to inflammation within the Central Nervous System, there is a glial activation or microglia activation which induces Nitric Oxide and superoxide production of free radicals.  These cause neural excitation and neurodegeneration of tissue.  Glial activation causes the chronic pain and allodynia in hyperalgesia via the impact a bidirectional signaling mechanism.

In regard to the unrefreshing sleep, we have already discussed the Hypothalamic-Pituitary-Adrenal Axis and the Hypocortisolism.  Two meta-analyses have shown an attenuated Cortisol awakening response which may contribute to this morning feeling of non-refreshing sleep.

In addition to exercise and antioxidants, a ketogenic diet, which is high fat and low carbohydrate and limits calorie restriction, or a fasting diet has been recommended.  This form of diet has variable results.

Recently from Stanford, a new blood test which produces a stressful environment to white blood cells, in this case mononuclear cells, was developed by Dr. Davis.  It appears that patients with ME/CFS have a very high abnormal gradient or electrical charge when exposed to a salt stress environment then cells from normal individuals.  Researchers are working arduously to develop these types of test, so we have more objective and easy ways to diagnose ME/CFS.  ME/CFS must be differentiated from other entities that have other symptoms which are active participants in causing a malaise, such as collagen vascular disease, cancer, anemia, depression, thyroid disease, drug or pharmacological effects, and other metabolic and infectious diseases.

We believe that mitochondrial mutations or chromosomal mutations in susceptible people may cause ME/CFS.  We believe that an autoimmune mechanism may be operative, where in some cases infections induce a normal immune response, but the pathogens may be close enough to our own receptors to cause them to be similarly attacked.  After this, additional infections or physical or psychological stress can intensify both the mitochondrial energy deficits and the autoimmunity, and this can create a vicious cycle of fatigue.  Patients can present with pain, brain fog, disability and poor exercise tolerance.  These are direct or indirect symptoms of Parasympathetic Excess.  The association of autoantibodies with similar autoantibodies with POTS and autonomic dysfunction syndrome in ME/CFS patients is not simply coincidence.  Note, the Parasympathetic nervous system controls and coordinates the immune system.  It may be possible that Parasympathetic Excess causes overactive and persistent immune responses that may lead to autoimmunity.  Studies have shown that positive autoimmune tests also show mutations in Mitochondria genes that play an important role in the five mitochondrial respiratory complexes (I, II, III, C & IV; see figure above) in the Electron Transport Chain that produces 90% of the body’s energy with ATP.

The overlap with Hypermobility syndrome, Chronic Fatigue and Autonomic Dysfunction with Orthostatic Intolerance or Parasympathetic Excess states leads us to believe that there is mechanism at the cellular level, which causes an acquired Mitochondria Dysfunction with abnormal energetics producing energy from the body, and that the insulting agents that trigger this are in may cases infectious or inflammatory and can be worsened by emotional stress or trauma stress.  They produce a state of inflammation known as oxidative stress which produces energy depleting agents (including oxidants) similar to autoimmunity.  Authors have shown that oxidation of critical parts, for example, the Pyruvate Kinase Enzyme System can affectively block the transition of Glycolysis to Aerobic Metabolism, and this demonstrates a biochemical feasibility mechanism.  Therefore, the autoimmune model involving the oxidative stress and acquired Mitochondria Dysfunction appear to have significant overlapping features when one looks at all of the studies that have been done on these populations of patients with ME/CFS.

What does this mean in terms of helping the patient?  More studies need to be done in terms of using immunomodulating agents in trials, such as IVIG, Corticosteroids and B cell depleting therapies.  More work is required assessing the types of exercise programs that are most effective, along with the types of diets that are more effective.  The typical American Diet, highly processed foods, full of chemicals, together with the high levels of Psychosocial stress in the American lifestyle may be more of a cause of Chronic Fatigue, than anything else.  More is required to study the components and dosages of Mitochondria cocktails that utilize antioxidant agents to see which are most valuable.  More work needs to be done to stratify the ME/CFS patients into different phenotypes or categories, as this is a heterogenous group of patients.  These patients have different presenting symptoms with different organ systems being more dysfunctional than others.

 

REFERENCES

1 Rasa S, Nora-Krukle Z, Henning N, Eliassen E, Shikova E, Harrer T, Scheibenbogen C, Murovska M, and Prusty BK.  Chronic viral infections in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).  J Translational Med.  2018; 16: 268, doi:10.1186/s12967-018-1644-y.

2 Myhill S, Booth NE, McLaren-Howard J. Chronic fatigue syndrome and mitochondrial dysfunction.  Int J Clin Exp Med. 2009; 2(1): 1–16. 

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CHRONIC FATIGUE SYNDROME, MITOCHONDRIAL DYSFUNCTION AND PARASYMPATHETIC EXCESS

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WHAT IS ME/CFS?

