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All Posts in Category: parasympathetic nervous system

Defining Long COVID

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By Dr. Nicholas DePace and Dr. Joseph Columbo

Long‑COVID Definition

What exactly is Long-COVID syndrome?

Long-COVID or post-COVID-19 is an umbrella term that refers to symptoms persisting past the initial phase. There are many definitions that have been offered.

Official Definition of Long-COVID

Long-COVID has recently been defined as “the condition that occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19, with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis”

 Likewise, there now exists an International Classification of Diseases, Tenth Revision (ICD-10) code corresponding to Long-COVID condition—U09.9.  Basically, there are individuals who do not completely recover over a period of weeks, usually 2–3 weeks. Since COVID-19 is a novel disease, there is still no consensus of the definition of Long-COVID symptoms.

Prevalence and Symptom Categories

Systematic Review Findings

A systematic review documented 20% of the reports of long-term COVID symptoms involved abnormal lung function, 24% involved neurological complaints and olfactory dysfunction, and 55% on specific widespread symptoms, mainly chronic fatigue and pain.

WHO’s Clinical Case Definition

The World Health Organization (WHO) developed a clinical case definition of Long-COVID by Delphi methodology that included 12 domains. However, the understanding of this definition has been going through changes as new evidence emerges, and we are gaining a better understanding of the consequences of COVID-19 and its mutations.

Symptom Duration and Impact

Usually, three or more months past the acute COVID-19 infection, symptoms that last for at least 2 months and cannot be explained by alternate diagnoses may ft this definition. These symptoms include fatigue, shortness of breath, cognitive dysfunction, and symptoms that affect the functional capacity of patients with daily living and productivity. Symptoms may fluctuate, fare up, or relapse over time, adversely affecting multiple organ systems.

P&S Nervous Systems Dysfunction in Long Covid

Role of P&S Nervous Systems

We propose that the delay between surviving the acute COVID infection and the onset of the Long-COVID symptoms is a function of the P&S nervous systems.

The P&S nervous systems function together to coordinate and control organs and organ systems to maintain normal organ function, even when the two nervous systems are dysfunctional.

Dysfunction and Symptoms

Prolonged P&S dysfunction, once severe enough, then leads to poor organ control and then symptoms. This process may take up to 3 months, faster if there were prior comorbidities, including age.

This is the basis for our claims that Long-COVID is a combination of both parasympathetic dysfunction(s) and sympathetic dysfunction(s). In our experience, the prolonged severe immune responses to COVID-19 seems to cause prolonged excessive parasympathetic responses, leading to secondary, prolonged, excessive beta-adrenergic (sympathetic) responses which prolongs and exaggerates heart rate, blood pressure, histaminergic, inflammatory, pain, and anxiety responses.

Gastrointestinal and Other Symptoms

The parasympathetic excess may also lead to both upper and lower GI symptoms.

The oxidative stress of the acute COVID-19 infection also causes oxidative stress which often leads to alpha-adrenergic (sympathetic) dysfunction which leads to orthostatic dysfunction and poor coronary and cerebral perfusion and the perfusion of the anatomy in between causing many of the rest of the symptoms of Long-COVID. Long-COVID may directly affect the lungs, heart, nervous system, kidneys, and pancreas.

Challenges in Research and Treatment

Lack of Standardized Definition

Unfortunately, the lack of a standardized definition for Long-COVID syndrome presents obstacles for researchers Fig. 1 The cytokine storm involved in COVID-19 infections is a source of oxidative stress.

Viruses and traumas (mental or physical) in general may lead to oxidative stress, which may lead to parasympathetic or sympathetic dysfunction(s), known as dysautonomia (adapted from Rasa et al.) ◂ Current Cardiology Reports 1 3 in studying the condition with controlled studies and arriving at a precise diagnosis and treatment algorithms. In addition, many patients with Long-COVID syndrome require rehospitalization especially those with comorbidities, such as cardiovascular disease, diabetes mellitus, obesity, cancer, and kidney disease.  