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ME/CFS is a heterogeneous group of patients. Recent studies [1, 2, 3, 4, 5] suggest triggering insults such as infections can cause autoantibodies and oxidative stress to dysregulate cellular and specifically mitochondrial energetics, both of which may lead to exercise intolerance. Other common symptoms of ME/CFS may be due to (1) disturbed gut microbiota possibly leading to “leaky-gut” or other GI consequences [6, 7, 8]; (2) microglial activation and inflammation of the nervous system, including the central nervous system, possibly leading to chronic pain due to allodynia and hyperalgesia [9, 10, 11, 12, 13, 14, 15, 16] (see the two figures from [13]); (3) neuronal inflammation is important in the pathophysiology of creating many disabling symptoms; (4) high levels of pro-inflammatory cytokines and low levels of antioxidants, such as CoQ10 or Glutathione, have been reported [17]; or (5) abnormalities of the Hypothalamus-Pituitary-Adrenal Axis possibly leading to “delayed cortisol awakening” [18, 19, 20] possibly leading to unrefreshing sleep. We recommend ALA because Glutathione does not penetrate into the Mitochondria whereas ALA does and helps to recycle Glutathione, along with many other benefits.

Myhill and coworkers [21] used an Adenosine Triphosphate (ATP) profile test (see Appendix) in neutrophils to establish mitochondrial dysfunction in ME/CSF patients. They concluded “our observations strongly implicate mitochondrial dysfunction as the immediate cause of CFS symptoms (see Figure from [21]). However, we cannot tell whether the damage to mitochondrial function is a primary effect or secondary effect to one or more of a number of comorbidities, for example, cellular hypoxia or oxidative stress, including excessive peroxynitrates.” A familial aggregation of ME/CFS has been noted [22]. Metabolic differences in ME/CFS patients demonstrate inability of CFS Peripheral Blood Mononuclear Cells (PBMCS) to fulfill cellular energetic demands both under basal conditions and when Mitochondria are stresses during periods of high metabolic demand such as hypoglycemia [20].

The concurrence of similar autoantibodies in patients with POTS [21] (which may be comorbid with Vasovagal Syncope) and ME/CFS (particularly muscarinic and adrenergic receptor abnormalities) [17, ] is more than coincidental. Parasympathetic and Sympathetic dysfunction and ME/CFS are apparently “joined at the hip.” Ehlers-Danlos Syndrome (EDS) and Hypermobile patients may have a genetic predisposition to autoimmunity and mitochondrial dysfunction. Many of these patients also manifest autonomic (P&S) dysfunction and ME/CFS. POTS, EDS and ME/CFS all have significant fatigue as a common symptom with a “dynamic” Parasympathetic Excess (PE) as a common dysautonomia. PE is central to Vasovagal Syncope [24]. Many of the symptoms of EDS or Hypermobility are due to “leaky” connective tissue which causes an excessively active immune system, which is associated with PE since the Parasympathetics control the immune system. We also find that PE is significantly associated with ME/CFS [24]. The adrenergic abnormalities may be explained by PE, including excessive adrenergic or Sympathetic activity. With PE, Sympathetic Excess is secondary, due to the Sympathetic response being abnormally amplified by the Parasympathetic increase (rather than the decrease that is expected to happen normally) [24]. In fact we believe, the autoimmunity to also be associated with PE. PE causes an overactive immune system, which in more normal patients may lead to autoimmunity. PE mediated autoimmunity results from the immune system being excessively active, and having exhausted any invading entities, turns on the host. We have seen that relieving PE has relieved some autoimmune symptoms [personal observation].

Fig. 1 Schematic diagram showing various viral pathogens potentially associated with ME/CFS and possible molecular mechanisms altered by these pathogens that can contribute to ME/CFS development [25]

This figure describes the putative role of immune brain communication in the pathogenesis of severe intractable fatigue. Toll-like receptors (TLRs) on antigen presentation cells (APCs) may be activated by pathogen- or damage-associated molecular patterns (PAMPs/DAMPs) leading to the activation of nuclear factor-κB (NF-κB) and the subsequent upregulation of pro-inflammatory cytokines (PICs), including interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α, and reactive oxygen and nitrogen species (ROS/RNS). These radical species may further damage macromolecules, increasing levels of redox-derived DAMPs which further engage TLRs in a self-sustaining cycle. PIC signals reach the brain via the afferent arm of the vagus nerve, engagement with transporters in the blood brain barrier (BBB) and passive diffusion. Inflammatory signaling from the periphery activates microglia which produce a range of neurotoxic molecules activating astrocytes causing a loss of brain homoeostasis and disruption of the BBB. The latter allows abnormally high numbers of activated T and B cells and macrophages to circulate between the periphery and the brain. This figure is original. [26]

Activation of microglia after peripheral nerve injury. Microgliosis in the spinal cord is coordinated by sensory afferent derived injury signals, whereby chemokines, nucleotides, and other pro-inflammatory mediators released from damaged afferent terminals could signal through post-synaptic surface receptors to activate microglia. Preclinical studies showed spinal nerve injury could lead to sustained neuronal upregulation and/or increased synaptic release of neuregulin-1, matrix metalloproteases, chemokine (C-C motif) ligand 2, fractalkine and its cognate receptor CXCR3. Release of danger/damage-associated molecular patterns (DAMPs), intracellular nucleotides or proteins that become highly immunogenic when liberated into extracellular space, could also occur in primary afferent injury. In particular, ATP signalling through ionotropic purinergic receptor (P2X4R and P2X7R) was shown to contribute to microglial activation and inflammatory cytokine release. Activation of microglial pattern recognition receptors (PRRs), for example toll-like receptors (TLR2 and TLR4) and receptor for advanced glycation end products (RAGE), by afferent-derived DAMP mediator high mobility group box protein 1 (HMGB1), represents another microglial activation pathway. Activated microglia will in turn release pro-inflammatory cytokines (TNF-α, IL-1β and IL-6), colony-stimulating factor 1 (CSF1), brain-derived neurotropic factor (BDNF), reactive oxygen species (ROS) among others into the spinal cord micro-environments, to direct multidirectional crosstalk between primary afferent, interneurons, secondary neurones, astrocytes and microglia. [13]

Interaction between microglia and other cell types during neuropathic pain. Microglia engage in extensive neuronal and immune cell crosstalk during neuropathic nociceptive transmission. (A). ATP-stimulated brain derived neurotrophic factor (BDNF) release from microglia was shown to depolarise nociceptive neurones in spinal cord, by inverting the polarising current from GABA-A receptor. (B). Microglia-astrocyte interaction was also evident during sensory nerve injury. IL-18 (also IL-1β) release from activated microglia likely signals through IL18R on astrocytes, together with increased chemokine CX3CL1-CX3C1R interaction between microglia and astrocyte, activates NF-kB pathway in astrocytes to upregulate the expression of pro-inflammatory cytokines. Astrocyte-derived interleukin-1β and interleukin-23 are thought to promote allodynia/behavioural sensitisation from nociceptive stimulation, by modulating NMDA receptor activities on post-synaptic neurones. (C) Activated microglia could also stimulate the endothelial expression of intracellular adhesion molecule 1 (ICAM1) from peripheral inflammatory pain stimulation, to alter the permeability of blood-brain barrier. (D) Sensory nerve injury also stimulated the spinal oligodendrocytes to release interleukin-33/alarmin, which targets the microglia and astrocytes to promote IL-1β and TNF-α release. (E) Microglia-mast cell interaction may also contribute to neuropathic pain. In peripheral nerves, resident mast cell degranulation could sensitise/activate nociceptors, likely through the action of histamine, to result in neuropathic pain. Mast cells are also located in the spinal cord, and upon activation, the release of mast cell tryptase could directly activate microglia through protease-activated receptor 2 (PAR2), upregulating the synthesis of pro-nociceptive TNF-a and interleukin-6. (F) CD4+ T-lymphocytes infiltrate the dorsal spinal horn after sensory nerve injury to contribute to spinal microglia activation, through the release of interferon-γ, to mediate tactile allodynia. [13]

Main stages and location of energy metabolism in a human cell (left), and simplified details of a mitochondrion showing the main metabolic cycles and the oxidative phosphorylation respiratory chain (right). The outer mitochondrial membrane is highly permeable whereas the inner membrane is permeable only to water and gases. Special carrier and Translocator proteins pass reactants through it. At the top are the proteins involved in the respiratory electron transfer chain (ETC) and in the transfer of ATP and ADP between the cytosol and mitochondrion. ADP and Pi are combined by ATP synthase to make ATP. The ADP/ATP Translocator opens OUT to transfer ADP into the matrix and opens IN to transfer ATP to the cytosol. Nicotinamide adenine dinucleotide plays a key role in its oxidized form NAD+ and its reduced form NADH + H+ in carrying and transferring protons (H+) and electrons (e−) [21].

 

APPENDIX:  THE “ATP PROFILE” TEST

The “ATP profile” test yields 5 independent numerical factors from 3 series of measurements, (A), (B), and (C) on blood samples (neutrophils).   The 3 series are:

  1. ATP concentration in the neutrophils is measured in the presence of excess magnesium which is needed for ATP reactions. This gives the factor ATP in units of nmol per million cells (or fmol/cell), the measure of how much ATP is present. Then a second measurement is made with just endogenous magnesium present. The ratio of this to the one with excess magnesium is the ATP Ratio. This tells us what fraction of the ATP is available for energy supply.
  2. The efficiency of the oxidative phosphorylation process is measured by first inhibiting the ADP to ATP conversion in the laboratory with sodium azide. This chemical inhibits both the mitochondrial protein cytochrome a3 (last step in the ETC) and ATP synthase [50]. ATP should then be rapidly used up and have a low measured concentration. Next, the inhibitor is removed by washing and re-suspending the cells in a buffer solution. The mitochondria should then rapidly replete the ATP from ADP and restore the ATP concentration. The overall result gives Ox Phos, which is the ADP to ATP recycling efficiency that makes more energy available as needed.
  3. The TL switches a single binding site between two states. In the first state ADP is recovered from the cytosol for re-conversion to ATP, and in the second state ATP produced in the mitochondria is passed into the cytosol to release its energy. Measurements are made by trapping the mitochondria on an affinity chromatography medium. First the mitochondrial ATP is measured. Next, an ADP-containing buffer is added at a pH that strongly biases the TL towards scavenging ADP for conversion to ATP. After 10 minutes the ATP in the mitochondria is measured. This yields the number TL OUT. This is a measure of the efficiency for transfer of ADP out of the cytosol for reconversion to ATP in the mitochondria. In the next measurement a buffer is added at a pH that strongly biases the TL in the direction to return ATP to the cytosol. After 10 minutes the mitochondria are washed free of the buffer and the ATP remaining in the mitochondria is measured and this gives the number TL IN. This is a measure of the efficiency for the transfer of ATP from the mitochondria into the cytosol where it can release its energy as needed.