This Post is an excerpt from Current Cardiology Reports:

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Parasympathetic and Sympathetic, Nervous System Dysfunction and Monitoring – Introduction

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By Dr. Nicholas DePace and Dr. Joseph Columbo

There are many consequences of Parasympathetic and Sympathetic Dysfunction (P&S Dysfunction; aka., Autonomic Dysfunction or Dysautonomia) 

Major consequences and their effects include:

  • Abnormal cardiovascular control, causing inappropriate peripheral vasoconstriction, inappropriate shifts in blood volume, poor perfusion and distribution, and inefficient cardiac contractility.  The net effects are (1)gravitational pooling of blood volume, usually to the lower half of the body upon or during upright posture; (2) difficulty in returning blood to the heart to produce an adequate cardiac output, which results in inappropriate rapid drops in BP or rapid increases in HR; and (3) an inappropriate distribution of blood flow throughout the various organs of the body, some receiving too much and some too little, resulting in many of the symptoms listed near the end of this Introduction;
  • P&S imbalance, both at rest and in response to challenges, causing abnormal organ function even when the organs themselves are normal and healthy.  Examples include: (1) unequal pupil sizes; (2) abnormal motility and pH of the gastrointestinal (GI) tract; (3) hormone dysregulation; (4) abnormal pain, inflammatory, histaminergic, BP, HR, blood glucose, or affective (g., anxiety or depression, ADD/ADHD, OCD, PTSD) responses; and
  • Compensation, causing many adverse symptoms that may arise when the body attempts to compensate for the P or S dysfunction, such as high resting BP (possibly resulting in secondary hypertension) in response to Orthostatic or Syncopal disorders and auto-immune-like responses resulting from exaggerated inflammatory responses due to Sympathetic Excess secondary to Parasympathetic Excess (see below).
  • Note: In cases where the P&S dysfunctions are relieved and symptoms persist, then the remaining dysfunctions or disorders are true end-organ dysfunctions and should be treated accordingly.

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Ehlers-Danlos Syndrome

Ehlers-Danlos Syndrome (EDS) and Autonomic Dysfunction

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Autonomic Nervous System Dysfunction in Ehlers-Danlos Syndrome

by Nicholas DePace MD, FACC, and Michael Edward Goldis DO, FACOI, MS, BS in Pharm

The autonomic nervous system (ANS) runs all background bodily functions that do not require a conscious thought process. Major consequences of autonomic dysfunction include abnormal and inappropriate blood volume and flow distribution to the body with gravitational pooling and difficulty returning blood to the heart.

Direct nerve dysfunction can affect pupil size and abnormal motility of the gastrointestinal (GI) tract, compensations which are adaptive mechanisms in the body’s attempt to compensate for autonomic dysfunction, which can cause adverse symptoms. There are 2 components: (1) the sympathetic nervous system, which releases predominantly norepinephrine and is the “accelerator” of the body; (2) the parasympathetic nervous system releases acetylcholine which is the “break” of the body.

The vagus nerve is the main component of the parasympathetic nervous system and is the longest nerve in the body. Because of its long distribution and size, it is susceptible to injury.

Impairment of blood flow to the brain, which is poor perfusion, leads to lightheadedness, tunnel vision, blackout vision, change in hearing, perception, complete loss of consciousness, syncope, presyncope, the need to lie down, giddiness, word-finding difficulties, and short term memory loss.

These occur in the standing position almost always or occasionally sitting, but not lying. These symptoms are known as orthostatic intolerance. Mental cloudiness and brain fog are described.

Lack of perfusion to the brain may precipitate migraines. Light intolerance, photophobia, bothersome sensation to loud noises, anxiety, insomnia, and depression may or may not reflect poor cerebral perfusion.

Ehlers Danlos Syndrome is often associated with GI motility and may be associated with mast cell activation. What the mast cells do is release histamine inflammatory mediators. This accounts for the overlapping features not EDS like abdominal pain and poor GI motility with foggy thinking.

There is an article in the New England Journal of Medicine that feels irritable bowel syndrome (IBS) is the result of a histamine abnormality. What the actual cause is controversial.

While some physicians believe there’s a component of autoimmunity, we believe there is an abnormal connective tissue in the veins precipitating the venous pooling phenomenon, there is poor cerebral perfusion, and Sympathetic overdrive leading to dysautonomia.

There may also be an anatomical component to the autonomic dysfunction when you consider the vagus nerve is a parasympathetic nerve and the most prominent and longest in the parasympathetic nervous system.

It is the 10th cranial nerve and arises from the brain stem located auth the junction between the cranium and the first cervical vertebrae, which is also at the base of the cerebellum.

Any craniocervical instability in this region or compression of the vagus nerve could potentially have profound effects on vagus nerve function. Craniocervical instability is common in EDS and needs flexion and extension radiographic images and proper measurements to clearly characterize it.