DETAILS

The “ATP profile” tests were developed and carried out at the Biolab Medical Unit, London, UK (www.biolab.co.uk), where one of us (JMH) was Laboratory Director until retirement in 2007. Blood samples in 3-ml heparin tubes were normally received, tested and processed within 72 hours of venepuncture. We briefly describe here the 3 series of measurements, (A), (B) and (C) and how the 5 numerical factors are calculated. (Step-by-step details can be obtained by contacting JMH at acumenlab@hotmail.co.uk).

Neutrophil cells are separated by HistopaqueTM density gradient centrifugation according to Sigma® Procedure No. 1119 (1119.pdf available at www.sigmaaldrich.com). Cell purity is checked using optical microscopy and cell concentration is assessed using an automated cell counter. Quantitative bioluminescent measurement of ATP is made using the Sigma® Adenosine 5’-triphosphate (ATP) Bioluminescent Somatic Cell Assay Kit (FLASC) according to the Sigma® Technical Bulletin No. BSCA-1 (FLASCBUL.pdf). In this method ATP is consumed and light is emitted when firefly luciferase catalyses the oxidation of D-luciferin. The light emitted is proportional to the ATP present, and is measured with a Perkin-Elmer LS 5B Fluorescence Spectrometer equipped with a flow-through micro cell. Sigma® ATP Standard (FLAA.pdf) is used as a control and as an addition-standard for checking recovery. Similar kits are available from other providers, e.g. the ENLITENTM ATP Assay System (Technical Bulletin at www.promega.com), and dedicated instruments are now available, e.g. Modulus Luminescence Modules (see Application Note www.turnerbiosystems.com/doc/appnotes /PDF/997_9304.pdf).

  1. ATP is first measured with excess magnesium added via Sigma® ATP Assay Mix giving result a. This is the first factor, the concentration of ATP in whole cells, ATP = a in units of nmol/106 cells (or fmol/cell).
    The measurement is repeated with just the endogenous magnesium present by using analogous reagents produced in-house without added magnesium, giving result b in the same units. The ratio, c = b/a, is the second factor, the ATP Ratio.
  2. In order to measure the ADP to ATP conversion efficiency via the ox-phos process, the ATP (with excess magnesium) result, a, is used and then the conversion is inhibited in the laboratory with sodium azide for 3 min and result d is obtained (also with excess magnesium). The laboratory inhibitor is then removed by washing with buffered saline and the mitochondria should rapidly replete (again 3 min) the ATP supply from ADP. This gives result e in the same units. The conversion efficiency Ox Phos is
    f = [(e – d) / (a – d)].

(C). In order to measure the effectiveness of the Translocator (TL) in the mitochondrial membrane the cells are ruptured and the mitochondria are trapped onto pellets of an affinity chromatography medium doped with a low concentration of atractyloside. This immobilises the mitochondria while the other cell components are washed away. The buffers used then free the mitochondria leaving the atractyloside on the solid support that plays no further part in the method. The mitochondrial ATP concentration is measured giving result g in units of pmol/million cells. For the next measurement some pellets are immersed in a buffer (which acts as an artificial cytosol) containing ADP at pH = (5.5 ± 0.2) which biases the TL towards scavenging ADP to be converted to ATP in the mitochondria. After 10 min the ATP is measured again, giving result h in the same units. The factor TL OUT is the fractional increase in ATP:
j = [(h – g) / g].
For the next measurement pellets are immersed in a buffer not containing ADP and the TL is biased away from ADP pickup and towards ATP transfer into the artificial cytosol at pH = (8.9 ± 0.2) After 10 min the mitochondrial ATP is again measured giving result k, and the factor TL IN is the fractional decrease:
l = [(g – k) / g].

 

REFERENCES

[1] Anand, S.K.; Tikoo, S.K. Viruses as modulators of mitochondrial functions. Adv. Virol. 2013, 2013, 1–17  doi:  10.1155/2013/738794.

[2] Fenouillet E, Vigouroux A, Steinberg JG, Chagvardieff A, Retornaz F, Guieu R, Jammes Y. Association of biomarkers with health-related quality of life and history of stressors in myalgic encephalomyelitis/chronic fatigue syndrome patients.  J Transl Med. 2016 Aug 31; 14(1):251. doi: 10.1186/s12967-016-1010-x.

[3] Komaroff, A.L. Inflammation correlates with symptoms in chronic fatigue syndrome. Proc. Natl. Acad. Sci.

USA 2017, 114, 8914–8916  doi:  10.1073/pnas.1712475114.

[4] Blomberg J,  Gottfries CG, Elfaitouri A, Rizwan M, Rosén, A. Infection elicited autoimmunity and Myalgic encephalomyelitis/chronic fatigue syndrome: An explanatory model. Front. Immunol. 2018, 9, 229  doi 10.3389/fimmu.2018.00229.

[5] Behan WM, More IA, Behan PO.  Mitochondrial abnormalities in the postviral fatigue syndrome.  Acta Neuropathol. 1991; 83(1): 61-5.

[6] Nagy-Szakal D, Williams BL, Mishra N, Che X, Lee B, Bateman L, Klimas NG, Komaroff AL, Levine S, Montoya JG, Peterson DL, Ramanan D, Jain K, Eddy ML, Hornig M, Lipkin WI. Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome.  Microbiome. 2017 Apr 26;5(1):44. doi: 10.1186/s40168-017-0261-y.

[7] Maes M, Twisk FN, Kubera M, Ringel K, Leunis JC, Geffard M.  Increased IgA responses to the LPS of commensal bacteria is associated with inflammation and activation of cell-mediated immunity in chronic fatigue syndrome.  J Affect Disord.  2012 Feb;136(3):909-17. doi: 10.1016/j.jad.2011.09.010.

[8] Giloteaux L, Goodrich JK, Walters WA. et al. Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome.  Microbiome. 2016; 4: 30.  doi:10.1186/s40168-016-0171-4.

[9] Glassford JAG. The neuroinflammatory etiopathology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Front. Physiol. 2017, 8, 1–9.  Doi:  10.3389/fphys.2017.00088.

[10] Nakatomi Y, Mizuno K, Ishii A, Wada Y, Tanaka M, Tazawa S, Onoe K, Fukuda S, Kawabe J, Takahashi K, et al. Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An 11C-(R)-PK11195 PET Study. J. Nucl. Med. 2014, 55, 945–950.  doi:  10.2967/jnumed.113.131045.

[11] Ji RR, Berta T, Nedergaard M. Glia and pain: is chronic pain a gliopathy?  Pain. 2013 Dec;154 Suppl 1(0 1):S10-28. doi: 10.1016/j.pain.2013.06.022..

[12] Ren K, Dubner R. Neuron-glia crosstalk gets serious: role in pain hypersensitivity.  Curr Opin Anaesthesiol. 2008 Oct;21(5):570-9. doi: 10.1097/ACO.0b013e32830edbdf.

[13] Zhao H, Alam A, Chen Q, A Eusman M, Pal A, Eguchi S, Wu L, Ma D.  The role of microglia in the pathobiology of neuropathic pain development: what do we know?  Br J Anaesth. 2017 Apr 1;118(4):504-516. doi: 10.1093/bja/aex006.

[14] Ricci, G., Volpi, L., Pasquali, L. et al.  Astrocyte–neuron interactions in neurological disorders.  J Biol Phys.  2009; 35: 317–336.  doi:10.1007/s10867-009-9157-9

[15] Puri BK, Jakeman PM, Agour M, Gunatilake KDR, Fernando KAC, Gurusinghe AI, Treasaden IH, Waldman AD, and Gishen P.  Regional grey and white matter volumetric changes in myalgic encephalomyelitis (chronic fatigue syndrome): a voxel-based morphometry 3 T MRI study.  B J Radiol. 2012; 85:1015, e270-e273.  doi:  10.1259/bjr/93889091.

[16] Meeus, M., Nijs, J. Central sensitization: a biopsychosocial explanation for chronic widespread pain in patients with fibromyalgia and chronic fatigue syndrome. Clin Rheumatol.  2007; 26:  465–473.  doi:10.1007/s10067-006-0433-9

[17] Maes M, Mihaylova I, Kubera M. et al.  IgM-mediated autoimmune responses directed against anchorage epitopes are greater in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) than in major depression.  Metab Brain Dis.  2012; 27: 415–423.  doi:10.1007/s11011-012-9316-8.

[18] Hall DL, Lattie EG, Antoni MH, et al. Stress management skills, cortisol awakening response, and post-exertional malaise in Chronic Fatigue Syndrome. Psychoneuroendocrinology. 2014;49:26–31. doi:10.1016/j.psyneuen.2014.06.021.

[19] Nijhof SL, Rutten JM, Uiterwaal CS, Bleijenberg G, Kimpen JL, Putte EM.  The role of hypocortisolism in chronic fatigue syndrome.  Psychoneuroendocrinology. 2014 Apr;42:199-206. doi: 10.1016/j.psyneuen.2014.01.017.

[20] Tomas C, Brown A, Strassheim V, Elson J, Newton J, Manning P (2017) Cellular bioenergetics is impaired in patients with chronic fatigue syndrome. PLoS ONE 2017; 12(10): e0186802. 10.1371/journal.pone.0186802.