The vagus nerve exits from this location along with the ninth cranial nerve, the glossopharyngeal nerve, and the eleventh cranial nerve which is known as the spinal accessory nerve.

The vagus nerve then branches throughout most of the body. The vagus is both afferent sensory and efferent motor. This sensory fiber for the vagus takes information from the GI tract and runs it back to the brain, while the motor activity directs the bodily functions in many organs.

Some physicians describe the enteric nervous system as an organism “second brain” which can function completely in the absence of central nervous system input. The vagus nerve as well as the parasympathetic nervous system in general uses the neurotransmitter acetylcholine to transmit information from the presynaptic nerve termination to the end organ.

There can be abnormalities from the brain to the ganglia or from the end receptors where acetylcholine is released. There are about 30 neurotransmitters within the enteric nervous system which include more than 90% of the body’s serotonin and 50% of the body’s dopamine.

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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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Autonomic Nervous System and EDS (Ehlers-Danlos Syndrome)

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Dr. DePace, MD, FACC

49% of hypermobile EDS (Ehlers-Danlos Syndrome) patients have POTS (postural orthostatic tachycardia syndrome), 31% orthostatic intolerance and 20% have normal hemodynamics. We call this orthostatic intolerance and postural orthostatic intolerance  in joint hypermobility syndrome / Ehlers-Danlos  hypermobility type, neurovegetative dysregulation or autonomic failure. The autonomic dysregulation is moderate to severe in one-third of our hypermobile EDS patients.

Coat-hanger pain is common in orthostatic intolerance associated with EDS. Coat-hanger syndrome consists of pain at the back of the neck (paracervical) and base of the head (suboccipital) that worsens in the upright position. It is believed to be due to poor blood flow to the muscles of the upper back and neck. It is due to pooling of blood due to abnormal sympathetic nervous system response due to standing and abnormal vasoconstriction. Coat-hanger pain can be quite profound, especially in conjunction with all the other chronic pain seen in EDS patients due to joint hypermobility.

Orthostatic headaches are also seen in EDS due to blood vessel malformation called Chiari malformation, CSF (cerebral spinal fluid) flow issues and CSF leaks. This may collagen problems, leading to stretchy blood vessels in EDS leading to venous pooling. This hypothesis has not been proven; however it makes empiric sense.

Autonomic dysfunction has often been attributed to autoimmunity and many times autoimmune antibodies are not detected, and many believe that this is because they have not been discovered as of yet. Diseases like rheumatoid arthritis, lupus and Sjogren’s disease have been seen with EDS. Nearly 10% had Raynaud’s, which is often associated with autoimmune disorders. It is kissable that abnormalities in the extracellular matrix might contribute to development of autoimmunity in the presence of other genetic or environmental influences.

The most common autoimmune diseases associated with EDS and POTS are Hashimoto’s, Sjogren’s, lupus and celiac disease. However, POTS is not the only dysautonomia disorder that is seen in EDS patients.

Mast cell activation syndrome is often seen in patients who have autonomic dysfunction including POTS and EDS. POTS and mast cell activation syndrome may frequently overlap. POTS patients with EDS tend to report dealing with POTS-like symptoms for most of their life. GI (gastrointestinal) are reported significantly more often by patients with EDS. Sensory neuropathic symptoms have been reported significantly more often in patients with EDS with POTS, including skin burning, hand tingling, hand burning, hand numbness and cold hands. The neuropathy noted in EDS patients suggests that the collagen in and around the nerve fibers may be damaged or abnormal.

Small fiber neuropathy in hypermobile EDS patients likely cause the burning sensations, hypesthesia and allodynia. Small fiber neuropathy refers to dysfunction or damage to the A-Delta and C fibers which relay thermal and nociceptive or unpleasant information as well as mediating autonomic function. There is strong evidence for a peripheral neuropathic contribution to the pain syndrome in hypermobile disorders in addition to the known nociceptive and central sensitization components. This raises the question if there is a neurological cause of hypermobile EDS; the only EDS syndrome without a known genetic cause. Physicians should assess for small fiber pathology in hypermobile EDS patients and hypermobility spectrum disorder patients for sensory and autonomic impact. EDS patients show an overactivity of the resting parasympathetic nerve tone and a decreased sympathetic nerve reactivity to stimuli.


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