[21] Myhill S, Booth NE, McLaren-Howard J. Chronic fatigue syndrome and mitochondrial dysfunction.  Int J Clin Exp Med. 2009; 2(1): 1–16. 

[22] Buchwald D, Herrell R, Ashton S, Belcourt M, Schmaling K, Sullivan P, Neale M, Goldberg J.  A twin study of chronic fatigue.  Psychosom Med.  2001 Nov-Dec;63(6):936-43.

[23] Reynolds, GK, Lewis, DP, Richardson, AM, Lidbury, BA The John Curtin School of Medical Research, The Australian National University, Canberra; Donvale Medical Centre, Donvale, Victoria; and Faculty of Education, Science, Technology and Mathematics, The University of Canberra, Canberra, Australia. Comorbidity of postural orthostatic tachycardia syndromeand chronic fatigue syndrome in an Australian cohort.  J Intern Med.  2014; 275: 409– 417.  doi:  10.1111/joim.12161

[24] Colombo J, Arora RR, DePace NL, Vinik AI.  Clinical Autonomic Dysfunction:  Measurement, Indications, Therapies, and Outcomes.  Springer Science + Business Media, New York, NY, 2014.

[25] Rasa S, Nora-Krukle Z, Henning N, Eliassen E, Shikova E, Harrer T, Scheibenbogen C, Murovska M, and Prusty BK.  Chronic viral infections in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).  J Translational Med.  2018; 16: 268, doi:10.1186/s12967-018-1644-y.

[26] Morris G, Berk M, Walder K, Maes M. Central pathways causing fatigue in neuro-inflammatory and autoimmune illnesses.  BMC Med. 2015; 13: 28. doi:10.1186/s12916-014-0259-2.

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Effects of Nitric Oxide

NITRIC OXIDE IN PROMOTING HEALTHY AUTONOMIC FUNCTION

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The following is a rephrased excerpt from the book Clinical Autonomic and Mitochondrial Disorders by Doctors DePace and Colombo,Springer Publishers, Switzerland, 2019.

What does nitric oxide do in the body?

  Nitric oxide is an important signaling molecule in the human body. It is very important in supporting mind-body wellness. Nitric oxide is a signaling molecule that helps all the cells communicate with each other in the body. It also regulates blood flow, aids in blood pressure regulation and activates the immune system.

Autonomic Dysfunction Treatment With Nitric Oxide

Our approach to treating autonomic dysfunction oftentimes involves using precursors of nitric oxide (see figure below), such as L-arginine and L-citrulline which use the enzyme nitric oxide synthase.

However, in younger people, L-arginine and L-citrulline as amino acids is not as effective in producing nitric oxide because they are already saturated with those amino acids, but they do benefit from beetroot, which is an inorganic source of nitrates which then can go into the nitric oxide production.

The L-arginine pathway (or Endogenous pathway) is limited and may become saturated (therefore limited), as in young people, and taking more of the amino acids does not help to increase nitric oxide. It is just wasteful. Taking supplemental beetroot (the Exogenous pathway) is not limited and creates as much nitric oxide as the bacteria in your mouth and gut can produce from what you ingest.

Key: 1) The action of bacterial nitrate reductases on the tongue and enzymes that have nitrate reductase activity in tissues, 2) Bacterial nitrate reductases, 3) Enzymes with nitrite reductase activity

 

Nitric oxide functions as a neurotransmitter. It is also a bactericide or antimicrobial and can destroy dangerous microbes in the body. It helps regulate blood vessels and dilates them thereby lowering blood pressure.

It can act as an anti-inflammatory and inhibits the white blood cells from adhering to blood vessels. It also functions as a reparative gas and has an antithrombotic, that is it can thin the blood and keep platelets from clumping together so arteries do not close down.

Nitric oxide has also been shown to promote blood vessel growth. Importantly, nitric oxide function as an antioxidant inhibits the bad LDL cholesterol from being oxidized in forming foam cells which are precursors to the atherosclerotic plaque.



Nitric oxide is known to regulate the immune system by enhancing T cell function. It also promotes sexual health in both males and females by increasing blood flow. It promotes better cerebral circulation and may prevent the “so called brain fog” or cognitive difficulties one may encounter when they have dysfunction of the autonomic nervous system.

It is postulated that nitric oxide can even prevent more damage when a heart attack even occurs. It may regulate cell death.

Nitric oxide increases the vagal tone in the body and this, therefore, protects the autonomic nervous system. It decreases sympathetic tone. It is known sympathetic tone increase can increase heart rate and blood pressure.

Therefore, precursors of nitric oxide, such as L-arginine, L-citrulline and beetroot may be effective ancillary agents in lowering blood pressure when antihypertensive medicines are used, or may be used in patients with borderline blood pressure elevation, or high-normal blood pressures to normalize blood pressure by themselves without adding medications. Physicians are usually required to make that judgment assessment. Therefore, nitric oxide is cardioprotective as it balances vagal and sympathetic tone.

Other benefits of nitric oxide is that it promotes bone remodeling and possibly may improve bone density and reduce joint pain and may minimize further cartilage damage by increasing blood flow to the joints.

When one is deficient in nitric oxide, blood pressure may be elevated as nitric oxide insufficiency causes vasoconstriction.

Also, it is believed that nitric oxide insufficiency promotes atherosclerosis, cognitive dysfunction, autoimmune dysfunction, immune dysfunction and most importantly mitochondrial dysfunction, and these can lead to negative symptoms. The mitochondria are the powerhouse of the cells, which produce ATP, the energy molecule, and nitric oxide deficiency by aversely affecting mitochondria can produce a fatigue.

Because of the many benefits of nitric oxide, it is often an important adjunctive ingredient in treating patients with high blood pressure, vascular disease, and autonomic dysfunction. It is also important for sexual health in both males and females for performance.

Many patients who have autonomic dysfunction and chronic fatigue syndrome obtain better exercise tolerance and better energy levels with nitric oxide-promoting regimens.

Simply adding beetroot, which is a source of inorganic nitrates, can increase one’s functional capacity when they have exercise intolerance. We use nitric oxide promotors such as the amino acids and beetroot in many patients who display symptoms and signs of autonomic dysfunction.

Dosing is variable and oftentimes it is better regulated by a physician and is usually better regulated by a physician who has experience in using these types of supplements.

They, however, can be purchased over-the-counter. It is true that too much nitric oxide potentially can be dangerous and therefore one needs to balance how much and what type of nitric oxide precursors would be most beneficial for their particular type problem. A physician experienced in this area can be helpful.

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Car gas and brake pedals, concept photography

OVERACTIVE SYMPATHETIC NERVOUS SYSTEM

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OVERACTIVE SYMPATHETIC NERVOUS SYSTEM

The autonomic nervous system is one of the three main portions of your entire nervous system. The autonomic nervous system is the portion that controls or coordinates all organs and virtually all cells of your body. The autonomic nervous system itself consists of two parts: the sympathetic nervous system and the parasympathetic nervous system. The sympathetic nervous system, which is like the accelerator of the body, is known as the flight or fight nervous system and deals with stress, typically speeding things up. The parasympathetic nervous system, which is like the brakes of the body, is known as the rest and digest nervous system and helps to conserve energy and protect, typically slowing things down. 

Again, like an automobile, the autonomic nervous system has divisions which can speed up or slow down various functions of the body. The sympathetics typically increase heart rate and blood pressure to pump more blood to deal with stress; and dilates pupils to see more, bronchi to inhale more oxygen, and peripheral blood vessels to bring more blood to the muscles. The parasympathetic nervous system does the opposite. If the sympathetic system, like the accelerator of a car, becomes over-reactive it may actually damage the other component of the autonomic nervous system, the parasympathetic nervous system. In the car analogy, this is like driving fast all the time and therefore, having to stop hard all the time. Doing this you wear out the brakes faster. The problem in the human body is that we cannot replace the “brakes” (the parasympathetics). Once the Parasympathetics wear out you are essentially a heart attack waiting to happen.

Even if both are worn, if the parasympathetics are significantly more worn, the sympathetics may still be too high; in comparison. It is the ratio between the two (SB = S/P, known as Sympathovagal Balance) that is the key. Again with the car analogy, even if you have no brakes and no accelerator (you are very old or very sick) you may still roll down hill; even then if you cannot stop you crash. A normal ratio of Sympathetic to Parasympathetic is approximately 1.0 (SB = 1.0 is perfect balance). If SB is high, indicating that the Sympathetics are much more reactive than the Parasympathetics, this may exaggerate or amplify all Sympathetic responses. For example, little stimuli may become painful, little stresses may cause anxiety, little allergic reactions may become rashes or hives (significant histamine reactions). Insufficient Parasympathetic activity with excessive Sympathetic activity (a typical result of persistent stress, including psychosocial stress) may suppress the immune system, over stimulate the production of oxidants leading to excessive oxidative stress, raise blood pressure, promote atherosclerosis, cause persistent inflammation, accelerate diabetes, promote atherosclerosis, and accelerate the onset of heart disease, kidney disease, or dementia.

Again, insufficient Parasympathetic activity with excessive Sympathetic activity (high SB) may make pain more amplified and make one’s reaction to simple stimuli appear excessive and also cause extreme anxiety-like states. This may even mimic a fibromyalgia-like disorder and can be seen in a post-traumatic stress-type disorder. Also, this prolonged excessive sympathetic stimulation can lead to chronic inflammation.

Since both the parasympathetic and sympathetic systems work together, one branch can affect the other branch. Excess activity of the sympathetic nervous system can wear down the parasympathetic nervous system. In everyday life when we get nervous or stressed, our sympathetic nervous system becomes more activated, and this can then accelerate the onset of parasympathetic neuropathy, or parasympathetic damage leading to an increased mortality risk (risk of life-threatening illness). The opposite is also true. Too much Parasympathetic activity can also cause too much Sympathetic activity. This is like “riding the brakes” in a car. If you ride the brakes, you must accelerate more just to reach normal speeds, over-revving your engine, causing more stress. Therefore, it is important to keep the sympathetic nervous system from becoming too overactive. This is why stress reduction is important. Stress reduction reduces heart attacks and chronic diseases like coronary artery disease (mortality risk) and also beneficially affects the parasympathetic nervous system by preventing it from getting worn down too fast.

As we have talked about above, the parasympathetic nervous system, or the brakes of the body, is sort of a protective mechanism and by wearing it down, one can develop a disorder known as cardiac autonomic neuropathy, or CAN, which can adversely affect one’s prognosis. While CAN is a normal function of aging, it is a risk indicator and the risk is significantly higher if the SB is abnormal, especially if SB is high indicating Sympathetic Excess. Ways to keep the sympathetic nervous system from becoming overactive or excessive include lifestyle changes, such as meditation, yoga, Tai Chi, or other forms of mild to moderate exercise. Various exercises can train the sympathetic nervous system not to become overactive and may also be good stress reducers.

One of the six components of our program for wellness, which entails balancing the autonomic nervous system, involves stress reduction. Another is exercise. They appear to go hand in hand. In fact, exercise works through reducing stress in two ways: 1) psychosocial stress which is systemic or whole body stress, as well as 2) oxidative stress which is stress at the cellular level caused by free radicals and other oxidants. Oxidants use excess oxygen or other chemicals to “burn” healthy cells and structures. This is like burning wood, known as fire: too little fire you freeze, too much fire you burn, somewhere in the middle is just right and you are warm and well fed. Oxidative stress is too much “fire” and causes things to “burn”.

Oxidative stress reduction is a third component of our wellness program. Of course antioxidants (both supplemental and those found in the Mediterranean Diet also help to reduce oxidative stress (the stress at the cellular level). A common antioxidant is Vitamin C. There are two super-antioxidants made by the body, which may also be supplemented: Alpha-Lipoic Acid (which is selective for nerves) and Co-Enzyme Q-10 (which is selective for the heart and blood vessels). Both help to provide more energy and improve how we feel about ourselves, and they help to reduce psychosocial stress. The Mediterranean Diet is a fourth component of our Mind-Body Wellness program. As you see, the whole Mind-Body Wellness program works together to establish and maintain health in all stages of life.

For patients who have difficulty exercising, because they have orthostatic dysfunction and cannot be upright for long periods of time (such as patients with POTS or orthostatic hypotension disorders) we generally begin with recumbent exercises, such as a recumbent bicycle, a rowing machine, or swimming (see insert, left). In the worst cases we recommend stating with exercises that including lying on the floor with your feet up on the bed or couch or the like and moving your lower legs like you are walking (see insert, left). In fact, a rowing machine is probably the best exercise initially for patients with POTS syndrome, as they can develop increasing heart mass, size and strength, which can improve the stroke volume. Stroke volume is the amount of blood your heart pumps with each beat. Stroke volume is very important, since patients with these disorders often have low stroke volumes which means their hearts are not pumping enough blood to the brain while you are upright (sitting or standing).

The body has two methods by which to increase blood flow to the brain: 1) increased pressure or 2) increased rate. In POTS patients, because of the (typically) smaller heart sizes, there is not enough muscle mass to increase pressure. Therefore, the body increases heart rate as the attempt to increase blood flow (stroke volume). The resultant increase in heart rate in POTS patients is the fast heart rates (tachycardia) they experience. In many instances, exercise is better than any pharmacology. Exercise being better has been validated in controlled studies which have compared exercise with pharmacology such as beta-blockers. These studies have shown that exercise is superior in improving the symptoms and quality of life in patients with POTS syndrome.

To help accelerate the ability to exercise or the effects of exercise we often recommend a therapy plan that includes low dose: beta blockers (e.g., Propranolol), Midodrine, proper daily hydration, Desmopressin, Electrolytes, and perhaps IV fluids in severe cases, and high dose Alpha-Lipoic Acid. Midodrine and Alpha-Lipoic Acid address the orthostatic dysfunction (the ‘O’ in POTS), retraining the peripheral nerves to constrict the peripheral blood vessels. The Propanolol addresses the tachycardia (the ‘T’ in POTS). The Electrolytes and Desmopressin help to keep the water (hydration) in the body to build blood volume and thin the blood to make it easier for the heart to pump. Once the POTS is relieved and the postural change is stabilized, the Propanolol, Midodrine, and Desmopressin may be weaned and the Alpha-Lipoic Acid and electrolytes may be reduced to maintenance dosing.

Again, for this exercise we are not saying you have to go out and beat yourself up. While hard exercise is fine for those who like it, all we are asking is “low and slow” exercise. Gentle exercises that slowly raise your heart rate over longer periods of time, like up to 40 minutes, is all we recommend that you start with; increasing intensity as your Parasympathetics and Sympathetics return to balance. In our practice, we have indeed seen were exercise is the best medicine for POTS patients. It leads to the quickest recoveries and the longest terms of improved quality of life and health and wellness.

 

 

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